Hemoglobin (Hb) transfusion thresholds are established in intensive care units. A restrictive transfusion threshold (Hb 70–75 g/l) is recommended in septic patients, and a liberal transfusion threshold (Hb 90 g/l) for cardiogenic shock. It is unclear whether these historically adopted transfusion thresholds meet the challenges of individual patients. We evaluated microvascular flow index (MFI) and proportion of perfused vessels (PPV) in the sublingual microcirculation with CytoCam-IDF microscopy and near-infrared spectroscopy (NIRS). A study team-independent, treating intensivist assigned a total of 64 patients to 1 of 2 two transfusion thresholds, 43 patients to the Hb 75 g/l threshold and 21 patients to the Hb 90 g/l threshold, at a surgical intensive care unit. We performed microcirculatory measurements 1 h before and 1 h after transfusion of 1 unit of red blood cells. Microcirculatory flow variables correlated negatively with pre-transfusion flow variables (ΔMFI: ρ = − 0.821, p < 0.001; ΔPPV: ρ = − 0.778, p < 0.001). Patients with good initial microcirculation (cutoffs: MFI > 2.84, PPV > 88%) showed a deteriorated microcirculation after red blood cell transfusion. An impaired microcirculation improved after transfusion. At both transfusion thresholds, approximately one third of the patients showed an initially impaired microcirculation. In contrast, one third in every group had good microcirculation above the cutoff variables and did not profit from the transfusion. The data suggest that the established transfusion thresholds and other hemodynamic variables do not reflect microcirculatory perfusion of patients. Blood transfusion at both thresholds 75 g/l and 90 g/l hemoglobin can either improve or harm the microcirculatory blood flow, questioning the concept of arbitrary transfusion thresholds.

The original article [1] contained a misspelling in first author, Baruch Berzon’s name which has since been corrected.

Abstract Background Few validated biomarker or clinical score combinations exist which can discriminate between cases of infection and other non-infectious conditions following activation of an in-hospital sepsis code, as well as provide an accurate severity assessment of the corresponding host response. This study aimed to identify suitable blood biomarker (MR-proADM, PCT, CRP and lactate) or clinical score (SOFA and APACHE II) combinations to address this unmet clinical need. Methods A prospective, observational study of patients activating the Vall d’Hebron University Hospital sepsis code (ISC) within the emergency department (ED), hospital wards and intensive care unit (ICU). Area under the receiver operating characteristic (AUROC) curves, logistic and Cox regression analysis were used to assess performance. Results 148 patients fulfilled the Vall d’Hebron ISC criteria, of which 130 (87.8%) were retrospectively found to have a confirmed diagnosis of infection. Both PCT and MR-proADM had a moderate-to-high performance in discriminating between infected and non-infected patients following ISC activation, although the optimal PCT cut-off varied significantly across departments. Similarly, MR-proADM and SOFA performed well in predicting 28- and 90-day mortality within the total infected patient population, as well as within patients presenting with a community-acquired infection or following a medical emergency or prior surgical procedure. Importantly, MR-proADM also showed a high association with the requirement for ICU admission after ED presentation [OR (95% CI) 8.18 (1.75–28.33)] or during treatment on the ward [OR (95% CI) 3.64 (1.43–9.29)], although the predictive performance of all biomarkers and clinical scores diminished between both settings. Conclusions Results suggest that the individual use of PCT and MR-proADM might help to accurately identify patients with infection and assess the overall severity of the host response, respectively. In addition, the use of MR-proADM could accurately identify patients requiring admission onto the ICU, irrespective of whether patients presented to the ED or were undergoing treatment on the ward. Initial measurement of both biomarkers might therefore facilitate early treatment strategies following activation of an in-hospital sepsis code.

Limited data exist regarding ventilation in patients with class III obesity [body mass index (BMI) > 40 kg/m2] and acute respiratory distress syndrome (ARDS). The aim of the present study was to determine whether an individualized titration of mechanical ventilation according to cardiopulmonary physiology reduces the mortality in patients with class III obesity and ARDS. In this retrospective study, we enrolled adults admitted to the ICU from 2012 to 2017 who had class III obesity and ARDS and received mechanical ventilation for > 48 h. Enrolled patients were divided in two cohorts: one cohort (2012–2014) had ventilator settings determined by the ARDSnet table for lower positive end-expiratory pressure/higher inspiratory fraction of oxygen (standard protocol-based cohort); the other cohort (2015–2017) had ventilator settings determined by an individualized protocol established by a lung rescue team (lung rescue team cohort). The lung rescue team used lung recruitment maneuvers, esophageal manometry, and hemodynamic monitoring. The standard protocol-based cohort included 70 patients (BMI = 49 ± 9 kg/m2), and the lung rescue team cohort included 50 patients (BMI = 54 ± 13 kg/m2). Patients in the standard protocol-based cohort compared to lung rescue team cohort had almost double the risk of dying at 28 days [31% versus 16%, P = 0.012; hazard ratio (HR) 0.32; 95% confidence interval (CI95%) 0.13–0.78] and 3 months (41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16–0.74), and this effect persisted at 6 months and 1 year (incidence of death unchanged 41% versus 22%, P = 0.006; HR 0.35; CI95% 0.16–0.74). Individualized titration of mechanical ventilation by a lung rescue team was associated with decreased mortality compared to use of an ARDSnet table.

Dear Editor, We read with great interest the editorial written by de Waele and Sakr [1], in which the authors described their pragmatic strategy on how to search the source of a sepsis. It appears of paramount importance to precise that searching for a source of infection does not always mean finding a source of infection. Indeed, the lack of documentation (clinical or microbiological) of a source of infection during the 24 first hours of a septic shock is a common but disturbing and challenging clinical scenario reflected by the classical question “what does my patient have?” often heard during the morning rounds in many ICUs. We recently reported in the Journal the results of a pragmatic multicenter prospective observational cohort study [2] including 508 patients admitted to the ICU for a suspicion of septic shock. It is worth notifying that more than a quarter of them (n = 134/506, 26%) had no source of infection nor microbiological documentation retrieved 24 h after shock onset (defined as the start of vasopressor infusion), despite an exhaustive diagnostic work-up. Indeed, these patients underwent more diagnostic testing with more imaging procedures—including computed tomography of the chest and abdomen and echocardiography—during the first 24 h of shock management, as compared to those with a source of infection identified within the first 24 h of shock. These patients without an “early confirmed septic shock” eventually had either a source of infection or a microbiological documentation retrieved after the 24 first hours (n = 37/134, 28%)—mostly a respiratory, urinary, or abdominal sepsis—or a sepsis mimicker (n = 59/134, 44%)—mostly an adverse event of drugs, an acute mesenteric ischemia, or a malignancy—or a shock of unknown origin (n = 38/134, 28%). Mortality did not differ between patients with an early confirmed septic shock and those with a non early confirmed septic shock. Intensivists should be aware that the absence of a source of infection is not so uncommon in the first 24 h of management of a patient with a suspected septic shock. A source of infection may be diagnosed later, but the hypothesis of a sepsis mimicker should be suspected in such a context. Jan J. De Waele and Yasser Sakr To the editor, We agree with Drs. Contou and de Prost that in some patients with sepsis or septic shock, an infection diagnosis cannot be established in the first 24 h. In their study on patients admitted to 10 ICUs in France, indeed a septic shock diagnosis could not be confirmed in 26% of patients [2]. In the majority of patients without confirmed septic shock, either no cause or another cause of the shock could be established, and only in less than 1 out of 3 patients, an infection cause was established later—most of these were pneumonia and urinary tract or abdominal infections. However, when only considering patients with a final diagnosis of septic shock, this diagnosis was in fact confirmed within 24 h in over 90% of the patients (374/411). The message here is that when an infection source cannot be identified within a 24-h timeframe, it is more likely that there is an alternative explanation for the shock and no infection is present. This does not mean however that the search for the infection source should not be continued. These data align with nicely the finding by Klein Klouwenberg et al. who demonstrated that in 1 out 6 patients in whom sepsis or septic shock was suspected in the emergency department, eventually no infection was documented [3]. Clearly this demonstrates that we remain poor at diagnosing sepsis—read diagnosing infection—and that we should acknowledge that in many patients in whom we suspect infection, in fact there is none. However, using a systematic approach, we should try to maximize the chances of establishing a final diagnosis of septic shock [1]. Not available. 1. De Waele JJ, Sakr Y. How I search for a sepsis source. Crit Care. 2019;23:386. Article Google Scholar 2. Contou D, Roux D, Jochmans S, Coudroy R, Guérot E, Grimaldi D, et al. Septic shock with no diagnosis at 24 hours: a pragmatic multicenter prospective cohort study. Crit Care. 2016;20:360. Article Google Scholar 3. Klein Klouwenberg PM, Cremer OL, van Vught LA, Ong DS, Frencken JF, Schultz MJ, Bonten MJ, van der Poll T. Likelihood of infection in patients with presumed sepsis at the time of intensive care unit admission: a cohort study. Crit Care. 2015;19:319. Article Google Scholar Download references None. Funding No funding. Affiliations Service de Réanimation Polyvalente, Centre Hospitalier Victor Dupouy, 69, rue du Lieutenant-Colonel Prud’hon, 95100, Argenteuil, France Damien Contou Service de Réanimation Médicale, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, 51 Avenue du Maréchal de Lattre de Tassigny, 94000, Créteil, France Damien Contou  & Nicolas de ProstAuthors Search for Damien Contou in: PubMed • Google Scholar Search for Nicolas de Prost in: PubMed • Google Scholar Contributions DC and NDP wrote the letter. Both authors read and approved the final manuscript. Corresponding author Correspondence to Damien Contou. Ethics approval and consent to participate Not available. Consent for publication Not available. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This comment refers to the article available at https://doi.org/10.1186/s13054-019-2675-3. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Contou, D., de Prost, N. Looking for a sepsis source. Crit Care 24, 16 (2020) doi:10.1186/s13054-019-2715-z Download citation Received: 04 December 2019 Accepted: 17 December 2019 Published: 14 January 2020 DOI: https://doi.org/10.1186/s13054-019-2715-z

To the Editor: We read with great interest the paper published in the Journal on November 19, 2019, by Abe et al. [1]. The authors reported not to retrieve any association between earlier antibiotic administration and reduction in in-hospital mortality of severe sepsis. First of all, the authors must be congratulated for their interesting work aiming to clarify the real impact of earlier antibiotic administration in septic shock, one of the key elements of care highlighted by the Surviving Sepsis Campaign (SSC) [2]. Nevertheless, to our opinion, some methodological issues deserve their results interpretation. From a statistical point of view, the categorization of the variable “time-to-antibiotic therapy” induces an information loss. Despite facilitating results interpretation, such categorization implies two consequences. First, it assumes that the treatment effect of antibiotic administration, from the 1st minute, if practically possible, to the 59th minute after diagnosis, is equivalent. Second, it would imply that the antibiotic therapy treatment effect is equivalent in all predefined categories, from 0–60 to 361–1440 min, which does not correspond to the reality, because the relationship between antibiotic therapy and mortality is not linear [3, 4]. In the present study, the negativity of the association between time to antibiotics (continuous variable) and mortality (OR = 0.999 [0.997–1.000]; p = 0.152) reflects this lack of linearity of the antibiotic therapy treatment effect. Furthermore, from a practical point of view, it is quite rare that the antibiotic therapy treatment effect is maximum since the first hour after administration. Beyond this, to reach infected tissues, antibiotics need the restoration of a sufficient tissue perfusion pressure [5]. In their study, the authors [1] take into account the compliance rate to the first line of hemodynamic optimization (fluid expansion completed within 3 h) as a potential cofounder in their multivariate analysis but do not inform about the mean blood pressure (the reflect of tissue perfusion pressure) reached [2]. We fully agree with the authors that the impact of earlier antibiotic therapy is greater for most severe septic patients, but as reminded in the SSC, the outcome of these patients is not only dependent on a sole therapy but more from a bundle of care [2]. More than the completion of guideline principles, we believe that impact on outcome is strongly affected by achievement of objectives, especially when the gravity is higher. Among the objectives to be achieved, we think that early hemodynamic optimization and antibiotic administration are the two utmost treatments allowing to reduce septic shock mortality. Toshikazu Abe We appreciate the consideration and comments from the SAMU de Paris regarding our study. Management of time data is one of the most important processes in “time to intervention” studies. We studied multiple different time intervals as we recorded time as a continuous variable; however, results with these values were not different from what we ultimately described. The relationship between time to antibiotic administration and mortality is not linear; therefore, we dealt with time data as a categorical variable. Hourly categorization is the most acceptable time interval used by clinicians. Because the number of patients receiving antibiotics after 361 min was small, we grouped those patients together. Our study did not mention causal inference, and it is a descriptive analysis using implementation science. We did not show mean blood pressure, but we controlled tissue perfusion pressure by using the Sequential Organ Failure Assessment (SOFA), which includes a cardiovascular score. We also stratified patients by the presence or absence of shock. However, we did not find any association between time to antibiotic and outcomes with adjustment of those variables. As you noted, the effect of antibiotics would be related to the time to administration and antibiotic sensitivity, concentration, and tissue perfusion. These variables may be even more important than time to administration. The lack of association between time to antibiotic administration and outcomes in our study may have been because of the lack of information about the variables. Other aspects of treatment may have differed among institutions, although we controlled for that using generalized estimating equations (GEE). We believe that the effect of time to administration will be significant only when the overall quality of care is excellent. As with the differences for door to balloon time for acute coronary syndrome noted in the research by Menees and colleagues [6] and the research by Nallamothu and colleagues [7], the difference in quality may only be distinguished in highly standardized facilities. A more accurate diagnosis may allow for better antibiotic choices, which is related to the outcome of time to antibiotic administration [8, 9]. Generally, antibiotics for meningitis should be administrated within 30 min, whereas antibiotics for infective endocarditis can wait for administration until culture results indicate the specific pathogen, as long as the patient’s vital signs are stable. Time recommendations for administration of antibiotics to patients with sepsis could be modified for different sites of infection as well as different clinical presentations, such as vague or apparent symptoms, and shock [10]. Not applicable 1. Abe T, Kushimoto S, Tokuda Y, Phillips GS, Rhodes A, Sugiyama T, et al. Implementation of earlier antibiotic administration in patients with severe sepsis and septic shock in Japan: a descriptive analysis of a prospective observational study. Crit Care. 2019;23:360. Article Google Scholar 2. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43:304–77. Article Google Scholar 3. Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017;376:2235–44. Article Google Scholar 4. Sherwin R, Winters ME, Vilke GM, Wardi G. Does early and appropriate antibiotic administration improve mortality in emergency department patients with severe sepsis or septic shock? J Emerg Med. 2017;53:588–95. Article Google Scholar 5. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34:1589–96. Article Google Scholar 6. Menees DS, Peterson ED, Wang Y, Curtis JP, Messenger JC, Rumsfeld JS, Gurm HS. Door-to-balloon time and mortality among patients undergoing primary PCI. N Engl J Med. 2013;369(10):901–9. CAS Article Google Scholar 7. Nallamothu BK, Normand SL, Wang Y, Hofer TP, Brush JE Jr, Messenger JC, Bradley EH, Rumsfeld JS, Krumholz HM. Relation between door-to-balloon times and mortality after primary percutaneous coronary intervention over time: a retrospective study. Lancet. 2015;385(9973):1114–22. Article Google Scholar 8. Abe T, Tokuda Y, Shiraishi A, Fujishima S, Mayumi T, Sugiyama T, Deshpande GA, Shiino Y, Hifumi T, Otomo Y, et al. In-hospital mortality associated with the misdiagnosis or unidentified site of infection at admission. Crit Care. 2019;23(1):202. Article Google Scholar 9. Abe T, Ogura H, Kushimoto S, Shiraishi A, Sugiyama T, Deshpande GA, Uchida M, Nagata I, Saitoh D, Fujishima S, et al. Variations in infection sites and mortality rates among patients in intensive care units with severe sepsis and septic shock in Japan. J Intensive Care. 2019;7:28. Article Google Scholar 10. Filbin MR, Lynch J, Gillingham TD, Thorsen JE, Pasakarnis CL, Nepal S, Matsushima M, Rhee C, Heldt T, Reisner AT. Presenting symptoms independently predict mortality in septic shock: importance of a previously unmeasured confounder. Crit Care Med. 2018;46(10):1592–99. Article Google Scholar Download references None Funding None Affiliations SAMU de Paris, Service d’Anesthésie Réanimation, Hôpital Universitaire Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, and Université Paris Descartes - Paris 5, Paris, France Romain Jouffroy  & Benoit VivienAuthors Search for Romain Jouffroy in: PubMed • Google Scholar Search for Benoit Vivien in: PubMed • Google Scholar Contributions BV and RJ both wrote the manuscript. Both authors read and approved the final manuscript. Authors’ information None Corresponding author Correspondence to Romain Jouffroy. Ethics approval and consent to participate Not applicable Consent for publication Not applicable Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This comment refers to the article available at https://doi.org/10.1186/s13054-019-2644-x. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Jouffroy, R., Vivien, B. Implementation of earlier antibiotic administration in patients with severe sepsis and septic shock in Japan: antibiotic action needs time and tissue perfusion to reach target. Crit Care 24, 17 (2020) doi:10.1186/s13054-020-2727-8 Download citation Received: 10 December 2019 Accepted: 01 January 2020 Published: 14 January 2020 DOI: https://doi.org/10.1186/s13054-020-2727-8

New-onset atrial fibrillation (NOAF) is commonly encountered in critically ill adults. Evidence evaluating the association between NOAF and patient-important outcomes in this population is conflicting. Furthermore, little is known regarding the association between NOAF and resource use or hospital costs. Retrospective analysis (2011–2016) of a prospectively collected registry from two Canadian hospitals of consecutive ICU patients aged ≥ 18 years. We excluded patients with a known history of AF prior to hospital admission. Any occurrence of atrial fibrillation (AF) was prospectively recorded by bedside nurses. The primary outcome was hospital mortality, and we used multivariable logistic regression to adjust for confounders. We used a generalized linear model to evaluate contributors to total cost. We included 15,014 patients, and 1541 (10.3%) had NOAF during their ICU admission. While NOAF was not associated with increased odds of hospital death among the entire cohort (adjusted odds ratio [aOR] 1.02 [95% confidence interval [CI] 0.97–1.08]), an interaction was noted between NOAF and sepsis, and the presence of both was associated with higher odds of hospital mortality (aOR 1.28 [95% CI 1.09–1.36]) than either alone. Patients with NOAF had higher total costs (cost ratio [CR] 1.09 [95% CI 1.02–1.20]). Among patients with NOAF, treatment with a rhythm-control strategy was associated with higher costs (CR 1.24 [95% CI 1.07–1.40]). While NOAF was not associated with death or requiring discharge to long-term care among critically ill patients, it was associated with increased length of stay in ICU and increased total costs.

The aim of this study was to investigate the concordance between ventilator-associated events (VAE) and ventilator-associated lower respiratory tract infections (VA-LRTI), and their impact on outcome.

Within each of the Sustainable Development Goals (SDGs), the World Health Organization (WHO) has identified key emergency care (EC) interventions that, if implemented effectively, could ensure that the SDG targets are met. The proposed EC intervention for reaching the maternal mortality benchmark calls for “timely access to emergency obstetric care.” This intervention, the WHO estimates, can avert up to 98% of maternal deaths across the African region. Access, however, is a complicated notion and is part of a larger framework of care delivery that constitutes the approachability of the proposed service, its acceptability by the target user, the perceived availability and accommodating nature of the service, its affordability, and its overall appropriateness. Without contextualizing each of these aspects of access to healthcare services within communities, utilization and sustainability of any EC intervention-be it ambulances or simple toll-free numbers to dial and activate EMS-will be futile. In this article, we propose an access framework that integrates the Three Delays Model in maternal health, with emergency care interventions. Within each of the three critical time points, we provide reasons why intended interventions should be contextualized to the needs of the community. We also propose measurable benchmarks in each of the phases, to evaluate the successes and failures of the proposed EC interventions within the framework. At the center of the framework is the pregnant woman, whose life hangs in a delicate balance in the hands of personal and health system factors that may or may not be within her control. The targeted SDGs for reducing maternal mortality in sub-Saharan Africa are unlikely to be met without a tailored integration of maternal health service delivery with emergency medicine. Our proposed framework integrates the fields of maternal health with emergency medicine by juxtaposing the three critical phases of emergency obstetric care with various aspects of healthcare access. The framework should be adopted in its entirety, with measureable benchmarks set to track the successes and failures of the various EC intervention programs being developed across the African continent.

To the Editor: We read with great interest the article published in a recent issue of Critical Care by Brouwer et al. [1]. Authors showed the beneficial effect of addition of CytoSorb filter to continuous renal replacement therapy (CRRT) for hemoadsorption of cytokines in management of septic shock. We would like to raise few points which may be important for authors and readers of the article. This was an investigator-initiated retrospective study of non-consecutive patients, treated by Cytosorb plus CRRT versus CRRT alone. This study was non-randomized, and analysis was not “intention to treat”. We believe both group populations were significantly different (disproportionately higher number of patients in control group with diabetes, hypertension, heart failure, and renal disease and nonsurgical patients) and difference in mortality may just be the result from this difference rather than intervention for the following reasons. Authors describe inclusion of all factors in regression model for determination for its association with treatment allocation; they should acknowledge that investigator initiation itself is a significant factor for bias which cannot be adjusted. Investigator-led management group will likely to have better attention and management. Relatively imperfect attention of physician taking care of patients in control group is reflected by the inappropriate assignment of renal failure as sepsis in 60 out of 109 patients. Authors used propensity score, though treatment effect made using propensity-score matching are valid only if a matched sample of treated and untreated subjects has similar distributions of measured baseline covariates [2]. Figure 2 suggests the difference in mortality only appears after application of “stabilized inverse probability of treatment weights (sIPTW)” methods to correct the imbalance between the groups. Additionally, there were factors not provided: difference in fluid management, time to start antibiotics, and ventilator strategy. These factors influence the course of disease and mortality. Lack of information about ultrafiltration rates also made it difficult to compare the quality of CRRT between groups. Without randomization and matching, investigator can erroneously assign patients with high unadjusted SOFA scores on admission but greatest potential for improvement (younger surgical patients without chronic illness) to the treatment group. Hence, the observed mortality is lower than expected. They used sIPTW to correct the imbalance between the groups to negligible levels for example for lactate (85% reduced to 10%), and noradrenaline (110% to 10%). Underestimation of the variance may produce inappropriately narrow confidence intervals and leads to false rejection of the null hypothesis because of inflated sample sizes [3]. This analysis may be more effective in removing the difference between variables between the cases and the controls than CytoSorb which is effective in removing the cytokines. Lastly, simulation testing ignores the most important factor “human factor,” the same factor which saved 155 lives of the US airways passengers when pilot Sully landed his plane on river Hudson after both engines failed in 2009. Simulation showed that he should have turned back to LaGuardia airport where he could have safely landed. Facts review determined that if he had acted like simulation, everyone would have died. To summarize, this study has multiple issues as outlined above, though it is a good start. No adverse effects reported so we can expect a well-designed prospective, randomized control trial to evaluate the impact of Cytosorb on clinical outcomes like mortality. Willem P. Brouwer, Servet Duran, Martijn Kuijper, Can Ince To the Editor: We thank Nadeem et al. for their interest in our work and comments regarding our publication and the opportunity to further clarify the complex analysis in our study. They raise several questions with regard to the comparability of the patients in our study, as well as not including a human factor. Although we appreciate the interesting comparison of the “Hudson River plane crash,” we respectfully believe this analogy has no relevance to our study. We agree however that because of the retrospective nature of our study, a human factor cannot be completely eradicated. Yet, by applying the “inverse probability of treatment weight (IPTW)” method, the patient characteristics at the start of therapy are comparable as shown in Table 1 and by the supplementary figure [1, 2, 4, 5]. IPTW is a methodology accepted in many key note publications. It can be applied to estimate causal treatment effects in situations where the treatment was non-randomized and confounding factors may be present. The propensity score (i.e., the probability of being treated, given the set of confounders) is constructed and used as a weighting factor in order to create a comparable set of patients. This means that, after applying the weights, the distribution of the patient characteristics at the start of therapy is now independent of the treatment assignment, such as is the case in a randomized controlled trial [1, 2, 4, 5]. In contrast to the statements in their letter, after applying IPTW, our patients had comparable distributions of covariates at the start of therapy. Moreover, Nadeem et al. wrongly claim that an unweighted regression analysis was performed to produce the final results, and also falsely claim that the sample size was inflated by using this method. The weights were normalized using the estimated marginal means of the propensity score, and as a result, there is not an inflated sample size and the confidence intervals are not falsely narrowed. Data with respect to the IPTW and the distribution of the covariates can be found in the supplementary figure [1]. The observed versus expected mortality rates were compared according to the SOFA score within, but not between groups. Again it should be stressed that a comparison of two completely different patient groups was not performed. Indeed, we agree that a p value in Figure 2B (no sIPTW) can lead to some confusion, but it was printed to show the difference in mortality between the groups in case they were not weighted (i.e., unadjusted for confounders). Lastly, Nadeem et al. summarize a list of limitations of our study. We would kindly like to refer the authors to the discussion section of our paper where these limitations had already been thoroughly considered [1]. Not applicable. 1. Brouwer WP, Duran S, Kuijper M, Ince C. Hemoadsorption with CytoSorb shows a decreased observed versus expected 28-day all-cause mortality in ICU patients with septic shock: a propensity-score-weighted retrospective study. Crit Care. 2019;23(1):317. 2. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28(25):3083–107. https://doi.org/10.1002/sim.3697. Article PubMed PubMed Central Google Scholar 3. Xu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value Health. 2010;13(2):273–7. Article Google Scholar 4. Harder VS, Stuart EA, Anthony JC. Propensity score techniques and the assessment of measured covariate balance to test causal associations in psychological research. Psychol Methods. 2010;15(3):234–49. Article Google Scholar 5. Robins JM, Hernan MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiology. 2000;11(5):550–60. CAS Article Google Scholar Download references None. Funding None. Affiliations Dubai Hospital, P O Box 7272, Dubai, United Arab Emirates Rashid Nadeem , Zainab Alameeer Obaida  & Sahish KamatAuthors Search for Rashid Nadeem in: PubMed • Google Scholar Search for Zainab Alameeer Obaida in: PubMed • Google Scholar Search for Sahish Kamat in: PubMed • Google Scholar Contributions All authors contributed equally. All authors read and approved the final manuscript. Corresponding author Correspondence to Rashid Nadeem. Ethics approval and consent to participate Not applicable. Consent for publication All authors gave consent to publication. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This comment refers to the article available at https://doi.org/10.1186/s13054-019-2588-1. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Nadeem, R., Obaida, Z.A. & Kamat, S. Hemoadsorption of cytokines by CytoSorb filter: a simulation study without human factor—pilot is the difference. Crit Care 24, 13 (2020) doi:10.1186/s13054-019-2716-y Download citation Received 16 October 2019 Accepted 17 December 2019 Published 13 January 2020 DOI https://doi.org/10.1186/s13054-019-2716-y

In critically ill patients, auscultation might be challenging as dorsal lung fields are difficult to reach in supine-positioned patients, and the environment is often noisy. In recent years, clinicians have started to consider lung ultrasound as a useful diagnostic tool for a variety of pulmonary pathologies, including pulmonary edema. The aim of this study was to compare lung ultrasound and pulmonary auscultation for detecting pulmonary edema in critically ill patients. This study was a planned sub-study of the Simple Intensive Care Studies-I, a single-center, prospective observational study. All acutely admitted patients who were 18 years and older with an expected ICU stay of at least 24 h were eligible for inclusion. All patients underwent clinical examination combined with lung ultrasound, conducted by researchers not involved in patient care. Clinical examination included auscultation of the bilateral regions for crepitations and rhonchi. Lung ultrasound was conducted according to the Bedside Lung Ultrasound in Emergency protocol. Pulmonary edema was defined as three or more B lines in at least two (bilateral) scan sites. An agreement was described by using the Cohen κ coefficient, sensitivity, specificity, negative predictive value, positive predictive value, and overall accuracy. Subgroup analysis were performed in patients who were not mechanically ventilated. The Simple Intensive Care Studies-I cohort included 1075 patients, of whom 926 (86%) were eligible for inclusion in this analysis. Three hundred seven of the 926 patients (33%) fulfilled the criteria for pulmonary edema on lung ultrasound. In 156 (51%) of these patients, auscultation was normal. A total of 302 patients (32%) had audible crepitations or rhonchi upon auscultation. From 130 patients with crepitations, 86 patients (66%) had pulmonary edema on lung ultrasound, and from 209 patients with rhonchi, 96 patients (46%) had pulmonary edema on lung ultrasound. The agreement between auscultation findings and lung ultrasound diagnosis was poor (κ statistic 0.25). Subgroup analysis showed that the diagnostic accuracy of auscultation was better in non-ventilated than in ventilated patients. The agreement between lung ultrasound and auscultation is poor. NCT02912624. Registered on September 23, 2016.

Abstract Background Currently, there are no reliable predictors of risk of development and severity of acute kidney injury (AKI) in septic patients. The surfactant protein D (SP-D) polymorphism rs721917C/T is associated with a greater susceptibility to AKI in the Chinese population. Our aim was to evaluate the value of SP-D polymorphisms rs721917C/T and of plasma SP-D levels to predict the risk of development of AKI (defined with KDIGO criterion) in septic patients. Methods The study enrolled septic patients admitted to the Critical Care Department of two tertiary care hospitals. SP-D rs721917C/T polymorphisms were determined using the PCR-SSP method. Plasma SP-D and urine NGAL contents were measured using commercially available ELISA kits. Results 330 septic patients were included. Their SOFA scores were 12 ± 3. Patients with AKI (n = 156) had higher plasma SP-D levels (median: 153 ng/mL, range 111–198 ng/mL) and urinary NGAL levels (median: 575 ng/mL, range 423–727 ng/mL) than those without AKI (SP-D median: 124 ng/mL, range 81–159 ng/mL, P = 0.001; NGAL median: 484 ng/mL, range 429–573 ng/mL). Plasma SP-D levels of AKI patients were correlated with urinary NGAL contents (r = 0.853). In 32 patients receiving continuous renal replacement therapy (CRRT), plasma SP-D levels correlated with duration of CRRT (r = 0.448). The area under the receiver operating characteristic curve for plasma SP-D levels to predict AKI was 0.84. Patients with AKI had a higher rate of rs721917 CC genotype (AKI: 35% vs. non-AKI: 20%; P = 0.012), but a significantly lower rate of TT genotype (AKI: 19% vs. non-AKI: 26%; P = 0.005). SP-D rs721917 CC genotype was an independent predictor of AKI (P = 0.044) and mortality (P = 0.014). Conclusion Our study showed that increased plasma SP-D level is associated with a higher risk of AKI in patients with sepsis. The SP-D rs721917CC genotype is an independent and significant predictor of AKI development and mortality of septic patients. The SP-D rs721917C/T polymorphisms should be further studied as diagnostic and prognostic biomarkers to facilitate early recognition of AKI.

Fever is a common symptom when patients present to Emergency Departments. It is unclear if the febrile response of bacteremic hemodialysis-dependent patients differs from bacteremic patients not receiving hemodialysis. The objective of this study was to compare Emergency Departments triage temperatures of patients with and without hemodialysis-dependent end-stage rental disease who have Staphylococcus aureus bacteremia and determine the incidence of afebrile S. aureus bacteremia. Paired, retrospective cohort study of 37 patients with and 37 patients without hemodialysis hospitalized with Methicillin-resistant or Methicillin-susceptible S. aureus bacteremia. Emergency Department triage temperatures were reviewed for all patients, as were potential confounding variables. 54% (95% CI, 38–70%) and 82% (95% CI 65–91%) of hemodialysis and non-hemodialysis patients did not have a detectable fever (<100.4 °F) at triage. Triage temperatures were 100.5 °F (95% CI 99.9–101.2 °F) and 99.0 °F (95% CI 98.4–99.6 °F) in the hemodialysis and non-hemodialysis cohorts, respectively (p < 0.001). Triage temperature in patients with and without diabetes mellitus was 99.2 °F (95% CI 98.4–99.9 °F) and 100.4 °F (95% CI 99.7–101.0 °F), respectively (p = 0.03). We were unable to detect a significant effect of diabetes mellitus and other potential confounding variables on differences in temperature between the hemodialysis and non-hemodialysis cohorts (all interactions p > 0.19). Hemodialysis-dependent patients with S. aureus bacteremia had significantly higher temperatures than non- hemodialysis-dependent end stage renal disease patients but more than half of patients were without detectable fever at triage, possibly reflecting use of insensitive methods for measuring temperature. Absence of fever at presentation to the Emergency Department should not delay blood culture acquisition in patients who are at increased risk of S. aureus bacteremia.

We have read the recent letter by Honore et al. [1] about our findings published in this journal regarding the influence of continuous renal replacement therapy (CRRT) on the pharmacokinetics of ceftolozane-tazobactam (C/T) [2]. In our report, we decided to administer a 3 g/iv dose every 8 h taking into account two previous studies referenced in our paper [2] and another one which showed CRRT to be an independent predictor of clinical failure (OR 4.5, 95% CI 1.18–17.39, p = 0.02) when C/T is administered at 1.5 g every 8 h [3]. As Honore et al. explain in their paper, the C/T eliminitation was assumed by hemodiafiltration and the adsorption was not assessed [1]. However, there is a misunderstanding in this letter [1], because we used a polysulphone membrane (Fresenius, Germany) instead of an acrylonitrile 69 Multiflow (AN-69-M). In contrast to highly adsorptive membranes (HAM; e.g., AN69 surface-treated, AN69-ST), the antibiotic adsorption with polysulphone ones is negligible, which facilitates antibiotic adaptation during CRRT [4]. Our data should not be extrapolated to other clinical scenarios, as noted by Honore et al. [1]. In our report, ceftolozane and tazobactam plasma concentrations remained above the minimal inhibitory concentration (MIC), for MICs of up to 8 μg/mL, but we estimated that the administration of standard doses of 1 g/0.5 g, even with polysulphone membranes, could compromise the effectiveness of C/T for not reaching adequate tazobactam concentrations. Thus, the use of HAM would represent a real risk factor of clinical failure when a C/T dose of 1.5 g every 8 h is administered, especially in multidrug-resistant infections [3]. Therefore, we agree with Honore et al. [1] that therapeutic drug monitoring (TDM) is critical when using C/T for patients receiving CRRT, especially when MICs of bacteria like multidrug-resistant (MDR) Pseudomonas aeruginosa are considered very high. However, the recommendation of continuous (over 24 h) vs extended (over 2 to 4 h) or intermittent (over 30 to 60 min) infusion of beta-lactams is still under debate [5]. Not applicable. AN-69-M: Acrylonitrile 69 Multiflow AN-69-ST: AN69-surface treated C/T: Ceftolozane-tazobactam CRRT: Continuous renal replacement therapy HAM: Highly adsorptive membranes MDR: Multidrug-resistant MIC: Minimal inhibitory concentration 1. Honore PM, Mugisha A, Gutierrez LB, Redant S, Kaefer K, Gallerani A, De Bels D. Optimizing ceftolozane-tazobactam dosage during continuous renal replacement therapy: additional insights. Crit Care. 2019;23(1):406. Article Google Scholar 2. Aguilar G, Ferriols R, Martínez-Castro S, Ezquer C, Pastor E, Carbonell JA, Alós M, Navarro D. Optimizing ceftolozane-tazobactam dosage in critically ill patients during continuous venovenous hemodiafiltration. Crit Care. 2019;23(1):145. Article Google Scholar 3. Bassetti M, Castaldo N, Cattelan A, Mussini C, Righi E, Tascini C, et al. Ceftolozane/tazobactam for the treatment of serious P. aeruginosa infections: a multicenter nationwide clinical experience. Int J Antimicrob Agents. 2019 Apr;53(4):408–15. CAS Article Google Scholar 4. Honore PM, Spapen HD. What a clinician should know about a renal replacement membrane? J Transl Intern Med. 2018;6:62–5. Article Google Scholar 5. Lee YR, Miller PD, Alzghari SK, Blanco DD, Hager JD, Kuntz KS. Continuous infusion versus intermittent bolus of beta-lactams in critically ill patients with respiratory infections: a systematic review and meta-analysis. Eur J Drug Metab Pharmacokinet. 2018;43(2):155–70. CAS Article Google Scholar Download references None Funding None. Affiliations Critical Care Unit, Anesthesiology and Critical Care Department, Hospital Clínico Universitario de Valencia, Valencia, Spain Gerardo Aguilar , Sara Martínez-Castro , Ernesto Pastor  & Jose A. Carbonell INCLIVA Health Research Institute, Avenida de Menéndez y Pelayo, 4, 46010, Valencia, Spain Gerardo Aguilar , Rafael Ferriols , Manuel Alós  & David Navarro School of Medicine, University of Valencia, Avenida Blasco Ibáñez, 15, 46010, Valencia, Spain Gerardo Aguilar , Rafael Ferriols , Carlos Ezquer , Manuel Alós  & David Navarro Department of Pharmacy, Hospital Clínico Universitario de Valencia, Avenida Blasco Ibáñez, 17, 46010, Valencia, Spain Rafael Ferriols , Carlos Ezquer  & Manuel Alós Department of Microbiology, Hospital Clínico Universitario de Valencia, Avenida Blasco Ibáñez, 17, 46010, Valencia, Spain David NavarroAuthors Search for Gerardo Aguilar in: PubMed • Google Scholar Search for Rafael Ferriols in: PubMed • Google Scholar Search for Sara Martínez-Castro in: PubMed • Google Scholar Search for Carlos Ezquer in: PubMed • Google Scholar Search for Ernesto Pastor in: PubMed • Google Scholar Search for Jose A. Carbonell in: PubMed • Google Scholar Search for Manuel Alós in: PubMed • Google Scholar Search for David Navarro in: PubMed • Google Scholar Contributions GA, RF, and DN designed the paper. All authors participated in drafting and reviewing the manuscript. All authors read and approved the final version of the manuscript. Corresponding author Correspondence to Gerardo Aguilar. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This reply refers to the comment available at: https://doi.org/10.1186/s13054-019-2692-2. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Aguilar, G., Ferriols, R., Martínez-Castro, S. et al. Optimizing ceftolozane-tazobactam dosage during continuous renal replacement therapy: some nuances. Crit Care 24, 11 (2020) doi:10.1186/s13054-019-2724-y Download citation Received 22 December 2019 Accepted 27 December 2019 Published 10 January 2020 DOI https://doi.org/10.1186/s13054-019-2724-y

Herpes simplex virus (HSV) replication can be detected in the respiratory secretions of a high proportion of ventilated intensive care unit (ICU) patients. However, the clinical significance remains poorly defined. We investigated whether patients with ventilator-associated pneumonia not responding to antibiotics and in whom high levels of HSV could be detected in respiratory secretions benefit from acyclovir treatment. Respiratory secretions (bronchoalveolar lavage fluid or tracheal aspirates) were tested for HSV replication by quantitative real-time PCR. ICU survival times, clinical parameters, and radiographic findings were retrospectively compared between untreated and acyclovir treated patients with high (> 105 HSV copies/mL) and low (103–105 HSV copies/mL) viral load. Fifty-seven low and 69 high viral load patients were identified. Fewer patients with high viral load responded to antibiotic treatment (12% compared to 40% of low load patients, p = 0.001). Acyclovir improved median ICU survival (8 vs 22 days, p = 0.014) and was associated with a significantly reduced hazard ratio for ICU death (HR = 0.31, 95% CI 0.11–0.92, p = 0.035) in high load patients only. Moreover, circulatory and pulmonary oxygenation function of high load patients improved significantly over the course of acyclovir treatment: mean norepinephrine doses decreased from 0.05 to 0.02 μg/kg body weight/min between days 0 and 6 of treatment (p = 0.049), and median PaO2/FiO2 ratio increased from 187 to 241 between day 3 and day 7 of treatment (p = 0.02). Chest radiographic findings also improved significantly (p < 0.001). In patients with ventilator-associated pneumonia, antibiotic treatment failure, and high levels of HSV replication, acyclovir treatment was associated with a significantly longer time to death in the ICU and improved circulatory and pulmonary function. This suggests a causative role for HSV in this highly selected group of patients.

Optimal anti-bacterial activity of meropenem requires maintenance of its plasma concentration (Cp) above the minimum inhibitory concentration (MIC) of the pathogen for at least 40% of the dosing interval (fT > MIC > 40). We aimed to determine whether a 3-h extended infusion (EI) of meropenem achieves fT > MIC > 40 on the first and third days of therapy in patients with severe sepsis or septic shock. We also simulated the performance of the EI with respect to other pharmacokinetic (PK) targets such as fT > 4 × MIC > 40, fT > MIC = 100, and fT > 4 × MIC = 100.

The urinary proteome reflects molecular drivers of disease. To construct a urinary proteomic biomarker predicting 1-year post-ICU mortality. In 1243 patients, the urinary proteome was measured on ICU admission, using capillary electrophoresis coupled with mass spectrometry along with clinical variables, circulating biomarkers (BNP, hsTnT, active ADM, and NGAL), and urinary albumin. Methods included support vector modeling to construct the classifier, Cox regression, the integrated discrimination (IDI), and net reclassification (NRI) improvement, and area under the curve (AUC) to assess predictive accuracy, and Proteasix and protein-proteome interactome analyses. In the discovery (deaths/survivors, 70/299) and test (175/699) datasets, the new classifier ACM128, mainly consisting of collagen fragments, yielding AUCs of 0.755 (95% CI, 0.708–0.798) and 0.688 (0.656–0.719), respectively. While accounting for study site and clinical risk factors, hazard ratios in 1243 patients were 2.41 (2.00–2.91) for ACM128 (+ 1 SD), 1.24 (1.16–1.32) for the Charlson Comorbidity Index (+ 1 point), and ≥ 1.19 (P ≤ 0.022) for other biomarkers (+ 1 SD). ACM128 improved (P ≤ 0.0001) IDI (≥ + 0.50), NRI (≥ + 53.7), and AUC (≥ + 0.037) over and beyond clinical risk indicators and other biomarkers. Interactome mapping, using parental proteins derived from sequenced peptides included in ACM128 and in silico predicted proteases, including/excluding urinary collagen fragments (63/35 peptides), revealed as top molecular pathways protein digestion and absorption, lysosomal activity, and apoptosis. The urinary proteomic classifier ACM128 predicts the 1-year post-ICU mortality over and beyond clinical risk factors and other biomarkers and revealed molecular pathways potentially contributing to a fatal outcome.

Dispatch services (DS’s) form an integral part of emergency medical service (EMS) systems. The role of a dispatcher has also evolved into a crucial link in patient care delivery, particularly in dispatcher assisted cardio-pulmonary resuscitation (DACPR) during out-of-hospital cardiac arrest (OHCA). Yet, there has been a paucity of research into the emerging area of dispatch science in Asia. This paper compares the characteristics of DS’s, and state of implementation of DACPR within the Pan-Asian Resuscitation Outcomes (PAROS) network. A cross-sectional descriptive survey addressing population characteristics, DS structures and levels of service, state of DACPR implementation (including protocols and quality improvement programs) among PAROS DS’s. 9 DS’s responded, representing a total of 23 dispatch centres from 9 countries that serve over 80 million people. Most PAROS DS’s operate a tiered dispatch response, have implemented medical oversight, and tend to be staffed by dispatchers with a predominantly medical background. Almost all PAROS DS’s have begun tracking key EMS indicators. 77.8% (n = 7) of PAROS DS’s have introduced DACPR. Of the DS’s that have rolled out DACPR, 71.4% (n = 5) provided instructions in over one language. All DS’s that implemented DACPR and provided feedback to dispatchers offered feedback on missed OHCA recognition. The majority of DS’s (83.3%; n = 5) that offered DACPR and provided feedback to dispatchers also implemented corrective feedback, while 66.7% (n = 4) offered positive feedback. Compression-only CPR was the standard instruction for PAROS DS’s. OHCA recognition sensitivity varied widely in PAROS DS’s, ranging from 32.6% (95% CI: 29.9–35.5%) to 79.2% (95% CI: 72.9–84.4%). Median time to first compression ranged from 120 s to 220 s. We found notable variations in characteristics and state of DACPR implementation between PAROS DS’s. These findings will lay the groundwork for future DS and DACPR studies in the PAROS network.

The brainstem conveys sensory and motor inputs between the spinal cord and the brain, and contains nuclei of the cranial nerves. It controls the sleep-wake cycle and vital functions via the ascending reticular activating system and the autonomic nuclei, respectively. Brainstem dysfunction may lead to sensory and motor deficits, cranial nerve palsies, impairment of consciousness, dysautonomia, and respiratory failure. The brainstem is prone to various primary and secondary insults, resulting in acute or chronic dysfunction. Of particular importance for characterizing brainstem dysfunction and identifying the underlying etiology are a detailed clinical examination, MRI, neurophysiologic tests such as brainstem auditory evoked potentials, and an analysis of the cerebrospinal fluid. Detection of brainstem dysfunction is challenging but of utmost importance in comatose and deeply sedated patients both to guide therapy and to support outcome prediction. In the present review, we summarize the neuroanatomy, clinical syndromes, and diagnostic techniques of critical illness-associated brainstem dysfunction for the critical care setting.

Targeted temperature management (TTM) is a complex intervention used with the aim of minimizing post-anoxic injury and improving neurological outcome after cardiac arrest. There is large variability in the devices used to achieve cooling and in protocols (e.g., for induction, target temperature, maintenance, rewarming, sedation, management of post-TTM fever). This variability can explain the limited benefits of TTM that have sometimes been reported. We therefore propose the concept of “high-quality TTM” as a way to increase the effectiveness of TTM and standardize its use in future interventional studies.

The use of extracorporeal membrane oxygenation during cardiac arrest (extracorporeal cardiopulmonary resuscitation (ECPR)) has increased in recent years [1] after evidence emerged that it was associated with better outcomes than conventional CPR for in-hospital cardiac arrest [2,3,4]. This success led some clinicians to attempt ECPR in highly selected patients who suffered out-of-hospital cardiac arrest (OHCA), often cannulating them on arrival in the emergency department [5]. One key determinant of the likelihood of survival in ECPR patients is the duration of CPR prior to cannulation [2, 3, 6, 7], so investigators inferred that the outcomes for OHCA patients might be improved by cannulation in the field (prehospital ECPR), thereby reducing the period of inadequate circulation. However, the logistic barriers to prehospital ECPR are formidable, including the difficulties inherent to undertaking complex medical procedures in a field setting, minimizing delays in cannulation without being indiscriminate about patient selection, as well as the resource consumption. Nonetheless, some hospital networks have created mobile intensive care units with prehospital ECPR capabilities [5]. The largest study to date on the use of ECPR for OHCA was recently published, shedding new light on the effectiveness of this approach. Bougouin et al. [8] reported on 13,191 OHCA cases in metropolitan Paris. Of the 12,396 patients managed with conventional CPR, 1061 (8.6%) survived to hospital discharge, compared with 44 (8.4%) of 523 ECPR patients. ECPR was attempted but failed in 58 (11%) patients. Factors associated with survival in the ECPR group included an initial shockable rhythm and transient return of spontaneous circulation (ROSC) prior to ECPR. Of note, prehospital ECPR was associated with both higher survival and more favourable neurological outcomes (OR 2.9, 95%CI 1.5–5.9, p = 0.002, and OR 2.9, 95%CI 1.3–6.4, p = 0.008, respectively) than in those patients receiving ECPR after arrival to hospital, only 7% of whom survived compared to 15% of prehospital ECPR patients. This study represents a significant setback to enthusiasts looking to use mechanical circulatory support as a means of addressing the poor outcomes seen in patients suffering from OHCA. The fact that there were no statistically significant differences in hospital mortality between those treated with ECPR and those treated with conventional CPR mandates a reappraisal of ECPR in OHCA patients. The study had a number of strengths, including its sheer size, the practical experience of these teams in facilitating rapid deployment ECPR [5], and its multicentre observational design, providing ‘real-world’ data. However, there were limitations to the study, most notably the selection bias. ECPR was not initiated per protocol but rather at the discretion of individual clinicians, and therefore influenced by both known and unknown confounders. This was reflected in the difference in baseline characteristics of the ECPR patients, who were younger and more likely to receive bystander CPR (81% vs 49%, p < 0.001) yet, importantly, were also more likely to have CPR duration exceed 30 min (99% vs 77%, p < 0.001). The authors attempted to control for known confounders but were unable to demonstrate that ECPR was associated with improved hospital survival either on multivariate analysis (OR 1.3, 95%CI 0.8–2.1, p = 0.24) or propensity matching (OR 0.8, 95%CI 0.5–1.3, p = 0.41). There were a number of different groups in the study, including those with non-shockable rhythms and those without ROSC. It is possible that ECPR yields different outcomes in these various subgroups, and this may benefit from more focused study. Most importantly, the long-term quality of life and neurological outcomes were not studied. There have been calls to move beyond in-hospital mortality as the primary outcome measure in ECPR and examine more robust outcomes, such as long-term survival with adequate neurological and functional recovery [9, 10]. There is an obvious discrepancy between the outcomes reported in this study and some single-centre studies (Table 1). For example, in one study from Australia of patients with cardiac arrest managed with a combination of hypothermia, ECPR and early reperfusion, over 50% of patients survived to hospital discharge with good neurological function, including 45% of those with OHCA, although not all of the latter actually received ECPR [11]. However, patient numbers were low and other larger studies have shown comparable results to those of Bougouin et al., with survival below 10% [6]. Nonetheless, it is likely that the geographical setting has an impact on outcomes. The immediacy of bystander CPR, the resources available to those providing prehospital care, the speed with which ECPR may be initiated, local traffic congestion, and the distances between the location of OHCA victims and suitably equipped hospitals all may influence results. The skill and experience of the team likely also influence the rate of serious complications as well as ultimate outcomes. Table 1 Selected outcomes with ECPRFull size table Is it time to call for a moratorium on ECPR in OHCA patients outside of clinical trials? Survival after ECPR for in-hospital cardiac arrest patients is approximately 25–30% [1, 2], which already places a significant financial and emotional burden on families and healthcare teams. If survival after ECPR for OHCA is genuinely below 10%, this burden may become crippling. Whether or not a healthcare system wishes to deploy ECPR for OHCA also raises questions about resource management and distributive justice [12, 13]. Should public healthcare systems channel vast resources into providing scaled-up prehospital ECPR or rather into effective public health campaigns aimed at reducing cardiovascular morbidity or improving bystander CPR? The next step is to conduct a randomized trial comparing prehospital ECPR to conventional care, although it must be acknowledged that such studies are extremely difficult to perform. Randomized trials are already underway but are generally initiating ECPR on arrival to hospital (e.g. Clinicaltrials.gov identifiers NCT03101787, NCT03065647, NCT01605409). It is also important to study other medical interventions alongside ECPR such as early coronary revascularization [11, 14]. The authors [8] suggested that ECPR for OHCA should be restricted to patients with shockable rhythms who achieve transient ROSC. This is important, given that shockable rhythms are a surrogate for the potential for revascularization. We agree and recommend that ECPR not be used routinely in OHCA patients outside of clinical trials. To do otherwise may invite an increase in unsalvageable patient admissions associated with higher costs of care, rising clinician burnout and an unjustified burden placed on families and patients. N/A 1. Extracorporeal Life Support Organization. ECLS registry report. Ann Arbor: International Summary; 2019. Google Scholar 2. Chen YS, Lin JW, Yu HY, et al. Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis. Lancet. 2008;372:554–61. Article Google Scholar 3. Shin TG, Jo IJ, Sim MS, et al. Two-year survival and neurological outcome of in-hospital cardiac arrest patients rescued by extracorporeal cardiopulmonary resuscitation. Int J Cardiol. 2013;168:3424–30. Article Google Scholar 4. Ouweneel DM, Schotborgh JV, Limpens J, et al. Extracorporeal life support during cardiac arrest and cardiogenic shock: a systematic review and meta-analysis. Intensive Care Med. 2016;42:1922–34. Article Google Scholar 5. Lamhaut L, Hutin A, Puymirat E, et al. A pre-hospital extracorporeal cardiopulmonary resuscitation (ECPR) strategy for treatment of refractory out hospital cardiac arrest: an observational study and propensity analysis. Resuscitation. 2017;117:109–17. Article Google Scholar 6. Wengenmayer T, Rombach S, Ramshom F, et al. Influence of low-flow time on survival after extracorporeal cardiopulmonary resuscitation (eCPR). Crit Care. 2017;21:157. Article Google Scholar 7. Abrams D, Garan AR, Abdelbary A, et al. Position paper for the organization of ECMO programs for cardiac failure in adults. Intensive Care Med. 2018;44:717–29. Article Google Scholar 8. Bougouin W, Dumas F, Lamhaut L, et al. Extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest: a registry study. Eur Heart J. 2019; [Epub ahead of print]. 9. Haywood K, Whitehead L, Nadkarni VM, et al. COSCA (core outcome set for cardiac arrest) in adults: an advisory statement from the International Liaison Committee on Resuscitation. Resuscitation 2018; 127:147–163. Article Google Scholar 10. Geocadin RG, Callaway CW, Fink EL, et al. Standards for studies of neurological prognostication in comatose survivors of cardiac arrest: a scientific statement from the American Heart Association. Circulation. 2019;140:e517–42. Article Google Scholar 11. Stub D, Bernard S, Pellegrino V, et al. Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial). Resuscitation. 2015;86:88–94. Article Google Scholar 12. MacLaren G. When to initiate ECMO with low likelihood of success. Crit Care. 2018;22:217. Article Google Scholar 13. Machado FR. All in a day’s work – equity vs. equality at a public ICU in Brazil. N Engl J Med. 2016;375:2420–1. Article Google Scholar 14. Kagawa E, Dote K, Kato M, et al. Should we emergently revascularize occluded coronaries for cardiac arrest? Rapid-response extracorporeal membrane oxygenation and intra-arrest percutaneous coronary intervention. Circulation. 2012;126:1605–13. Article Google Scholar Download references None Funding None Affiliations Cardiothoracic Intensive Care Unit, National University Health System, 5 Lower Kent Ridge Rd., Singapore, 119074, Singapore Graeme MacLaren Paediatric Intensive Care Unit, Department of Paediatrics, The Royal Children’s Hospital, University of Melbourne, Flemington Rd., Parkville, VIC, 3052, Australia Graeme MacLaren Columbia University College of Physicians and Surgeons/New York-Presbyterian Hospital, New York, USA Amirali Masoumi  & Daniel BrodieAuthors Search for Graeme MacLaren in: PubMed • Google Scholar Search for Amirali Masoumi in: PubMed • Google Scholar Search for Daniel Brodie in: PubMed • Google Scholar Contributions GM wrote the initial draft. AM and DB critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript. Corresponding author Correspondence to Graeme MacLaren. Ethics approval and consent to participate N/A Consent for publication N/A Competing interests Dr. Brodie receives research support from ALung Technologies; he was previously on their medical advisory board. He has been on the medical advisory boards for Baxter, BREETHE, Xenios and Hemovent. All other authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article MacLaren, G., Masoumi, A. & Brodie, D. ECPR for out-of-hospital cardiac arrest: more evidence is needed. Crit Care 24, 7 (2020) doi:10.1186/s13054-019-2722-0 Download citation Received 04 December 2019 Accepted 27 December 2019 Published 07 January 2020 DOI https://doi.org/10.1186/s13054-019-2722-0 Keywords Extracorporeal membrane oxygenation Extracorporeal life support Adult Mobile Field Extracorporeal cardiopulmonary resuscitation ECMO ECLS ECPR

As an important antioxidant, vitamin C deficiency has frequently been observed in critically ill patients [1]. The treatment with early high-dose intravenous vitamin C has shown beneficial effects on patients with sepsis, septic shock, and myocardial ischemia in both preclinical and clinical studies [2]. Recently, 2 original articles caught my attention. In December 2019, a nationwide cohort study involving 2713 patients reported in Critical Care demonstrated that high-dose vitamin C therapy was associated with reduced mortality in patients with severe burns [3]. The pleiotropic effects of vitamin C may result from its protection against oxidative stress-mediated cell damage and organ dysfunction [1]. However, the CITRIS-ALI trial, reported earlier by Fowler and colleagues in JAMA, October 2019, showed an inconsistent result. In this study, 167 adults with sepsis and acute respiratory distress syndrome were randomized to receive either high-dose vitamin C or placebo for 96 h, and the primary outcomes including modified Sequential Organ Failure Assessment (mSOFA) scores were not statistically different between the groups [4], despite the expected protective effects of vitamin C against multiple organ failure, inflammation, and endothelial injury as shown in their phase I safety trial [5]. After scrutinizing the results in the CITRIS-ALI trial, we proposed that a survivorship bias may have contributed to the conflicting result. As we noted from their results (Fig. 3, page 1268), there were sudden increases in the overall mortality probability from day 0 to day 7 in the placebo group. Thus, we performed further analyses according to Fig. 3 and discovered that the overall mortalities in the placebo group had more intensive increases on day 2 (10.8 vs. 1.2%; P = 0.021), day 3 (14.5 vs. 2.4%; P = 0.005), and day 4 (19.3 vs. 3.6%; P = 0.001) than those in the vitamin C group (shown in Table 1). Those sudden increases in mortality in the placebo group may result from the deteriorated conditions of certain patients, leaving the survived patients with less severe conditions for statistical analyses at the primary end points. Therefore, when the mSOFA at 96 h and the levels of C-reactive protein and thrombomodulin at 168 h were evaluated, the survivorship bias rendered the differences between the vitamin C group and placebo group uncomparable, causing decreased reliability of the results. Nevertheless, a positive effect of vitamin C still gleams behind the results presented, as a misunderstood ally. Table 1 A rough estimate of mortalities from day 0 to day 7Full size table Not applicable. mSOFA scores: Modified Sequential Organ Failure Assessment scores 1. Spoelstra-de Man AME, Elbers PWG, Oudemans-van Straaten HM. Making sense of early high-dose intravenous vitamin C in ischemia/reperfusion injury. Crit Care. 2018;22(1):70. Article Google Scholar 2. Li J. Evidence is stronger than you think: a meta-analysis of vitamin C use in patients with sepsis. Crit Care. 2018;22(1):258. Article Google Scholar 3. Nakajima M, Kojiro M, Aso S, Matsui H, Fushimi K, Kaita Y, Goto H, Yamaguchi Y, Yasunaga H. Effect of high-dose vitamin C therapy on severe burn patients: a nationwide cohort study. Crit Care. 2019;23(1):407. Article Google Scholar 4. Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, Fisher B, Thacker LR 2nd, Natarajan R, Brophy DF, et al. Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial. Jama. 2019;322(13):1261–70. Article Google Scholar 5. Fowler AA 3rd, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, Farthing CA, Larus TL, Martin E, Brophy DF, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32. Article Google Scholar Download references Not applicable. Funding This work was supported by the National Natural Science Foundation of China (No. 81770057). Affiliations Department of Critical Care Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, Shaanxi Province, China Jiajia Ren , Xuting Jin , Ya Gao , Ruohan Li , Jiamei Li , Jingjing Zhang , Xiaochuang Wang  & Gang WangAuthors Search for Jiajia Ren in: PubMed • Google Scholar Search for Xuting Jin in: PubMed • Google Scholar Search for Ya Gao in: PubMed • Google Scholar Search for Ruohan Li in: PubMed • Google Scholar Search for Jiamei Li in: PubMed • Google Scholar Search for Jingjing Zhang in: PubMed • Google Scholar Search for Xiaochuang Wang in: PubMed • Google Scholar Search for Gang Wang in: PubMed • Google Scholar Contributions JR, XJ, YG, RL, JL, JZ, and XW performed the analyses and interpreted the results. JR and XJ wrote the manuscript. XJ, YG, RL, JL, JZ, and XW revised the manuscript. GW raised the hypothesis and supervised the work. All authors read and approved the final manuscript. Corresponding author Correspondence to Gang Wang. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Ren, J., Jin, X., Gao, Y. et al. Vitamin C: a misunderstood ally?. Crit Care 24, 8 (2020) doi:10.1186/s13054-020-2725-x Download citation Received 11 December 2019 Accepted 01 January 2020 Published 07 January 2020 DOI https://doi.org/10.1186/s13054-020-2725-x

AlRawahi et al. concluded that sepsis and multiple organ failure (MOF) are the predominant cause of late death in severe multiple trauma (MT) [1]. They suggested that repeated measures of procalcitonin (PCT) during disease course may allow for early recognition of septic complications and detection of multiple organ failure (MOF), resulting in earlier therapeutic decisions and an impact on survival and improve outcomes [1]. We would like to make some comments. A recent meta-analysis evaluating more than 26,000 MT patients revealed a pooled incidence of acute kidney injury (AKI) in MT of more than 20% [2]. In addition, in a further breakdown of the A KI stages, over 40% of these patients were classified with more severe forms of AKI (RIFLE I or F or stages 2–3) [2] suggesting a probable use of renal replacement therapy (RRT) between 5 and 10% [2]. This incidence could be even higher (up to 20%) if MT is complicated by sepsis and MOF [3]. If we apply the same trends for the study of AlRawahi et al., the incidence of RRT in MT with sepsis and MOF could have an impact upon the reliability of the PCT level under those conditions. PCT has an approximate molecular weight of 14.5 kDa [4]. The contemporary continuous RRT (CRRT) membranes are able to remove molecules as large as 35 kDa [4]. Hence, most of the PCT mass will be eliminated by convective flow [4], but adsorption also contributes to the elimination if using new highly adsorptive membranes (HAM) [5]. Accordingly, an imbalance between the use of CRRT in the two cohorts (MT alone or MT with sepsis and MOF) will have an important impact upon the values of PCT in each cohort but more so in the MT cohort with sepsis and MOF. PCT levels may therefore be affected not only by the complications of MT but also by the incidence of RRT. In conclusion, we believe there is a critical need for a future study with a focus on the performance of the currently known biomarkers among patients receiving CRRT [5]. Not applicable. AKI: Acute kidney injury CRRT: Continuous renal replacement therapy HAM: Highly adsorptive membranes MOF: Multiple organ failure MT: Multiple trauma PCT: Procalcitonin RRT: Renal replacement therapy 1. AlRawahi AN, AlHinai FA, Doig CJ, et al. The prognostic value of serum procalcitonin measurements in critically injured patients: a systematic review. Crit Care. 2019;23:390. https://doi.org/10.1186/s13054-019-2669-1. Article PubMed PubMed Central Google Scholar 2. Haines RW, Fowler AJ, Kirwan CJ, Prowle JR. The incidence and associations of acute kidney injury in trauma patients admitted to critical care: a systematic review and meta-analysis. J Trauma Acute Care Surg. 2019;86(1):141–7. https://doi.org/10.1097/TA.0000000000002085. Article PubMed Google Scholar 3. Peters E, Antonelli M, Wittebole X, Nanchal R, François B, Sakr Y, et al. A worldwide multicentre evaluation of the influence of deterioration or improvement of acute kidney injury on clinical outcome in critically ill patients with and without sepsis at ICU admission: results from the Intensive Care Over Nations audit. Crit Care. 2018;22(1):188. https://doi.org/10.1186/s13054-018-2112-z. Article PubMed PubMed Central Google Scholar 4. Level C, Chauveau P, Guisset O, Cazin MC, Lasseur C, Gabinsky C, et al. Mass transfer, clearance and plasma concentration of procalcitonin during continuous venovenous hemofiltration in patients with septic shock and acute oliguric renal failure. Crit Care. 2003;6:R160–6. Article Google Scholar 5. Honoré PM, Jacobs R, De Waele E, Van Gorp V, Spapen HD. Evaluating sepsis during continuous dialysis: are biomarkers still valid? Blood Purif. 2014;38(2):104–5. https://doi.org/10.1159/000363497 Epub 2014 Oct 17. Article PubMed Google Scholar Download references We would like to thank Dr. Melissa Jackson for the critical review and complete editing process of the letter. Funding None. Affiliations ICU Department, Centre Hospitalier Universitaire Brugmann, Place Van Gehuchtenplein 4, 1020, Brussels, Belgium Patrick M. Honore , Christina David , Rachid Attou , Sebastien Redant , Andrea Gallerani  & David De BelsAuthors Search for Patrick M. Honore in: PubMed • Google Scholar Search for Christina David in: PubMed • Google Scholar Search for Rachid Attou in: PubMed • Google Scholar Search for Sebastien Redant in: PubMed • Google Scholar Search for Andrea Gallerani in: PubMed • Google Scholar Search for David De Bels in: PubMed • Google Scholar Contributions PMH, SR, and DDB designed the paper. All authors participated in the drafting of the manuscript. All authors have read and approved the final version. Corresponding author Correspondence to Patrick M. Honore. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This comment refers to the article available at https://doi.org/10.1186/s13054-019-2669-1. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Honore, P.M., David, C., Attou, R. et al. Procalcitonin to allow early detection of sepsis and multiple organ failure in severe multiple trauma: beware of some confounders. Crit Care 24, 9 (2020) doi:10.1186/s13054-020-2729-6 Download citation Received 12 December 2019 Accepted 01 January 2020 Published 07 January 2020 DOI https://doi.org/10.1186/s13054-020-2729-6

In the publication of this article [1], there was an error in the cited reference 23 [2] within the Family Name. This has now been updated in the original article.

Abstract Background Intensive care unit (ICU)-acquired weakness and diaphragm dysfunction are frequent conditions, both associated with poor prognosis in critically ill patients. While it is well established that ICU-acquired weakness severely impairs long-term prognosis, the association of diaphragm dysfunction with this outcome has never been reported. This study investigated whether diaphragm dysfunction is associated with negative long-term outcomes and whether the coexistence of diaphragm dysfunction and ICU-acquired weakness has a particular association with 2-year survival and health-related quality of life (HRQOL). Methods This study is an ancillary study derived from an observational cohort study. Patients under mechanical ventilation were enrolled at the time of their first spontaneous breathing trial. Diaphragm dysfunction was defined by tracheal pressure generated by phrenic nerve stimulation < 11 cmH2O and ICU-acquired weakness was defined by Medical Research Council (MRC) score < 48. HRQOL was evaluated with the SF-36 questionnaire. Results Sixty-nine of the 76 patients enrolled in the original study were included in the survival analysis and 40 were interviewed. Overall 2-year survival was 67% (46/69): 64% (29/45) in patients with diaphragm dysfunction, 71% (17/24) in patients without diaphragm dysfunction, 46% (11/24) in patients with ICU-acquired weakness and 76% (34/45) in patients without ICU-acquired weakness. Patients with concomitant diaphragm dysfunction and ICU-acquired weakness had a poorer outcome with a 2-year survival rate of 36% (5/14) compared to patients without diaphragm function and ICU-acquired weakness [79% (11/14) (p < 0.01)]. Health-related quality of life was not influenced by the presence of ICU-acquired weakness, diaphragm dysfunction or their coexistence. Conclusions ICU-acquired weakness but not diaphragm dysfunction was associated with a poor 2-year survival of critically ill patients.

Abstract Background Intubation is a lifesaving procedure that is often performed in intensive care unit (ICU) patients, but leads to serious adverse events in 20–40% of cases. Recent trials aimed to provide guidance about which medications, devices, and modalities maximize patient safety. Videolaryngoscopes are being offered in an increasing range of options and used in broadening indications (from difficult to unremarkable intubation). The objective of this study was to describe intubation practices and device availability in French ICUs. Materials and methods We conducted an online nationwide survey by emailing an anonymous 26-item questionnaire to physicians in French ICUs. A single questionnaire was sent to either the head or the intubation expert at each ICU. Results Of 257 ICUs, 180 (70%) returned the completed questionnaire. The results showed that 43% of intubators were not fully proficient in intubation; among them, 18.8% had no intubation training or had received only basic training (lectures and observation at the bedside). Among the participating ICUs, 94.4% had a difficult intubation trolley, 74.5% an intubation protocol, 92.2% a capnography device (used routinely to check tube position in 69.3% of ICUs having the device), 91.6% a laryngeal mask, 97.2% front-of-neck access capabilities, and 76.6% a videolaryngoscope. In case of difficult intubation, 85.6% of ICUs used a bougie (154/180) and 7.8% switched to a videolaryngoscope (14/180). Use of a videolaryngoscope was reserved for difficult intubation in 84% of ICUs (154/180). Having a videolaryngoscope was significantly associated with having an intubation protocol (P = 0.043) and using capnography (P = 0.02). Airtraq® was the most often used videolaryngoscope (39.3%), followed by McGrath®Mac (36.9%) then by Glidescope® (14.5%). Conclusion Nearly half the intubators in French ICUs are not fully proficient with OTI. Access to modern training methods such as simulation is inadequate. Most ICUs own a videolaryngoscope, but reserve it for difficult intubations.

Acute kidney injury (AKI) is an important complication encountered during the course of diabetic ketoacidosis (DKA). Plasma-Lyte with lower chloride concentration than saline has been shown to be associated with reduced incidence of AKI in adults with septic shock. No study has compared this in DKA. This double-blind, parallel-arm, investigator-initiated, randomized controlled trial compared 0.9% saline with Plasma-Lyte-A as initial fluid in pediatric DKA. The study was done in a tertiary care, teaching, and referral hospital in India in children (> 1 month–12 years) with DKA as defined by ISPAD. Children with cerebral edema or known chronic kidney/liver disease or who had received pre-referral fluids and/or insulin were excluded. Sixty-six children were randomized to receive either Plasma-Lyte (n = 34) or 0.9% saline (n = 32). Primary outcome was incidence of new or progressive AKI, defined as a composite outcome of change in creatinine (defined by KDIGO), estimated creatinine clearance (defined by p-RIFLE), and NGAL levels. The secondary outcomes were resolution of AKI, time to resolution of DKA (pH > 7.3, bicarbonate> 15 mEq/L & normal sensorium), change in chloride, pH and bicarbonate levels, proportion of in-hospital all-cause mortality, need for renal replacement therapy (RRT), and length of ICU and hospital stay. Baseline characteristics were similar in both groups. The incidence of new or progressive AKI was similar in both [Plasma-Lyte 13 (38.2%) versus 0.9% saline 15 (46.9%); adjusted OR 1.22; 95% CI 0.43–3.43, p = 0.70]. The median (IQR) time to resolution of DKA in Plasma-Lyte-A and 0.9% saline were 14.5 (12 to 20) and 16 (8 to 20) h respectively. Time to resolution of AKI was similar in both [Plasma-Lyte 22.1 versus 0.9% saline 18.8 h (adjusted HR 1.72; 95% CI 0.83–3.57; p = 0.14)]. Length of hospital stay was also similar in both [Plasma-Lyte 9 (8 to 12) versus 0.9% saline 10 (8.25 to 11) days; p = 0.39]. The incidence of new or progressive AKI and resolution of AKI were similar in both groups. Plasma-Lyte-A was similar to 0.9% Saline in time to resolution of DKA, need for RRT, mortality, and lengths of PICU and hospital stay. Clinical trial registry of India, CTRI/2018/05/014042 (ctri.nic.in) (Retrospectively registered).

Acute kidney injury (AKI) is a common complication in burn patients admitted to the intensive care unit (ICU) associated with increased morbidity and mortality. Our primary aim was to review incidence, risk factors, and outcomes of AKI in burn patients admitted to the ICU. Secondary aims were to review the use of renal replacement therapy (RRT) and impact on health care costs. We conducted a systematic search in PubMed, UpToDate, and NICE through 3 December 2018. All reviews in Cochrane Database of Systematic Reviews except protocols were added to the PubMed search. We searched for studies on AKI according to Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE); Acute Kidney Injury Network (AKIN); and/or Kidney Disease: Improving Global Outcomes (KDIGO) criteria in burn patients admitted to the ICU. We collected data on AKI incidence, risk factors, use of RRT, renal recovery, length of stay (LOS), mortality, and health care costs. We included 33 observational studies comprising 8200 patients. Overall study quality, scored according to the Newcastle-Ottawa scale, was moderate. Random effect model meta-analysis revealed that the incidence of AKI among burn patients in the ICU was 38 (30–46) %. Patients with AKI were almost evenly distributed in the mild, moderate, and severe AKI subgroups. RRT was used in 12 (8–16) % of all patients. Risk factors for AKI were high age, chronic hypertension, diabetes mellitus, high Total Body Surface Area percent burnt, high Abbreviated Burn Severity Index score, inhalation injury, rhabdomyolysis, surgery, high Acute Physiology and Chronic Health Evaluation II score, high Sequential Organ Failure Assessment score, sepsis, and mechanical ventilation. AKI patients had 8.6 (4.0–13.2) days longer ICU LOS and higher mortality than non-AKI patients, OR 11.3 (7.3–17.4). Few studies reported renal recovery, and no study reported health care costs. AKI occurred in 38% of burn patients admitted to the ICU, and 12% of all patients received RRT. Presence of AKI was associated with increased LOS and mortality. PROSPERO (CRD42017060420)

Peroxisome proliferator-activated receptor gamma (PPARγ) is a major regulator in sepsis. Our previous study identified the enhancer polymorphism rs10865710C/G to be associated with susceptibility to sepsis in trauma patients. We performed two-stage cohort studies integrating biological experiments of potential functional variants that modify susceptibility to traumatic sepsis. Improved multiplex ligation detection reaction (iMLDR) was used to genotype rs10865710 in 797 Han Chinese trauma patients in Chongqing. Clinical relevance was validated in 334 patients in Guizhou. The potential function of rs10865710 in transcriptional regulation was explored through a dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). Expression of PPARγ was assessed by expression quantitative trait locus (e-QTL) and western blot analyses. The association results confirmed rs10865710 to be significantly strongly associated with sepsis risk in trauma patients of the Chongqing and Guizhou cohorts (OR = 1.41 (1.11–1.79), P = 0.004 and OR = 1.45 (1.01–2.09), P = 0.046, both for allele-dose effect, respectively). A meta-analysis of both cohorts and a previous study indicated strong evidence for this association (OR = 1.41 (1.17–1.71), P = 0.0004 for the dominant model, OR = 1.78 (1.34–2.36), P < 0.0001 for the recessive model and OR = 1.38 (1.20–1.58), P < 0.0001 for the allelic model). Functional experiments verified that rs10865710 was a causative variant influencing enhancer activity (G vs. C, 0.068 ± 0.004 vs. 0.096 ± 0.002, P = 0.0005) and CREB2 binding. Expression analysis also indicatevd rs10865710 genotypes to be associated with levels of PPARγ expression (P = 9.2 × 10−5 for dominant effect and P = 0.005 for recessive effect). Our study provides evidence that the enhancer-region polymorphism rs10865710 might influence transcription factor binding and regulate PPARγ expression, thus conferring susceptibility to traumatic sepsis. ClinicalTrials.gov, NCT01713205. Registered 18 October 2012, retrospectively registered.

Emergency ambulance services are integral to providing a service for those with unplanned urgent and life-threatening health conditions. However, high use of the service by a small minority of patients is a concern. Our objectives were to describe: service-wide and local policies or pathways for people classified as Frequent Caller; call volume; and results of any audit or evaluation. We conducted a national survey of current practice in ambulance services in relation to the management of people who call the emergency ambulance service frequently using a structured questionnaire for completion by email and telephone interview. We analysed responses using a descriptive and thematic approach. Twelve of 13 UK ambulance services responded. Most services used nationally agreed definitions for ‘Frequent Caller’, with 600–900 people meeting this classification each month. Service-wide policies were in place, with local variations. Models of care varied from within-service care where calls are flagged in the call centre; contact made with callers; and their General Practitioner (GP) with an aim of discouraging further calls, to case management through cross-service, multi-disciplinary team meetings aiming to resolve callers’ needs. Although data were available related to volume of calls and number of callers meeting the threshold for definition as Frequent Caller, no formal audits or evaluations were reported. Ambulance services are under pressure to meet challenging response times for high acuity patients. Tensions are apparent in the provision of care to patients who have complex needs and call frequently. Multi-disciplinary case management approaches may help to provide appropriate care, and reduce demand on emergency services. However, there is currently inadequate evidence to inform commissioning, policy or practice development.

Previous systematic reviews have examined the effectiveness of interventions for frequent presenters to the Emergency Department (ED) but not the costs and cost-effectiveness of such interventions. A systematic literature review was conducted which screened the following databases: Pubmed, Medline, Embase, Cochrane and Econlit. An inclusion and exclusion criteria were developed following PRISMA guidelines. A narrative review methodology was adopted due to the heterogeneity of the reporting of the costs across the studies. One thousand three hundred eighty-nine papers were found and 16 were included in the review. All of the interventions were variations of a case management approach. Apart from one study which had mixed results, all of the papers reported a decrease in ED use and costs. There were no cost effectiveness studies. The majority of interventions for frequent presenters to the ED were found to decrease ED use and cost. Future research should be undertaken to examine the cost effectiveness of these interventions.

In patients with acute respiratory distress syndrome (ARDS), low tidal volume ventilation has been associated with reduced mortality. Driving pressure (tidal volume normalized to respiratory system compliance) may be an even stronger predictor of ARDS survival than tidal volume. We sought to study whether these associations hold true in acute respiratory failure patients without ARDS. This is a retrospectively cohort analysis of mechanically ventilated adult patients admitted to ICUs from 12 hospitals over 2 years. We used natural language processing of chest radiograph reports and data from the electronic medical record to identify patients who had ARDS. We used multivariable logistic regression and generalized linear models to estimate associations between tidal volume, driving pressure, and respiratory system compliance with adjusted 30-day mortality using covariates of Acute Physiology Score (APS), Charlson Comorbidity Index (CCI), age, and PaO2/FiO2 ratio. We studied 2641 patients; 48% had ARDS (n = 1273). Patients with ARDS had higher mean APS (25 vs. 23, p < .001) but similar CCI (4 vs. 3, p = 0.6) scores. For non-ARDS patients, tidal volume was associated with increased adjusted mortality (OR 1.18 per 1 mL/kg PBW increase in tidal volume, CI 1.04 to 1.35, p = 0.010). We observed no association between driving pressure or respiratory compliance and mortality in patients without ARDS. In ARDS patients, both ΔP (OR1.1, CI 1.06–1.14, p < 0.001) and tidal volume (OR 1.17, CI 1.04–1.31, p = 0.007) were associated with mortality. In a large retrospective analysis of critically ill non-ARDS patients receiving mechanical ventilation, we found that tidal volume was associated with 30-day mortality, while driving pressure was not.

Recently, the largest randomized clinical trial (RCT) of intravenous vitamin C in septic patients until now, the CITRIS-ALI trial, showed a 16.5% lower mortality in the vitamin C group compared to placebo, while the primary endpoint deltaSOFA-score after 96 h was negative [1]. Mortality curves parted from day 2, which may be due to early circulatory stabilization by vitamin C [2]. Many comments on this trial addressed the methodological problem due to the exclusion of deceased and discharged patients from the deltaSOFA-score. Given the early mortality reduction in favor of vitamin C, recalculation with assignment of the worst SOFA score to deceased patients and the best score to discharged patients will undoubtedly show less organ dysfunction. So, the results of the CITRIS-ALI study support the promising role of adjuvant high-dose intravenous vitamin C for septic patients. The CITRIS-ALI trial differed in two important aspects from the groundbreaking before-after study of Marik et al. which showed a 30% absolute mortality reduction, but had the limitation of not being randomized [2]. First, the i.v. dose of 200 mg/kg/day vitamin C (i.e., 16 g/day for 80 kg BW) was higher than the 6 g/day of the HAT-therapy. Second, vitamin C was administered as monotherapy and not in combination with hydrocortisone and thiamine (HAT-therapy, based on the hypothesis that hydrocortisone and thiamine have potentially synergistic effects with vitamin C). Although the positive results of the CITRIS-ALI study on mortality question the necessity of co-administration of hydrocortisone and thiamine when vitamin C is dosed sufficiently high, notably 66% of patients in CITRIS-ALI study received corticosteroids. The rationale for vitamin C in sepsis is strong. Humans are unable to synthesize vitamin C, while animals acutely increase its production during stress to protect cells against the overwhelming production of reactive oxygen species (ROS) causing endothelial and mitochondrial injury with subsequent organ failure [3]. In animals, the endogenous vitamin C production is inversely correlated to the cortisol response. Higher cortisol responses are associated with poorer outcomes, which may be attributed to higher severity of illness, but also to vitamin C deficiency [4]. Vitamin C is our central antioxidant, which directly scavenges free radicals, prevents production of ROS, and restores other antioxidants, reducing endothelial permeability and cellular apoptosis. Furthermore, vitamin C is a neuroprotector, immunomodulator, and cofactor for synthesis of vasopressors. Increased vitamin C consumption and reduced recycling lead to abrupt hypovitaminosis C (≤ 23 μmol/l) and deficiency (≤ 11 μmol/l) as measured in 88% and 38% of the patients with septic shock [5]. The optimal dose of vitamin C is unknown, and systematic dose-finding during critical illness has not been performed. However, several facts are known. First, the antioxidant capacity of vitamin C is dose-dependent and direct radical scavenging capacity is maximal at a plasma vitamin C level > 175 mg/l (1000 μmol/l), more than ten times normal [6]. In addition, other functions like immune modulation, inhibition of bacterial replication, and neuroprotection are dose-dependent as well. Second, intravenous dosing is necessary, because enteral uptake is limited [3]. Third, intravenous vitamin C doses of 2–3 g/day are needed to normalize plasma concentrations and sustained therapy is needed to prevent reoccurrence of hypovitaminosis [7]. The dose-concentration relationship is linear, so higher doses yield proportionally higher plasma concentrations [7]. Plasma concentrations > 1000 μmol/l can be obtained with 10 g i.v. vitamin C/day [7]. In the only dose-effect study in septic patients, the higher dose of i.v. vitamin C (200 mg/kg/day) improved organ dysfunction more than the lower dose of 50 mg/kg/day. A recent meta-analysis found a reduced mortality with medium-dose vitamin C (3–10 g/day) in critically ill patients, in contrast to low (< 3 g/day) or high doses (≥ 10 g/day) [8]. However, this meta-analysis included small studies, one third of these were retrospective, duration of treatment varied, and the CITRIS-ALI was not included. So more and larger studies comparing different doses are required before recommendations can be made about the optimal dose. Thiamine levels are reduced in 20–70% of the septic patients due to increased metabolic consumption, decreased intake, and increased loss. Low thiamine status in critically ill patients is associated with worse outcome [9]. Deficiency reduces the activity of thiamine-dependent enzymes, linked to (mitochondrial) energy production (aerobic glycolysis, Krebs cycle) and maintenance of NADPH (pentose phosphate pathway). Deficiency promotes the production of lactate and hampers the production of ATP. NADPH is essential for the maintenance of cellular pH. Thiamine is also cofactor in the production of glucose-derived neurotransmitters and of acetylcholine and myelin, thereby maintaining neuronal activity. The main role of non-phosphorylated thiamine is being an antioxidant. Furthermore, adequate thiamine status stimulates the conversion of glyoxylate into glycine instead of oxalate. This reduces the risk of oxalate nephropathy due to high-dose vitamin C [9]. The only human RCT with thiamine (200 mg/12 h) in septic shock had no impact on mortality, but post hoc analysis showed improvement of renal function with thiamine [10]. Hydrocortisone and vitamin C have several functions in common, including attenuation of nuclear factor-κB activation and subsequent generation of pro-inflammatory mediators with improvement of the endothelial barrier and microcirculatory patency. Both are necessary for the synthesis of catecholamines and improve vasopressor sensitivity. During sepsis, high amounts of ROS hamper glucocorticoid binding to its receptor and the cellular uptake of vitamin C by the sodium-vitamin C transporter2 (SVCT2). Synergy is therefore possible: vitamin C can restore glucocorticoid receptor function, and glucocorticoids can increase expression of the vitamin SVCT2 transporter [11]. In vitro, the combination showed a superior barrier-protective effect after lipopolysaccharide exposure compared to either agent alone [12]. In line with the study of Marik et al. [2], two other small retrospective studies in patients with septic shock [13] and severe pneumonia [14] showed reduced mortality with HAT-therapy, whereas another retrospective study in septic shock did not [15]. Large RCTs are currently being performed. So, the CITRIS-ALI results support a potential role for adjuvant high-dose i.v. vitamin C for sepsis. Large RCTs are under way to confirm these results. Whether HAT-therapy induces additional beneficial effect when vitamin C is dosed sufficiently high remains to be demonstrated, although hydrocortisone and thiamine are certainly indicated in specific patient groups. Not applicable. RCT: Randomized clinical trial SOFA score: Sequential Organ Failure Assessment score i.v.: Intravenous BW: Bodyweight HAT-therapy: Hydrocortisone-ascorbic acid-thiamine therapy ROS: Reactive oxygen species NADPH: Nicotinamide adenine dinucleotide phosphate SVCT2: Sodium-vitamin C transporter 2 1. Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, et al. Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial. JAMA. 2019;322(13):1261–70. Article Google Scholar 2. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229–38. Article Google Scholar 3. Padayatty SJ, Levine M. Vitamin C: the known and the unknown and Goldilocks. Oral Dis. 2016;22(6):463–93. CAS Article Google Scholar 4. Hooper MH, Carr A, Marik PE. The adrenal-vitamin C axis: from fish to guinea pigs and primates. Crit Care. 2019;23(1):29. Article Google Scholar 5. Carr AC, Rosengrave PC, Bayer S, Chambers S, Mehrtens J, Shaw GM. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care. 2017;21(1):300. Article Google Scholar 6. Jackson TS, Xu A, Vita JA, Keaney JF Jr. Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res. 1998;83(9):916–22. CAS Article Google Scholar 7. de Grooth HJ, Manubulu-Choo WP, Zandvliet AS, Spoelstra-de Man AME, Girbes AR, Swart EL, et al. Vitamin C pharmacokinetics in critically ill patients: a randomized trial of four IV regimens. Chest. 2018;153(6):1368–77. Article Google Scholar 8. Wang Y, Lin H, Lin BW, Lin JD. Effects of different ascorbic acid doses on the mortality of critically ill patients: a meta-analysis. Ann Intensive Care. 2019;9(1):58. Article Google Scholar 9. Cruickshank AM, Telfer AB, Shenkin A. Thiamine deficiency in the critically ill. Intensive Care Med. 1988;14(4):384–7. CAS Article Google Scholar 10. Moskowitz A, Andersen LW, Cocchi MN, Karlsson M, Patel PV, Donnino MW. Thiamine as a renal protective agent in septic shock. A secondary analysis of a randomized, double-blind, placebo-controlled trial. Ann Am Thorac Soc. 2017;14(5):737–41. Article Google Scholar 11. Moskowitz A, Andersen LW, Huang DT, Berg KM, Grossestreuer AV, Marik PE, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit Care. 2018;22(1):283. Article Google Scholar 12. Barabutis N, Khangoora V, Marik PE, Catravas JD. Hydrocortisone and ascorbic acid synergistically prevent and repair lipopolysaccharide-induced pulmonary endothelial barrier dysfunction. Chest. 2017;152(5):954–62. Article Google Scholar 13. Sadaka F, Grady J, Organti N, Donepudi B, Korobey M, Tannehill D, et al. Ascorbic acid, thiamine, and steroids in septic shock: propensity matched analysis. J Intensive Care Med. 2019;885066619864541:1–5. 14. Kim WY, Jo EJ, Eom JS, Mok J, Kim MH, Kim KU, et al. Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: propensity score-based analysis of a before-after cohort study. J Crit Care. 2018;47:211–8. CAS Article Google Scholar 15. Litwak JJ, Cho N, Nguyen HB, Moussavi K, Bushell T. Vitamin C, Hydrocortisone, and thiamine for the treatment of severe sepsis and septic shock: a retrospective analysis of real-world application. J Clin Med. 2019;8(4):478. Download references Not applicable. Funding The authors received no specific funding for this work. Affiliations Department of Intensive Care, Amsterdam UMC, location VUmc, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands Angelique M. E. Spoelstra–de Man  & Heleen M. Oudemans–van Straaten Service of Intensive Care Medicine and Burns, Lausanne University Hospital (CHUV), Rue du Bugnon 46, CH-1011, Lausanne, Switzerland Mette M. BergerAuthors Search for Angelique M. E. Spoelstra–de Man in: PubMed • Google Scholar Search for Heleen M. Oudemans–van Straaten in: PubMed • Google Scholar Search for Mette M. Berger in: PubMed • Google Scholar Contributions All authors helped to write the manuscript and read and approved the final manuscript. Corresponding author Correspondence to Angelique M. E. Spoelstra–de Man. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests A.M.E. Spoelstra–de Man and H.M. Oudemans–van Straaten received a grant from the Netherlands Organisation for Health Research and Development to perform a multicenter RCT investigating the effect of high-dose i.v. vitamin C post-cardiac arrest. The remaining author declares that there are no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Spoelstra–de Man, A.M.E., Oudemans–van Straaten, H.M. & Berger, M.M. Adjuvant vitamin C for sepsis: mono or triple?. Crit Care 23, 425 (2019) doi:10.1186/s13054-019-2717-x Download citation Received 11 December 2019 Accepted 19 December 2019 Published 27 December 2019 DOI https://doi.org/10.1186/s13054-019-2717-x Keywords Vitamin C Hydrocortisone Thiamine Sepsis

Systemic blood flow in patients on extracorporeal assist devices is frequently not or only minimally pulsatile. Loss of pulsatile brain perfusion, however, has been implicated in neurological complications. Furthermore, the adverse effects of absent pulsatility on the cerebral microcirculation are modulated similarly as CO2 vasoreactivity in resistance vessels. During support with an extracorporeal assist device swings in arterial carbon dioxide partial pressures (PaCO2) that determine cerebral oxygen delivery are not uncommon—especially when CO2 is eliminated by the respirator as well as via the gas exchanger of an extracorporeal membrane oxygenation machine. We, therefore, investigated whether non-pulsatile flow affects cerebrovascular CO2 reactivity (CVR) and regional brain oxygenation (rSO2). In this prospective, single-centre case-control trial, we studied 32 patients undergoing elective cardiac surgery. Blood flow velocity in the middle cerebral artery (MCAv) as well as rSO2 was determined during step changes of PaCO2 between 30, 40, and 50 mmHg. Measurements were conducted on cardiopulmonary bypass during non-pulsatile and postoperatively under pulsatile blood flow at comparable test conditions. Corresponding changes of CVR and concomitant rSO2 alterations were determined for each flow mode. Each patient served as her own control. MCAv was generally lower during hypocapnia than during normocapnia and hypercapnia (p < 0.0001). However, the MCAv/PaCO2 slope during non-pulsatile flow was 14.4 cm/s/mmHg [CI 11.8–16.9] and 10.4 cm/s/mmHg [CI 7.9–13.0] after return of pulsatility (p = 0.03). During hypocapnia, non-pulsatile CVR (4.3 ± 1.7%/mmHg) was higher than pulsatile CVR (3.1 ± 1.3%/mmHg, p = 0.01). Independent of the flow mode, we observed a decline in rSO2 during hypocapnia and a corresponding rise during hypercapnia (p < 0.0001). However, the relationship between ΔrSO2 and ΔMCAv was less pronounced during non-pulsatile flow. Non-pulsatile perfusion is associated with enhanced cerebrovascular CVR resulting in greater relative decreases of cerebral blood flow during hypocapnia. Heterogenic microvascular perfusion may account for the attenuated ΔrSO2/ΔMCAv slope. Potential hazards related to this altered regulation of cerebral perfusion still need to be assessed. The study was retrospectively registered on October 30, 2018, with Clinical Trial.gov (NCT03732651).

Spreading depolarizations (SD) are characterized by breakdown of transmembrane ion gradients and excitotoxicity. Experimentally, N-methyl-d-aspartate receptor (NMDAR) antagonists block a majority of SDs. In many hospitals, the NMDAR antagonist s-ketamine and the GABAA agonist midazolam represent the current second-line combination treatment to sedate patients with devastating cerebral injuries. A pressing clinical question is whether this option should become first-line in sedation-requiring individuals in whom SDs are detected, yet the s-ketamine dose necessary to adequately inhibit SDs is unknown. Moreover, use-dependent tolerance could be a problem for SD inhibition in the clinic. We performed a retrospective cohort study of 66 patients with aneurysmal subarachnoid hemorrhage (aSAH) from a prospectively collected database. Thirty-three of 66 patients received s-ketamine during electrocorticographic neuromonitoring of SDs in neurointensive care. The decision to give s-ketamine was dependent on the need for stronger sedation, so it was expected that patients receiving s-ketamine would have a worse clinical outcome. S-ketamine application started 4.2 ± 3.5 days after aSAH. The mean dose was 2.8 ± 1.4 mg/kg body weight (BW)/h and thus higher than the dose recommended for sedation. First, patients were divided according to whether they received s-ketamine at any time or not. No significant difference in SD counts was found between groups (negative binomial model using the SD count per patient as outcome variable, p = 0.288). This most likely resulted from the fact that 368 SDs had already occurred in the s-ketamine group before s-ketamine was given. However, in patients receiving s-ketamine, we found a significant decrease in SD incidence when s-ketamine was started (Poisson model with a random intercept for patient, coefficient − 1.83 (95% confidence intervals − 2.17; − 1.50), p < 0.001; logistic regression model, odds ratio (OR) 0.13 (0.08; 0.19), p < 0.001). Thereafter, data was further divided into low-dose (0.1–2.0 mg/kg BW/h) and high-dose (2.1–7.0 mg/kg/h) segments. High-dose s-ketamine resulted in further significant decrease in SD incidence (Poisson model, − 1.10 (− 1.71; − 0.49), p < 0.001; logistic regression model, OR 0.33 (0.17; 0.63), p < 0.001). There was little evidence of SD tolerance to long-term s-ketamine sedation through 5 days. These results provide a foundation for a multicenter, neuromonitoring-guided, proof-of-concept trial of ketamine and midazolam as a first-line sedative regime.

The administration of levosimendan prophylactically to patients undergoing cardiac surgery remains a controversial practice, and few studies have specifically assessed the value of this approach in pediatric patients. This study therefore sought to explore the safety and efficacy of prophylactic levosimendan administration to pediatric patients as a means of preventing low cardiac output syndrome (LCOS) based upon hemodynamic, biomarker, and pharmacokinetic readouts. This was a single-center, double-blind, randomized, placebo-controlled trial. Patients ≤ 48 months old were enrolled between July 2018 and April 2019 and were randomly assigned to groups that received either placebo or levosimendan infusions for 48 h post-surgery, along with all other standard methods of care. LCOS incidence was the primary outcome of this study. A total of 187 patients were enrolled, of whom 94 and 93 received levosimendan and placebo, respectively. LCOS incidence did not differ significantly between the levosimendan and placebo groups (10 [10.6%] versus 18 [19.4%] patients, respectively; 95% confidence interval [CI] 0.19–1.13; p = 0.090) nor did 90-day mortality (3 [3.2%] versus 4 [4.3%] patients, CI 0.14–3.69, p = 0.693), duration of mechanical ventilation (median, 47.5 h and 39.5 h, respectively; p = 0.532), ICU stay (median, 114.5 h and 118 h, respectively; p = 0.442), and hospital stay (median, 20 days and 20 days, respectively; p = 0.806). The incidence of hypotension and cardiac arrhythmia did not differ significantly between the groups. Levels of levosimendan fell rapidly without any plateau in plasma concentrations during infusion. A multiple logistic regression indicated that randomization to the levosimendan group was a predictor of LCOS. Prophylactic levosimendan administration was safe in pediatric patients and had some benefit to postoperative hemodynamic parameters, but failed to provide significant benefit with respect to LCOS or 90-day mortality relative to placebo. Name of the registry: Safety evaluation and therapeutic effect of levosimendan on the low cardiac output syndrome in patients after cardiopulmonary bypass. Trial registration number: ChiCTR1800016594. Date of registration: 11 June 2018. URL of trial registry record: http://www.chictr.org.cn/index.aspx

The surviving sepsis campaign recommends consideration for extracorporeal membrane oxygenation (ECMO) in refractory septic shock. We aimed to define the benefit threshold of ECMO in pediatric septic shock. Retrospective binational multicenter cohort study of all ICUs contributing to the Australian and New Zealand Paediatric Intensive Care Registry. We included patients < 16 years admitted to ICU with sepsis and septic shock between 2002 and 2016. Sepsis-specific risk-adjusted models to establish ECMO benefit thresholds with mortality as the primary outcome were performed. Models were based on clinical variables available early after admission to ICU. Multivariate analyses were performed to identify predictors of survival in children treated with ECMO. Five thousand sixty-two children with sepsis and septic shock met eligibility criteria, of which 80 (1.6%) were treated with veno-arterial ECMO. A model based on 12 clinical variables predicted mortality with an AUROC of 0.879 (95% CI 0.864–0.895). The benefit threshold was calculated as 47.1% predicted risk of mortality. The observed mortality for children treated with ECMO below the threshold was 41.8% (23 deaths), compared to a predicted mortality of 30.0% as per the baseline model (16.5 deaths; standardized mortality rate 1.40, 95% CI 0.89–2.09). Among patients above the benefit threshold, the observed mortality was 52.0% (13 deaths) compared to 68.2% as per the baseline model (16.5 deaths; standardized mortality rate 0.61, 95% CI 0.39–0.92). Multivariable analyses identified lower lactate, the absence of cardiac arrest prior to ECMO, and the central cannulation (OR 0.31, 95% CI 0.10–0.98, p = 0.046) as significant predictors of survival for those treated with VA-ECMO. This binational study demonstrates that a rapidly available sepsis mortality prediction model can define thresholds for survival benefit in children with septic shock considered for ECMO. Survival on ECMO was associated with central cannulation. Our findings suggest that a fully powered RCT on ECMO in sepsis is unlikely to be feasible.

Editorial The goal of modern health care is to improve outcomes and reduce costs. Centralisation, defined as the reorganisation of healthcare services into fewer specialised units, is one of the common strategies. The rationale is that increasing the volume and variety of cases promotes the development of highly specialised services, increases experience and efficiency, facilitates training, limits costs and reduces clinical variability [1,2,3]. The notion of focussing on volume to promote specialist expertise is well established in surgery. There is a clear association between volume of surgical cases and survival, even if workload increases [1]. Obvious examples are large cardiovascular units and trauma centres. The reasons for better outcomes are multifactorial, including expert teams, a high-level infrastructure with evidence-based protocols and standardised governance processes, state-of-the-art diagnostic tests and therapies, and cost-effective purchasing (Table 1). Table 1 Benefits and challenges of centralised and de-centralised provision of critical careFull size table Critical care medicine is a complex, expensive and resource intensive specialty where centralisation has also received attention. A retrospective study of >20,000 mechanically ventilated, non-surgical adult patients concluded that ICU and hospital mortality were significantly lower in high-volume hospitals [4]. The “Conventional ventilatory support versus Extracorporeal membrane oxygenation (ECMO) for Severe Adult Respiratory failure” (CESAR) trial showed that outcomes were better in all patients transferred to the specialist unit regardless of whether they received ECMO or not [5]. Neurocritical care units have been shown to improve patient outcomes and reduce mortality, resource utilisation and costs compared to district hospitals [6]. Apart from specialist-led care, rapid access to neurosurgical intervention plays a role. Finally, a review of centralised paediatric critical care in Australia revealed that the odds ratio of mortality in the UK versus Australia was 2.09 [7]. The authors estimated that 453 deaths a year in the UK could be avoided if all children requiring mechanical ventilation for >12–24 h were transferred to specialist paediatric ICUs. However, the association between volume and outcomes is not consistently seen. Data from 2812 US hospitals showed that quality of care for elderly patients with pneumonia was lower among hospitals with the highest rates of ICU admission [8]. Similarly, an analysis of > 18,000 ECMO patients revealed that mortality was higher in high-volume compared to low-volume centres [9]. Whether this represents selection bias, differences in criteria for applying ECMO or any other variation in practice is unclear. Centralisation of limited resources has other unpredictable negative effects which can be broadly categorised into factors related to the geographical distance between centres, transport, the effects on staff in non-specialist centres, and the psychological impact on the patient and their relatives. Serious in-transit critical events may occur, including equipment failure and technical problems [10,11,12]. A review of 5144 urgent land transports revealed that critical events occurred in approximately 1 in 15 transports [12]. Hypotension was the most common incident. An observational study of > 10,000 patients with potentially life-threatening conditions showed an association between journey distance to hospital and mortality after adjustment for age, sex, clinical category and illness severity [10]. A 10-km increase in distance was associated with a 1% absolute increase in mortality. In contrast, a Canadian retrospective case-cohort study did not find an association between duration of transport and hospital mortality [13]. Instead, a longer time spent by paramedics at the sending hospital was associated with shorter length of stay in the referring hospital. At an institutional level, centralisation may lead to a reduction in available specialists in regional centres and the closure of specialty programmes, resulting in reduced job satisfaction and staff morale [11]. Another drawback is the impact on families and relatives, together with longer travel times and increased costs. Furthermore, patients are removed from their local networks which makes it more challenging to organise long-term support and chronic disease management after critical illness (i.e. social service, psychological follow-up). Little is known about the patient’s perspective. Work by the Swedish National Board of Health and Welfare concluded that patients valued quality of care and treatment outcomes as the most important factors regarding centralisation of healthcare; continuity of treatment and a well-functioning care pathway were also very important [14]. To date, the discussions related to the benefits of centralisation versus de-centralisation have focused mainly on the impact on mortality and healthcare costs but less on other outcomes like ICU-acquired infections, patient and family satisfaction, risk of post-traumatic stress and quality of life. There are good reasons to explore new ways of delivering high quality patient-centred affordable care. Decentralisation of health systems is a potential alternative strategy (Table 1). It is considered to improve efficiency and quality of service as well as promoting accountability, local governance and sharing of knowledge and expertise. This shift towards integration of specialist expertise in the local environment holds great promise to improve the patient experience and facilitate training while keeping healthcare costs under control. Through telemedicine and robust electronic medical record platforms, distant care providers can interact with the clinical team and also potentially with the patient and their family so that direct round-the-clock access to specialist expertise is provided. Such a system can promote training, dissemination of knowledge and cross-fertilisation but whether it reduces variability in clinical care and improves patient outcomes and staff morale is unclear. Among the key concerns about telemedicine are the need to maintain privacy, confidentiality and security of personal data, and the risk of incorrect diagnosis or treatment. In 2019, the General Medicine Council UK commissioned Europe Economics to review the regulatory approaches to telemedicine [15]. The panel concluded that telemedicine needed to (i) deliver the same standard of care as that of face-to-face healthcare; (ii) ensure confidentiality, safety and security of the exchanged information; (iii) uphold patient safety where prescribing may be contemplated, and (iv) include the patient’s consent. The panel highlighted that the requirement to obtain patients’ consent was covered by only 11 jurisdictions across the world. In conclusion, critical care medicine of the future is likely to look very differently and determining the extent of centralisation versus de-centralisation will be necessary. As the utilisation of new technologies expands, the regulatory framework needs to evolve, too. Not applicable. 1. Chowdhury MM, Dagash H, Pierro A. A systematic review of the impact of volume of surgery and specialization on patient outcome. Br J Surg. 2007;94(2):145–61. CAS Article Google Scholar 2. Gabbe BJ, Simpson PM, Sutherland AM, et al. Improved functional outcomes for major trauma patients in a regionalized, inclusive trauma system. Ann Surg. 2012;255:1009–15. Article Google Scholar 3. Metcalfe D, Bouamra O, Parsons NR, et al. Effect of regional trauma centralization on volume, injury severity and outcomes of injured patients admitted to trauma centres. Br J Surg. 2014;101:959–64. CAS Article Google Scholar 4. Kahn JM, Goss CH, Heagerty PJ, et al. Hospital volumes and the outcomes of mechanical ventilation. N Engl J Med. 2006;355:41–50. CAS Article Google Scholar 5. Peek G, Mugford M, Tiruvoipati T, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374:1351–63. Article Google Scholar 6. Suarez JI. Outcome in neurocritical care: advances in monitoring and treatment and effect of a specialized neurocritical care team. Crit Care Med. 2006;34:S232–8. Article Google Scholar 7. Pearson G, Shann F, Barry P, et al. Should paediatric intensive care be centralised? Trent versus Victoria. Lancet. 1997;349:1213–7. CAS Article Google Scholar 8. Sjoding MW, Prescott HC, Wunsch H, Iwashyna TJ, Cooke CR. Hospitals with the highest intensive care utilization provide lower quality pneumonia care to the elderly. Crit Care Med. 2015;43(6):1178–86. Article Google Scholar 9. Bailey KL, Downey P, Sanaiha Y, et al. National trends in volume-outcome relationships for extracorporeal membrane oxygenation. J Surg Res. 2018;231:421–7. Article Google Scholar 10. Nicholl J, West J, Goodacre S, et al. The relationship between distance to hospital and patient mortality in emergencies: an observational study. Emerg Med J. 2007;24:665–8. Article Google Scholar 11. Singh JM, MacDonald RD. Pro/con debate: do the benefits of regionalized critical care delivery outweigh the risks of interfacility patient transport? Crit Care. 2009;13(4):219. Article Google Scholar 12. Singh JM, MacDonald RD, Ahghari M. Critical events during land-based interfacility transport. Ann Emerg Med. 2014;64(1):9–15. Article Google Scholar 13. Belway D, Dodek PM, Keenan SP, et al. The role of transport intervals in outcomes for critically ill patients who are transferred to referral centers. J Crit Care. 2006;21:8–17. Article Google Scholar 14. https://www.gmc-uk.org/about/what-we-do-and-why/data-and-research/research-and-insight-archive/regulatory-approaches-to-telemedicine. Accessed 24 Nov 2019 15. Svederud I, Virhage M, Medin E, Grundström J, Friberg S, Ramsberg J. Patient perspectives on centralisation of low volume, highly specialised procedures in Sweden. Health Policy. 2015;119(8):1068–75. Article Google Scholar Download references Not applicable. Funding Not applicable. Affiliations Department of Critical Care, King’s College London, Guy’s and St Thomas’ NHS Foundation Trust, London, SE1 7EH, UK Marlies Ostermann Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium Jean-Louis VincentAuthors Search for Marlies Ostermann in: PubMed • Google Scholar Search for Jean-Louis Vincent in: PubMed • Google Scholar Contributions Both authors contributed equally to the manuscript. Both authors approved the final manuscript. Corresponding author Correspondence to Marlies Ostermann. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Ostermann, M., Vincent, J. How much centralization of critical care services in the era of telemedicine?. Crit Care 23, 423 (2019) doi:10.1186/s13054-019-2705-1 Download citation Received 16 November 2019 Accepted 16 December 2019 Published 26 December 2019 DOI https://doi.org/10.1186/s13054-019-2705-1

Dear editor, We read with great interest of the report by Coppola and colleagues [1] about the presence and possible factors of dynamic hyperinflation and intrinsic positive end-expiratory pressure (PEEP) in severe acute respiratory distress syndrome (ARDS) patients. They suggested that in sedated, paralyzed ARDS patients without a known obstructive disease, the amount of intrinsic PEEP during lung-protective ventilation is negligible and does not influence respiratory mechanical properties. However, some details about who, when, and how for monitoring and managing dynamic hyperinflation and intrinsic PEEP in ARDS patients is still needed to be defined. First, who needs more attention for monitoring dynamic hyperinflation and intrinsic PEEP with ARDS? During lung-protective ventilation in ARDS, when a respiratory rate (RR) up to a maximal of 35 breaths/min was needed to provide a minute ventilation that minimized hypercapnia and respiratory acidosis, the shortening of the expiratory time consequent to the higher RR may generate substantial intrinsic PEEP [2, 3]. In the study by Coppola et al. [1], average RR was only 16 breaths/min. Therefore, severe ARDS patients with a high RR requirement for hypercapnia and respiratory acidosis are at high risk of dynamic hyperinflation and intrinsic PEEP, which needs more investigation. The second question is when should we focus on dynamic hyperinflation and intrinsic PEEP with ARDS? In the article reported by Coppola et al. [1], only paralyzed patients in the very early stage of ARDS were investigated. However, in deeply sedated ARDS patients without paralysis, the respiratory entrainment with reverse triggering may cause breath stacking in deeply sedated non-paralyzed ARDS patient, which led to volumes and pressures that were incompatible with lung-protective ventilation, and may lead to intrinsic PEEP and dynamic hyperinflation [4]. Finally, how to recognize and calculate intrinsic PEEP in patients with ARDS, especially in patients without neuromuscular blocking agents. In Coppola’s report [1], intrinsic PEEP was defined as the total PEEP minus the external PEEP, and intrinsic PEEP decreased when external PEEP was raised. Expiratory flow limitation and airway closure may be two factors mainly responsible for the development of intrinsic PEEP in ARDS patients, and the response to a raising external PEEP might be due to airway closure and flow limitation at low PEEP and an airway opening pressure at high PEEP. Thus, reliability of the calculation for intrinsic PEEP in Coppola’s study may not be valid under condition of flow limitation, which can occur in patients with ARDS. A measurement of intrinsic PEEP at zero PEEP should be more accurate. Furthermore, for patients with spontaneous breath, an increasing number of reports indicate that measurement of intrinsic PEEP can be obtained both with advanced monitoring systems (esophageal and gastric manometry, diaphragm electromyography, electrical impedance tomography) and, with some limitations, with simple airways occlusion maneuvers in patients with spontaneous breath [5]. Therefore, details about who, when, and how to investigate intrinsic PEEP and dynamic hyperinflation in ARDS patients are still needed to be evaluated. Further researches are needed for early recognition and better measurement of intrinsic PEEP and dynamic hyperinflation in this population.AuthorGroup Author AuthorName GivenNameCoppola FamilyNameSilvia Author AuthorName GivenNameCaccioppola FamilyNameAlessio Author AuthorName GivenNameFroio FamilyNameSara Author AuthorName GivenNameFerrari FamilyNameErica Author AuthorName GivenNameGotti FamilyNameMiriam Author AuthorName GivenNameFormenti FamilyNamePaolo Author AuthorName GivenNameChiumello FamilyNameDavide Contact Emailchiumello@libero.it Affiliation OrgIDgrid.415093.a OrgDivisionDepartment of Anesthesia and Intensive Care, ASST Santi Paolo e Carlo OrgNameSan Paolo University Hospital OrgAddress StreetVia Di Rudinì CityMilan CountryItaly Affiliation OrgID0000 0004 1757 2822 OrgIDgrid.4708.b OrgDivisionDepartment of Health Sciences OrgNameUniversity of Milan OrgAddress CityMilan CountryItaly Affiliation OrgID0000 0004 1757 2822 OrgIDgrid.4708.b OrgDivisionCoordinated Research Center on Respiratory Failure OrgNameUniversity of Milan OrgAddress CityMilan CountryItaly We appreciate the time the authors have taken to read our recent article published in critical care on the dynamic hyperinflation and intrinsic positive end-expiratory pressure in ARDS patients [1]. The development of dynamic hyperinflation and intrinsic PEEP is usually generated by the presence of one or by a combination of these variables such as the expiratory flow limitation, the increase in expiratory resistance, the alteration in respiratory mechanics (resistance and compliance) and the ventilator setting (respiratory rate) [3, 6]. Concerning the respiratory rate in promoting the dynamic hyperinflation, we found that the respiratory rate in our population was very similar to that found by Bellani et al. in the “Lung Safe” study (18 vs. 18 bpm, respectively), thus we can assume that our data reflect the common management of ARDS patients [7]. We completely agree that the higher is the respiratory rate, the higher is the possibility to increase dynamic hyperinflation and the intrinsic PEEP [3, 6]. Our patients were sedated and paralyzed, thus there was no double trigger or any form of asynchrony which could have increased the tidal volume or minute ventilation; moreover, the ventilatory setting was maintained fixed throughout the entire study period. We measured the intrinsic PEEP by the occlusion of the airway at the end expiration for a period of 3–5 s, this pressure should represent the average pressure (static intrinsic PEEP) in the different lung regions. Although we did not measure the expiratory flow limitation based on the pressure volume loop, the intrinsic PEEP did not clinically change by increasing PEEP suggesting a minimal role of expiratory flow limitation in the development of intrinsic PEEP [8]. Not applicable. 1. Coppola S, Caccioppola A, Froio S, Ferrari E, Gotti M, Formenti P, Chiumello D. Dynamic hyperinflation and intrinsic positive end-expiratory pressure in ARDS patients. Crit Care. 2019;23(1):375. Article Google Scholar 2. de Durante G, del Turco M, Rustichini L, Cosimini P, Giunta F, Hudson LD, Slutsky AS, Ranieri VM. ARDSNet lower tidal volume ventilatory strategy may generate intrinsic positive end-expiratory pressure in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2002;165(9):1271–4. Article Google Scholar 3. Richard JC, Brochard L, Breton L, Aboab J, Vandelet P, Tamion F, Maggiore SM, Mercat A, Bonmarchand G. Influence of respiratory rate on gas trapping during low volume ventilation of patients with acute lung injury. Intensive Care Med. 2002;28(8):1078–83. Article Google Scholar 4. Bourenne J, Guervilly C, Mechati M, Hraiech S, Fraisse M, Bisbal M, Roch A, Forel JM, Papazian L, Gainnier M. Variability of reverse triggering in deeply sedated ARDS patients. Intensive Care Med. 2019;45(5):725–6. Article Google Scholar 5. Grasselli G, Brioni M, Zanella A. Monitoring respiratory mechanics during assisted ventilation. Curr Opin Crit Care. 2019;25:000–000. Epub ahead of print. https://doi.org/10.1097/MCC.0000000000000681. 6. Marini JJ. Dynamic hyperinflation and auto–positive end-expiratory pressure. Am J Respir Crit Care Med. 2011 Oct 1;184(7):756–62. Article Google Scholar 7. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788–800. CAS Article Google Scholar 8. Koutsoukou A, Armaganidis A, Stavrakaki-Kallergi C, Vassilakopoulos T, Lymberis A, Roussos C, et al. Expiratory flow limitation and intrinsic positive end-expiratory pressure at zero positive end-expiratory pressure in patients with adult respiratory distress syndrome. Am J Respir Crit Care Med. 2000 May;161(5):1590–6. CAS Article Google Scholar Download references None. Funding None. Affiliations Department of Critical Care Medicine, The Sixth Hospital of Guiyang, Guiyang City, Guizhou Province, China Heyan Wang Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, 100020, China Hangyong HeAuthors Search for Heyan Wang in: PubMed • Google Scholar Search for Hangyong He in: PubMed • Google Scholar Contributions HW and HH are responsible for the study design and writing, and this manuscript is approved by HH. Both authors read and approved the final manuscript. Corresponding authors Correspondence to Hangyong He or Chiumello Davide. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Comment on: Silvia Coppola, Alessio Caccioppola, Sara Froio, Erica Ferrari, Miriam Gotti, Paolo Formenti and Davide Chiumello. Dynamic hyperinflation and intrinsic positive end-expiratory pressure in ARDS patients. Critical Care 2019, 23:375(https://doi.org/10.1186/s13054-019-2611-6. Published on: 27 November 2019) This comment refers to the article available at https://doi.org/10.1186/s13054-019-2611-6 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Wang, H., He, H. Dynamic hyperinflation and intrinsic PEEP in ARDS patients: who, when, and how needs more focus?. Crit Care 23, 422 (2019) doi:10.1186/s13054-019-2713-1 Download citation Received 01 December 2019 Accepted 17 December 2019 Published 23 December 2019 DOI https://doi.org/10.1186/s13054-019-2713-1

To the editor With interest we read the letter by Rilinger and coworkers who reported retrospective data on 18 patients with severe Pneumocystis carinii pneumonia (PcP)-associated adult respiratory distress syndrome (ARDS) supported with extracorporeal membrane oxygenation (ECMO) [1]. Overall hospital survival was 22% and with 50 vs. 8%, considerably more favorable in HIV than with other underlying immunosuppressive conditions. The authors concluded that ECMO support should mainly be considered for HIV-associated PcP. Recently, our group has also reported the use of ECMO in this specific ARDS cohort [2]. The cohorts are strikingly similar in terms of group size (16 in our study), observation period (10 years vs. 8 years), relation of HIV to non-HIV patients, and most demographic characteristics including age, BMI, and importantly ARDS severity. However, the overall hospital survival rate was 31% in our series and we did not observe an inferior survival in non-HIV patients compared to HIV patients (30 vs 33%, p = 0.51, Fig. 1). Fig. 1 Survival in intubated vs. awake and in HIV vs. no HIV patients with PcP-associated ARDS receiving ECMO support. Kaplan-Meier graphs showing the 40-day survival course in awake (n = 6) and intubated (n = 10), HIV (n = 6) and no HIV (n = 10) patients, as well as all VV-ECMO patients with PcP-associated ARDS (mortality awake ECMO 2/6, 33% vs. intubated ECMO 9/10, 90%, p = 0.01, mortality HIV patients 4/6, 67% vs. no HIV patients 7/10, 70%, p = 0.51)Full size image In contrast to Rilinger’s cohort, we employed a concept called “awake ECMO” in a subset of patients, who were conscious and spontaneously breathing during ECMO. Of note, 4 of the 6 patients, who primarily received awake ECMO support, survived until discharge from the hospital (67%) with better survival compared to primarily intubated ECMO patients (10%, p = 0.011). The awake ECMO strategy was a predictor for survival in our overall cohort of PcP patients (OR 18, 95% CI 1.2–260.9, p = 0.034), with a comparable proportion of HIV (2/6, 33%) and non-HIV patients (4/10, 40%). Despite the inherent limitations on non-controlled observations and small sample size, we think that the use of an awake ECMO concept may partially explain the better survival rate in our cohort. Using awake ECMO might avoid complications associated with sedation and prolonged invasive mechanical ventilation such as pneumothorax, ventilator-associated pneumonia, ventilator-induced lung injury, systemic inflammation, and multi-organ damage [3, 4]. PcP usually leads to an isolated single organ failure without accompanying systemic complications such as septic shock, thus perhaps presenting an ideal scenario for consideration of an awake ECMO strategy [5]. Rilinger’s cohort appears comparable in this regard. Although not reporting on the necessity of hemodynamic support measures, a rather low degree of extra-pulmonary organ failure indicated by moderate SOFA scores and low proportions of renal replacement therapy were reported. We therefore believe that an awake ECMO strategy should be further explored in patients with PcP and ARDS. Not applicable. 1. Rilinger J, Staudacher DL, Rieg S, Duerschmied D, Bode C, Wengenmayer T. Extracorporeal membrane oxygenation in Pneumocystis jirovecii pneumonia: outcome in HIV and non-HIV patients. Crit Care. 2019;23(1):356. Article Google Scholar 2. Stahl K, Schenk H, Seeliger B, Wiesner O, Schmidt JJ, Bauersachs J, et al. Extracorporeal membrane oxygenation for acute respiratory distress syndrome due to Pneumocystis pneumonia. Eur Respir J. 2019;54(3):1900410. Article Google Scholar 3. Langer T, Santini A, Bottino N, Crotti S, Batchinsky AI, Pesenti A, et al. “Awake” extracorporeal membrane oxygenation (ECMO): pathophysiology, technical considerations, and clinical pioneering. Critical Care. 2016;20(1):150. Article Google Scholar 4. Curley GF, Laffey JG, Zhang H, Slutsky AS. Biotrauma and ventilator-induced lung injury: clinical implications. Chest. 2016;150(5):1109–17. Article Google Scholar 5. Schmidt JJ, Lueck C, Ziesing S, Stoll M, Haller H, Gottlieb J, Eder M, Welte T, Hoeper M, Sherag A, David S. Clinical course, treatment and outcome of Pneumocystis pneumonia in immunocompromised adults: a retrospective analysis over 17 years. Critical Care. 2018;22:307. Article Google Scholar Download references Not applicable. Funding SD is supported by the German Research Foundation (DA 1209/4-3). Affiliations Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany Klaus Stahl Department of Respiratory Medicine and German Centre of Lung Research (DZL), Hannover Medical School, Hannover, Germany Benjamin Seeliger  & Marius M. Hoeper Department of Nephrology and Hypertension, Hannover Medical School, Carl-Neuberg-Str.1, 30625, Hannover, Germany Sascha DavidAuthors Search for Klaus Stahl in: PubMed • Google Scholar Search for Benjamin Seeliger in: PubMed • Google Scholar Search for Marius M. Hoeper in: PubMed • Google Scholar Search for Sascha David in: PubMed • Google Scholar Contributions KS, BS, MMH, and SD wrote the manuscript. All authors read and approved the final manuscript. Corresponding author Correspondence to Sascha David. Ethics approval and consent to participate Not applicable. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This comment refers to the article available at https://doi.org/10.1186/s13054-019-2661-9. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Stahl, K., Seeliger, B., Hoeper, M.M. et al. “Better be awake”—a role for awake extracorporeal membrane oxygenation in acute respiratory distress syndrome due to Pneumocystis pneumonia. Crit Care 23, 418 (2019) doi:10.1186/s13054-019-2703-3 Download citation Received 29 November 2019 Accepted 12 December 2019 Published 23 December 2019 DOI https://doi.org/10.1186/s13054-019-2703-3

Dear Editor, We have read the recent article written by Gershkovich et al. [1]. In this paper, the authors sought to examine the outcomes of hospitalized hematologic oncology patients requiring rapid response system (RRS) activation after clinical deterioration and to identify the factors that are independently associated with in-hospital mortality. The authors concluded that hematologic oncology patients who are admitted to the hospital and suffer an acute deterioration experience high rates of ICU admission and in-hospital mortality. In recent years, there has been an increase in the number of hematologic oncology patients admitted to ICUs. Currently, this condition is no longer a criterion to dismiss admission to the ICU [2]. Due to the continuous increase in the number of these patients and the complexity of their disease, we developed in 2012 a new strategy to optimize the management of this type of patients. We considered that RRS did not reflect accurately the severity of their condition. To date, the role of these alert systems is not yet clearly established [1]. Our strategy is based on daily multidisciplinary ward rounds with hematologists and intensivists in order to identify the high-risk patients and to admit them early to the ICU. The association between early versus late ICU admission and improved survival in hematologic oncology patients has been previously established [3]. Our data before (2000–2011) and after (2012–2016) implementation shows the following: 1. An 8% increase in the total number of admissions to critical care after implementation 2. Reduction of in-ICU mortality, 90-day mortality, and post 90-day mortality (44%, 54%, and 62% in the 2012–2016 period) as compared with the pre-implementation period (53%, 61%, and 66%) According to Azoulay et al. [3], teamwork and high-quality communication between hematologists and intensivists improve patient management. In our center, this new strategy of early admission of high-risk hematologic oncology patients resulted in a higher number of admissions and a lower mortality both in the ICU and after ICU and hospital discharge. These promising outcomes have led to a new collaboration agreement with the Oncology Department with the final aim of replicating these results in patients with solid tumors. Since the RRS has not yet demonstrated improved outcomes in the hematologic oncology patients, we believe that our model could be a valid alternative to those by facilitating an early admission to critical care, improving outcomes and being cost neutral. The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request. 1. Gershkovich B, Fernando SM, Herritt B, Castellucci LA, Rochwerg B, Munshi L, et al. Outcomes of hospitalized hematologic oncology patients receiving rapid response system activation for acute deterioration. Crit Care. 2019;23:286. Article Google Scholar 2. Azoulay E, Soares M, Darmon M, Benoit D, Pastores S, Afessa B. Intensive care of the cancer patient: recent achievements and remaining challenges. Ann Intensive Care. 2011;1(1):5. Article Google Scholar 3. Azoulay E, Pène F, Darmon M, Lengliné E, Benoit D, Soares M, et al. Managing critically ill hematology patients: time to think differently. Blood Rev. 2015;29(6):359–67. Article Google Scholar Download references Not applicable Funding None Affiliations Servicio de Medicina Intensiva, Hospital Universitario La Paz-Carlos III-Cantoblanco, IdiPAZ, Paseo de la Castellana 261, 28046, Madrid, Spain Belén Civantos , José Manuel Añón , Santiago Yus , María José Asensio  & Abelardo García-de-Lorenzo CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain José Manuel AñónAuthors Search for Belén Civantos in: PubMed • Google Scholar Search for José Manuel Añón in: PubMed • Google Scholar Search for Santiago Yus in: PubMed • Google Scholar Search for María José Asensio in: PubMed • Google Scholar Search for Abelardo García-de-Lorenzo in: PubMed • Google Scholar Contributions BC, MJA, and AGDL contributed to the initial concept and design. BC, SY, and JMA participated in the data analysis and the final draft of the manuscript. All authors read and approved the final manuscript. Authors’ information Not applicable Corresponding author Correspondence to Belén Civantos. Ethics approval and consent to participate Comité Ético de Investigación Clínica (Ethical Committee of Clinical Research), Hospital Universitario La Paz, IdiPAZ, Madrid, Spain. Reference number CEIm: PI-3894 Consent for publication Not applicable Competing interests The authors declare that they have no competing interest. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This comment refers to the article available at https://doi.org/10.1186/s13054-019-2568-5. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Civantos, B., Añón, J.M., Yus, S. et al. Outcomes of hospitalized hematologic oncology patients receiving rapid response system activation for acute deterioration: another time, another way. Crit Care 23, 419 (2019) doi:10.1186/s13054-019-2714-0 Download citation Received 16 November 2019 Accepted 17 December 2019 Published 23 December 2019 DOI https://doi.org/10.1186/s13054-019-2714-0 Keywords Malignancy Critical care Hematology Mortality

Transcranial Doppler (TCD) is a bedside, low-cost, and non-invasive technique able to evaluate cerebral hemodynamics [1]; the implementation of transcranial color-coded duplex sonography (TCCS) aids in evaluating the brain anatomy and intracranial lesions [2], real-time monitoring of “basic” (flow velocity (FV) and pulsatility index (PI)) as well as “advanced” TCD-derived parameters (Table 1; Fig. 1). In practice, we use a 2-MHz probe, and most information is obtained by insonating the middle cerebral artery through the temporal window; other windows include the transorbital, occipital, and submandibular windows. TCCD has the advantage to provide a direct visualization of the cerebral anatomy vessels and allow angle correction to assess FV [2]. TCD/TCCD practice is part of the standard training in our institution, and examinations are routinely performed by the medical staff. Table 1 Common parameters derived from transcranial DopplerFull size table Fig. 1 Simplified algorithms on the use of TCD to assess intracranial hypertension, brain death, autoregulation, and cerebral vasospasm in clinical practice. PI, pulsatility index; Vd, diastolic flow velocity; Vm, mean flow velocity; Vs, systolic flow velocity; LR, Lindegaard ratio; CCA, cerebral circulatory arrest. *The three reported images represent reverberating flow (top), systolic pikes (middle), and no flow (bottom), respectivelyFull size image We discussed herein on how we use TCD in neuro-critically ill patients for hemodynamic indications; some of these proposals could also be used in non-brain injured critically ill patients at a high risk of cerebral complications. When the indications for invasive intracranial pressure (ICP) monitoring are met, we recommend intraparenchymal or intraventricular probes, as TCD cannot substitute invasive ICP measurement [3]. However, when indications are unclear or invasive methods are not available (i.e., low-income countries) or contraindicated (i.e., severe coagulopathy), we use TCD as a “triage” tool to non-invasively discriminate patients who are at risk of developing intracranial hypertension [1, 4, 5]. We do not rely on only PI (i.e., PI > 1.4), because other conditions (Additional file 1: Table S1) could affect this parameter [2]. As such, after having considered these conditions, we use the combination of elevated PI and low diastolic FV (< 20 cm/s) to suggest elevated ICP at the bedside. Moreover, we also estimate ICP using formulas combining FV and blood pressure [5, 6], but only as “confirmatory” findings before additional validation of their accuracy will be available. Finally, we perform repeated TCD assessment rather than a single examination (i.e., every 1–2 h) to better understand the changes in the brain hemodynamics following an increase in ICP or after specific ICP-directed therapies. Although the diagnosis of brain death is based on neurological examination, we use routinely TCD as an ancillary test to demonstrate the absence of cerebral blood flow (CBF) [7]. We use one of the following TCD patterns to determine “cerebral” circulatory arrest (CCA): reverberating flow, systolic spikes, and disappearance of previously recorded FV [2, 7]. According to local practices, when we perform TCD and analyze the waveforms suggesting impending CCA, all the vessels of the circle of Willis through the trans-temporal and occipital windows are examined, as only the detection of the abovementioned flow patterns in all the major intracranial vessels is consistent for brain death [8]. When no intracranial signal is found but brain death criteria are met, we perform a brain CT perfusion or angiography to detect CCA. We assess cerebral autoregulation (CA) at the bedside as altered CA is related with a poor outcome in many diseases and may increase the risk of cerebral damage [9]. In case of impaired CA, we use TCD to target blood pressure to a level corresponding to the patient’s individual optimal autoregulatory status. The most simple methods to assess CA at the bedside are (a) the static autoregulatory index [9], which is obtained by calculating the percentage of changes in cerebrovascular resistance (CVR = mean arterial pressure/mean FV) after changes in arterial blood pressure, or (b) the transient hyperemic response test (if there are no risks of embolism or hemodynamic instability), which is obtained by compressing the carotid artery and calculating the percentage of change in systolic FV from the baseline (an increase ≥ 10% is considered as intact CA) [10]. Clinicians have to consider that the monitoring of dynamic autoregulation, using the mean flow index (Mx), which is calculated as the correlation coefficient indices between FV and CPP during spontaneous fluctuations in blood pressure, would be more accurate to assess CA [11]. However, this method requires a specific software and a higher competency to interpret the data to improve patients’ management. Detection of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is crucial as this is one of the main determinants of delayed cerebral ischemia and poor neurological outcome in this setting [12]. Although angiography remains the gold standard, we use TCD daily to assess vasospasm, to guide additional investigations, and to monitor the clinical treatment. Indeed, we evaluate the constriction of the cerebral vessels that is associated with a progressive increase of mean FV [13]. In daily practice, we perform serial TCD examinations (one to two/day) in all SAH patients, together with close neurological clinical monitoring; we use TCD for the assessment of all main intracranial vessels and, using TCCD, investigate different segments of such vessels, as vasospasm could be extremely localized. In the presence of clinical suspicious of vasospasm (i.e., neurological deterioration), we use the cutoff of MCA mean flow velocity (mFV) > 200 cm/s [14] to immediately initiate therapy and perform additional confirmatory imaging tests (i.e., cerebral CT perfusion or angiography). If mFV > 120 cm/s and < 200 cm/s, we assess the mFV in the extracranial internal carotid artery using the submandibular window and calculate the Lindegaard ratio (LR; Table 1) to differentiate vasospasm from cerebral hyperemia [15]. As TCD has a sensitivity of 90% (95% confidence intervals [CIs] 77–96%), specificity of 71% (95% CI 51–84%), positive predictive value of 57% (95% CI 38–71%), and negative predictive value of 92% (95% CI 83–96%) to diagnose vasospasm of MCA [13], we still perform cerebral CT perfusion or angiography in case of clinical suspicion of vasospasm with mFV below < 120 cm/s. For other intracranial vessels, in the absence of validated mFV cutoffs, we combine clinical examination, repeated TCD showing a progressive increase in FV, and CT perfusion to detect vasospasm. We often use TCD to monitor brain hemodynamics in critically ill patients. Future TCD development, such as the assessment of the compliance of arterial and cerebrospinal fluid compartment as well as critical capillary closing pressure, will further expand its use in this setting [1]. Not applicable CA: Cerebral autoregulation CBF: Cerebral blood flow CPP: Cerebral perfusion pressure CVR: Cerebrovascular resistance CT: Computed tomography FV: Flow velocity ICP: Intracranial pressure LR: Lindegaard ratio mFV: Mean flow velocity Mx: Mean flow index NIC: Neurointensive care PI: Pulsatility index sARI: Static autoregulatory index sROR: Static rate of regulation SAH: Subarachnoid hemorrhage TCD: Transcranial Doppler TBI: Traumatic brain injury 1. Robba C, Cardim D, Sekhon M, Budohoski K, Czosnyka M. Transcranial Doppler: a stethoscope for the brain-neurocritical care use. J Neurosci Res. 2018;96:720–30. CAS Article Google Scholar 2. Robba C, Goffi A, Geeraerts T, Cardim D, Via G, Czosnyka M, et al. Brain ultrasonography: methodology, basic and advanced principles and clinical applications. A narrative review. Intensive Care Med. 2019;45:913–27. Article Google Scholar 3. Ract C, Le Moigno S, Bruder N, Vigué B. Transcranial Doppler ultrasound goal-directed therapy for the early management of severe traumatic brain injury. Intensive Care Med. 2007;33(4):645–51 Epub 2007 Feb 27. Article Google Scholar 4. Robba C, Cardim D, Tajsic T, Pietersen J, Bulman M, Donnelly J, et al. Ultrasound non-invasive measurement of intracranial pressure in neurointensive care: a prospective observational study. PLoS Med. 2017;14:e1002356. Article Google Scholar 5. Rasulo FA, Bertuetti R, Robba C, Lusenti F, Cantoni A, Bernini M, et al. The accuracy of transcranial Doppler in excluding intracranial hypertension following acute brain injury: a multicenter prospective pilot study. Crit Care. 2017;21:44. Article Google Scholar 6. Robba C, Donnelly J, Bertuetti R, Cardim D, Sekhon MS, Aries M, et al. Doppler non-invasive monitoring of ICP in an animal model of acute intracranial hypertension. Neurocrit Care. 2015;23:419–26. Article Google Scholar 7. Consensus Group on Transcranial Doppler in Diagnosis of Brain Death. Latin American consensus on the use of transcranial Doppler in the diagnosis of brain death. Rev Bras Ter Intensiva. 2014;26(3):240–52. Article Google Scholar 8. Kuo J, Chen C, Chio C, Chang C, Wang C, Yang C, et al. Time dependent validity in the diagnosis of brain death using transcranial Doppler sonography. J Neurol Neurosurg Psychiatry. 2006;77:646–9. Article Google Scholar 9. Donnelly J, Aries MJ, Czosnyka M. Further understanding of cerebral autoregulation at the bedside: possible implications for future therapy. Expert Rev Neurother. 2015;15:169–85. CAS Article Google Scholar 10. Panerai RB. Transcranial Doppler for evaluation of cerebral autoregulation. Clin Auton Res. 2009;19:197–211. Article Google Scholar 11. Czosnyka M, Smielewski P, Kirkpatrick P, Menon DK, Pickard JD. Monitoring of cerebral autoregulation in head-injured patients. Stroke. 1996;27:1829–34. CAS Article Google Scholar 12. Diringer MN, Bleck TP, Claude Hemphill J, Menon D, Shutter L, Vespa P, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care Society’s Multidisciplinary Consensus Conference. Neurocrit Care. 2011;15:211–40. Article Google Scholar 13. Kumar G, Shahripour RB, Harrigan MR. Vasospasm on transcranial Doppler is predictive of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurosurg. 2016;124:1257–64. Article Google Scholar 14. Vora Y, Suarez-Almazor M, Steinke D, Martin M, Findlay J. Role of transcranial Doppler monitoring in the diagnosis of cerebral vasospasm after subarachnoid hemorrhage. Neurosurgery. 1999;44:1237–47-8. CAS PubMed Google Scholar 15. Lindegaard KF, Nornes H, Bakke SJ, Sorteberg W, Nakstad P. Cerebral vasospasm diagnosis by means of angiography and blood velocity measurements. Acta Neurochir. 1989;100:12–24. CAS Article Google Scholar Download references Not applicable Funding No funding was provided for this study. Affiliations Policlinico San Martino, IRCCS per l’Oncologia e Neuroscienze, Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate, Università degli Studi di Genova, Genova, Italy Chiara Robba Department of Intensive Care Medicine, Erasme Hospital, Université Libre de Bruxelles (ULB), Route de Lennik, 808, 1070, Brussels, Belgium Fabio Silvio TacconeAuthors Search for Chiara Robba in: PubMed • Google Scholar Search for Fabio Silvio Taccone in: PubMed • Google Scholar Contributions FST and CR conceived the study and drafted the present manuscript. Both authors read and approved the final manuscript. Corresponding author Correspondence to Fabio Silvio Taccone. Ethics approval and consent to participate Not applicable Consent for publication Not applicable Competing interests The authors declare that they have no competing interests for this manuscript. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Additional file 1: Table S1. Factors that may influence pulsatility index (PI) and flow velocities. (DOCX 13 kb) Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Robba, C., Taccone, F.S. How I use Transcranial Doppler. Crit Care 23, 420 (2019) doi:10.1186/s13054-019-2700-6 Download citation Received 26 September 2019 Accepted 11 December 2019 Published 23 December 2019 DOI https://doi.org/10.1186/s13054-019-2700-6 Keywords Transcranial Doppler Flow velocity Cerebral blood flow Neurointensive care

The use of hydroxocobalamin has long been advocated for treating suspected cyanide poisoning after smoke inhalation. Intravenous hydroxocobalamin has however been shown to cause oxalate nephropathy in a single-center study. The impact of hydroxocobalamin on the risk of acute kidney injury (AKI) and survival after smoke inhalation in a multicenter setting remains unexplored. We conducted a multicenter retrospective study in 21 intensive care units (ICUs) in France. We included patients admitted to an ICU for smoke inhalation between January 2011 and December 2017. We excluded patients discharged at home alive within 24 h of admission. We assessed the risk of AKI (primary endpoint), severe AKI, major adverse kidney (MAKE) events, and survival (secondary endpoints) after administration of hydroxocobalamin using logistic regression models. Among 854 patients screened, 739 patients were included. Three hundred six and 386 (55.2%) patients received hydroxocobalamin. Mortality in ICU was 32.9% (n = 243). Two hundred eighty-eight (39%) patients developed AKI, including 186 (25.2%) who developed severe AKI during the first week. Patients who received hydroxocobalamin were more severe and had higher mortality (38.1% vs 27.2%, p = 0.0022). The adjusted odds ratio (95% confidence interval) of AKI after intravenous hydroxocobalamin was 1.597 (1.055, 2.419) and 1.772 (1.137, 2.762) for severe AKI; intravenous hydroxocobalamin was not associated with survival or MAKE with an adjusted odds ratio (95% confidence interval) of 1.114 (0.691, 1.797) and 0.784 (0.456, 1.349) respectively. Hydroxocobalamin was associated with an increased risk of AKI and severe AKI but was not associated with survival after smoke inhalation. ClinicalTrials.gov, NCT03558646

The Irish ambulance services have traditionally transported all patients following an emergency (112/999) call, regardless of acuity, to an emergency department (ED). A proposal to introduce Treat and Referral, an established care pathway in some jurisdictions, is under active consideration in Ireland. This will present a significant change. Stakeholder engagement is recognised as an essential component of management of such change. This study has conducted a multicentre, cross-sectional survey exploring opinions on the introduction of Treat and Referral among key Irish stakeholders; consultants in emergency medicine, paramedics and advanced paramedics. Public-sector consultants in emergency medicine (EM), registered paramedics and advanced paramedics, in Ireland at the time of the study, were invited to complete an on-line survey. A significant finding was that 90% of both cohorts (EM consultants and registered paramedic practitioners) support written after-care instructions being given to referred patients, that > 83% agree that Treat and Referral will reduce unnecessary ambulance journeys and that 70% are in favour of their own family member being offered Treat and Referral. Consensus was reached between respondents that Treat and Referral would improve care and increase clinical judgement of practitioners. Differences were identified in relation to the increased availability of ambulances locally, that only adults should be included, and that research was required to extend Treat and Referral beyond the index conditions. There was no consensus on whether general practitioners (GPs) should be directly informed. This study identified that the Irish healthcare practitioners surveyed are supportive of the introduction of Treat and Referral into Ireland. It also affords healthcare policymakers the opportunity to address the concerns raised, in particular the clinical level which will be targeted for inclusion in this extended scope of practice.

Dear Editor, Necrotizing soft tissue infections (NSTIs) are a heterogeneous group of devastating diseases involving a wide variety of microorganisms and affecting different body areas. The need for individualized treatment strategies has been recently put forward in a prospective cohort study of 402 patients in which group A streptococcus (GAS) infections were associated with more frequent septic shock [1]. Early identification of patients with GAS-related NSTIs could prompt initiation of targeted interventions, including clindamycin and intravenous immunoglobulins (IVIg). These drugs might be associated with beneficial anti-toxinic properties, but the level of evidence supporting them remains low (clindamycin) or highly controversial (IVIg) [2, 3]. The only randomized clinical trial evaluating the effect of IVIg specifically in patients with NSTI could not demonstrate a benefit on a composite outcome of death and quality-of-life evaluation at 6 months [4]. As previously commented [5], only 15% (n = 13/87) of included patients eventually had a microbiologically proven GAS NSTI. This was a major limitation and early identification of patients with a high probability of GAS-associated NSTIs would thus be crucial for further studies evaluating similar interventions. A secondary analysis of a retrospective cohort including 224 patients admitted to our center for NSTI between 2006 and 2017 was conducted [6]. In accordance with the most recent guidelines, only patients with surgically confirmed NSTI were included (i.e., macroscopic appearance of tissues during operation as swollen, dull gray with a thin, brownish exudate with or without necrosis). Admission characteristics and microbiological documentation based on surgical samples, blood cultures, or subcutaneous puncture were recorded. We compared patients with a documented GAS infection to other patients regarding admission characteristics. A multivariable logistic regression model was used to identify admission characteristics associated with a subsequent GAS documentation. Among 224 patients, 60 (27%) had a GAS infection, which was monomicrobial in 39 (17%) cases. Overall, 134 (59.8%) patients were admitted to the intensive care unit during their stay, of whom 113 during the first 24 h. Ninety-one (41%) patients presented with shock (i.e., required vasopressors), and 89 (40%) required mechanical ventilation. Sixty days after admission, 51 (23%) patients had died, including 10 (17%) with GAS, and 41 (25%) with non-GAS infections (p = 0.255, Mann-Whitney test). Admission characteristics associated with GAS infections by univariable analysis were non-steroidal anti-inflammatory drug treatment before admission and leukocytosis as a continuous variable. Those inversely associated with GAS infections were immunodeficiency, the nosocomial onset of infection, and an abdominoperineal location (Table 1). After multivariable analysis, only immunodeficiency (adjusted odds ratio (aOR) = 0.29 [0.10–0.74], p = 0.015) and an abdominoperineal location (aOR = 0.06 [0.00–0.30], p = 0.007) remained associated with the absence of GAS infection (Table 1). A sensitivity analysis using “monomicrobial GAS NSTI” as the dependent variable yielded similar results, except for younger age that remained in the model after adjustment (data not shown). Immunodeficiency (n = 58) and an abdominoperineal location (n = 38) had respective positive predictive values for the absence of a GAS infection (both mono- or polymicrobial) of 90% [79–96] and 97% [86–100] (Fig. 1). Table 1 Admission characteristics associated with group A streptococcal documentationFull size table Fig. 1 Diagnostic performances of abdominoperineal location and immunodeficiency for predicting absence of group A streptococcal documentation. The three top pie charts represent the proportions of group A streptococcal documentation, abdominoperineal infections and immunodeficiency in the whole 224-patient population of surgically confirmed necrotizing soft tissue infections. The two bottom pie charts represent the proportion of group A streptococcal documentation in the subgroup of patients with abdominoperineal infections (bottom left chart) or in immunocompromised patients (bottom right chart). Diagnostic performances of an abdominoperineal location of infection and of immunodeficiency for predicting the absence of group A streptococcal documentation were calculated using a contingency table approach. Immunodeficiency encompassed active cancer, chemotherapy within the last 3 months, previous HIV infection whatever the AIDS status, the CD4 lymphocytes counts or the viral load, any immunosuppressive drugs including chronic systemic steroid treatment (whatever the dose but for at least 3 months). PPV, positive predictive value; NPP, negative predictive value; Se, sensitivity; Sp, specificityFull size image In conclusion, we retrospectively identified two simple and available upon admission clinical predictors of GAS documentation among a large cohort of surgically proven NSTIs. Our results show that NSTI patients with pre-existing immunodeficiency or an abdominal infection have a low probability of GAS infection and might thus not be suitable for inclusion in a trial assessing the effect of GAS-specific interventions. Such findings need to be assessed in a validation cohort in order to reinforce their generalizability. Improving identification upon admission of a subgroup of patients with a higher prevalence of GAS infection might help design future prospective trials aimed at assessing personalized treatment strategies [2]. The dataset used during the current study is available from the corresponding author upon reasonable request. GAS: Group A streptococcus IVIG: Intravenous immunoglobulins NSTI: Necrotizing soft tissue infection OR: Odds ratio PPV: Positive predictive value NPP: Negative predictive value Se: Sensitivity Sp: Specificity 1. INFECT study group, Madsen MB, Skrede S, Perner A, Arnell P, Nekludov M, et al. Patient’s characteristics and outcomes in necrotising soft-tissue infections: results from a Scandinavian, multicentre, prospective cohort study. Intensive Care Med. 2019;45(9):1241–51. Article Google Scholar 2. Darenberg J, Ihendyane N, Sjölin J, Aufwerber E, Haidl S, Follin P, et al. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2003;37(3):333–40. Article Google Scholar 3. Carapetis JR, Jacoby P, Carville K, Ang S-JJ, Curtis N, Andrews R. Effectiveness of clindamycin and intravenous immunoglobulin, and risk of disease in contacts, in invasive group a streptococcal infections. Clin Infect Dis Off Publ Infect Dis Soc Am. 2014;59(3):358–65. Article Google Scholar 4. Madsen MB, Hjortrup PB, Hansen MB, Lange T, Norrby-Teglund A, Hyldegaard O, et al. Immunoglobulin G for patients with necrotising soft tissue infection (INSTINCT): a randomised, blinded, placebo-controlled trial. Intensive Care Med. 2017;43(11):1585–93. Article Google Scholar 5. de Prost N, Lipman J, Mimoz O. Therapeutic targets in necrotizing soft tissue infections. Intensive Care Med. 2017;43(11):1717–9. Article Google Scholar 6. Urbina T, Hua C, Sbidian E, Bosc R, Tomberli F, Lepeule R, et al. Impact of a multidisciplinary care bundle for necrotizing skin and soft tissue infections: a retrospective cohort study. Ann Intensive Care. 2019;9(1):123. Article Google Scholar Download references The members of the Henri Mondor Hospital Necrotizing Fasciitis Group are Romain BOSC, Cécile CHAMPY, Olivier CHOSIDOW, Nicolas de PROST, Nicola DE ANGELIS, Jean-Winoc DECOUSSER, Camille GOMART, Jean-Michel GRACIES, Barbara HERSANT, Camille HUA, Raphaël LEPEULE, Alain LUCIANI, Lionel NAKAD, Alain RAHMOUNI†, Emilie SBIDIAN, Françoise TOMBERLI, Tomas URBINA, and Paul-Louis WOERTHER. Funding This work did not receive any funding. Affiliations Service de Réanimation Médicale, Hôpitaux Universitaires Henri Mondor, Assistance Publique – Hôpitaux de Paris (AP-HP), Créteil, France Tomas Urbina , Armand Mekontso Dessap  & Nicolas de Prost Service de Dermatologie, Hôpitaux Universitaires Henri Mondor, Assistance Publique – Hôpitaux de Paris (AP-HP), Créteil, France Camille Hua  & Olivier Chosidow Université Paris-Est Créteil Val de Marne (UPEC), Créteil, France Camille Hua , Paul-Louis Woerther , Armand Mekontso Dessap , Olivier Chosidow  & Nicolas de Prost Laboratoire de Bactériologie-Hygiène, Hôpitaux Universitaires Henri Mondor, Assistance Publique – Hôpitaux de Paris (AP-HP), Créteil, France Paul-Louis Woerther Équipe EA 7380 Dynamyc, Unité de Formation et de Recherche (UFR) de Médecine - site Créteil, Université Paris-Est Créteil Val-de-Marne, Créteil, France Paul-Louis Woerther  & Olivier Chosidow Groupe de Recherche Clinique CARMAS, Université Paris Est-Créteil, Créteil, France Armand Mekontso Dessap  & Nicolas de ProstAuthors Search for Tomas Urbina in: PubMed • Google Scholar Search for Camille Hua in: PubMed • Google Scholar Search for Paul-Louis Woerther in: PubMed • Google Scholar Search for Armand Mekontso Dessap in: PubMed • Google Scholar Search for Olivier Chosidow in: PubMed • Google Scholar Search for Nicolas de Prost in: PubMed • Google Scholar Contributions All authors were involved in the study conception and design and conducted the study on behalf of the Henri Mondor Hospital Necrotizing Fasciitis Group. TU and NdP collected the data, performed statistical analyses, and wrote the original draft. All authors were involved in interpreting the data and reviewing the final manuscript. All authors read and approved the final manuscript. Corresponding author Correspondence to Nicolas de Prost. Ethics approval and consent to participate The study was approved by the Comité de Protection des Personnes Ile-de-France V on March 8, 2018 (reference #16165). Patients received information during hospital stay that data abstracted from their medical charts could be used for research purposes. Consent for publication Not applicable. Competing interests PLW declares having received lecture fees and conference invitations from MSD. All other authors declare no competing interest for this work. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Urbina, T., Hua, C., Woerther, P. et al. Early identification of patients at high risk of group A streptococcus-associated necrotizing skin and soft tissue infections: a retrospective cohort study. Crit Care 23, 417 (2019) doi:10.1186/s13054-019-2708-y Download citation Received 27 November 2019 Accepted 16 December 2019 Published 21 December 2019 DOI https://doi.org/10.1186/s13054-019-2708-y Keywords Necrotizing soft tissue infection Group A streptococcus Toxin Intravenous immunoglobulins Clindamycin

The simultaneous and independent worldwide outbreaks of Candida auris invasive infections seem to be a puzzling paradox [1, 2]. Since its first isolation, C. auris has risen several questions on how it could have appeared, survived, and thrived [1]. Several speculative hypotheses have been proposed. Although misuse of antimicrobials and over-abuse of azoles have been considered the main contributors to C. auris emergence [2, 3], these do not completely justify its spreading. One of the most recent theories considers changes in climate conditions as a causative factor altering infectious disease ecology [4, 5] (Fig. 1). Humans and microbes had been influencing each other for decades. Global warming is one of the major components of climate change connected to human activities, having considerable impact on health and indirectly boosting infectious diseases. Only few fungal species can be considered as pathogenetic for humans, as the majority of mammals are remarkably resistant to invasive fungal diseases. Besides immunological responses, humans are characterized by a “thermal restriction zone” that protects against infections. Human-induced climate changes may be responsible for the progressive narrowing of this thermal restriction zone, defined as the difference between human basal temperature and environmental temperature. As C. auris is more thermotolerant if compared to other yeasts, global warming might have played an important role in its emergence [4]. Although the specific ecological niche has not been identified yet, the climatic oscillations effect on wetlands might have contributed to enrich this potential habitat, conferring thermal and salinity tolerance to C. auris non-pathogenetic naïve strains. Acquisition of virulence factors might be explained considering the potential transfer of virulence genes from other pathogenetic Candida spp. to C. auris naïve strains, or by the combination of global warming and UV radiations that might have induced genetic mutations. The upgrade of C. auris strains, from saprophyte to pathogenetic yeasts, has witnessed an intermediate avian host, thus permitting its transmission to humans. Overtime, genetic and epigenetic changes have led to an extreme adaptability of C. auris to different ecological niches, leading to the development of persistent outbreaks in healthcare settings [4, 5]. Fig. 1 Global warming and the climate changes theory for C. auris emergence and spread. Rising ambient temperatures (caused by human activities) might have selected thermotolerant yeasts in wetlands; subsequently, acquiring opportunistic traits, C. auris might have spread through different ecosystems (wetlands, rural, and urban areas) thanks to intermediate avian hosts; following development of resistance and resilience through interspecies transmission, C. auris invades healthcare settings, leading to persistent outbreaks and causing infections in susceptible critically ill patientsFull size image Although global warming seems to be an appealing theory, it is not possible to ignore other factors which might explain C. auris rise. High population densities, poor hygiene, migrations, international travels, and pollution might indeed have contributed to the persistence of C. auris and acquisition of antifungal resistance [4]. Future studies are needed to identify its evolutionary reservoirs and validate the climate changes theory. Not applicable. ICU: Intensive care unit 1. Cortegiani A, Misseri G, Fasciana T, Giammanco A, Giarratano A, Chowdhary A. Epidemiology, clinical characteristics, resistance, and treatment of infections by Candida auris. J Intensive Care. 2018;6:69. https://doi.org/10.1186/s40560-018-0342-4. Article PubMed PubMed Central Google Scholar 2. Cortegiani A, Misseri G, Chowdhary A. What’s new on emerging resistant Candida species. Intensive Care Med. 2018. https://doi.org/10.1007/s00134-018-5363-x. Article Google Scholar 3. Cortegiani A, Misseri G, Giarratano A, Bassetti M, Eyre D. The global challenge of Candida auris in the intensive care unit. Crit Care. 2019;23:150. https://doi.org/10.1186/s13054-019-2449-y. Article PubMed PubMed Central Google Scholar 4. Casadevall A, Kontoyiannis DP, Robert V. On the emergence of Candida auris: climate change, azoles, swamps, and birds. mBio 10:e01397-19. 2019. https://doi.org/10.1128/mBio.01397-19. 5. Jackson BR, Chow N, Forsberg K, Litvintseva AP, et al. On the origins of a species: what might explain the rise of Candida auris? J Fungi. 2019;5:58. https://doi.org/10.3390/jof5030058. Article Google Scholar Download references None. Funding None. Affiliations Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.). Section of Anesthesia, Analgesia, Intensive Care and Emergency. Policlinico Paolo Giaccone, University of Palermo, Via del vespro 129, 90127, Palermo, Italy Giovanni Misseri , Mariachiara Ippolito  & Andrea CortegianiAuthors Search for Giovanni Misseri in: PubMed • Google Scholar Search for Mariachiara Ippolito in: PubMed • Google Scholar Search for Andrea Cortegiani in: PubMed • Google Scholar Contributions GM, MI, and AC conceived the content, wrote the manuscript, and approved the last version. Corresponding author Correspondence to Andrea Cortegiani. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests GM and MI declare to have no competing interests. AC is member of the Advisory Board of Critical Care. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Misseri, G., Ippolito, M. & Cortegiani, A. Global warming “heating up” the ICU through Candida auris infections: the climate changes theory. Crit Care 23, 416 (2019) doi:10.1186/s13054-019-2702-4 Download citation Received 19 November 2019 Accepted 12 December 2019 Published 19 December 2019 DOI https://doi.org/10.1186/s13054-019-2702-4

Septic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock. We performed whole blood RNA sequencing in 21 SS, 11 CS, and 5 SC. In shock patients, blood samples were collected within 16 h from ICU admission (T1), 48 h after ICU admission (T2), and at day 7 or before discharge (T3). In controls, blood samples were available at T1 and T2. Gene expression changes over time have been studied in CS, SS, and SC separately with a paired analysis. Genes with p value < 0.01 (Benjamini-Hochberg multiple test correction) were defined differentially expressed (DEGs). We used gene set enrichment analysis (GSEA) to identify the biological processes and transcriptional regulators significantly enriched in both types of shock. In both CS and SS patients, GO terms of inflammatory response and pattern recognition receptors (PRRs) were downregulated following ICU admission, whereas gene sets of DNA replication were upregulated. At the gene level, we observed that alarmins, interleukin receptors, PRRs, inflammasome, and DNA replication genes significantly changed their expression in CS and SS, but not in SC. Analysis of transcription factor targets showed in both CS and SS patients, an enrichment of CCAAT-enhancer-binding protein beta (CEBPB) targets in genes downregulated over time and an enrichment of E2F targets in genes with an increasing expression trend. This pilot study supports, within the limits of a small sample size, the role of alarmins, PRRs, DNA replication, and immunoglobulins in the pathophysiology of circulatory shock, either in the presence of infection or not. We hypothesize that these genes could be potential targets of therapeutic interventions in CS and SS. ClinicalTrials.gov, NCT02141607. Registered 19 May 2014.

Our objectives were (1) to characterize the distribution of serum potassium levels at ICU admission, (2) to examine the relationship between dyskalemia at ICU admission and occurrence of cardiac events, and (3) to study both the association between dyskalemia at ICU admission and dyskalemia correction by day 2 on 28-day mortality. Inception cohort study from the longitudinal prospective French multicenter OUTCOMEREA database (1999–2014) 22 French OUTCOMEREA network ICUs Patients were classified into six groups according to their serum potassium level at admission: three groups of hypokalemia and three groups of hyperkalemia defined as serious hypokalemia [K+] < 2.5 and serious hyperkalemia [K+] > 7 mmol/L, moderate hypokalemia 2.5 ≤ [K+] < 3 mmol/L and moderate hyperkalemia 6 < [K+] ≤ 7 mmol/L, and mild hypokalemia 3 ≤ [K+] < 3.5 mmol/L and mild hyperkalemia 5 < [K+] ≤ 6 mmol/L. We sorted evolution at day 2 of dyskalemia into three categories: balanced, not-balanced, and overbalanced. None Of 12,090 patients, 2108 (17.4%) had hypokalemia and 1445 (12%) had hyperkalemia. Prognostic impact of dyskalemia and its correction was assessed using multivariate Cox models. After adjustment, hypokalemia and hyperkalemia were independently associated with a greater risk of 28-day mortality. Mild hyperkalemic patients had the highest mortality (hazard ratio (HR) 1.29, 95% confidence interval (CI) [1.13–1.47], p < 0.001). Adjusted 28-day mortality was higher if serum potassium level was not-balanced at day 2 (aHR = 1.51, 95% CI [1.30–1.76], p < 0.0001) and numerically higher but not significantly different if serum potassium level was overbalanced at day 2 (aHR = 1.157, 95% CI [0.84–1.60], p = 0.38). Occurrence of cardiac events was evaluated by logistic regression. Except for patients with serious hypokalemia at admission, the depth of dyskalemia was associated with increased risk of cardiac events. Dyskalemia is common at ICU admission and associated with increased mortality. Occurrence of cardiac events increased with dyskalemia depth. A correction of serum potassium level by day 2 was associated with improved prognosis.

Warfarin, a vitamin K antagonist, is a widely used medication for the treatment and prophylaxis of thromboembolic events. Patients with various clinical conditions due to warfarin overdose present to emergency departments. Although there may be serious bleeding due to a warfarin overdose, no bleeding may also be seen in some clinical conditions. Some of these bleedings may be life-threatening and result in death. Warfarin overdose and related cases of spontaneous bladder rupture are not frequently observed in the literature. We present a case of spontaneous bladder rupture due to warfarin overdose that was unexpectedly seen in a patient using warfarin for coronary artery disease and arrhythmia. A 77-year-old Caucasian male patient was admitted to the emergency department with abdominal pain, haematuria, and a reduced volume of urine lasting for three days. The patient’s amount of urine was reduced, and he came to the hospital for the first time with this complaint. The patient had local bruises on his arms and legs. From the ultrasound, retrograde cystography and computed tomography images, it was thought that there was blood accumulation due to bladder rupture to the intraperitoneal region. Spontaneous bladder rupture secondary to warfarin overdose was considered for this patient who also had an international normalized ratio (INR) level of 13.4. After the INR level was normalized with vitamin K and a prothrombin complex concentrate, the patient underwent surgery. During the operation, a catheter was placed in the bladder, and the bladder mucosa and muscle were closed separately with a primary repair performed by a urologist. The patient was discharged on the 8th postoperative day without any complications. In addition to the known findings of warfarin overdose in these patients presenting to the emergency department, we think that the emergency department staff should suspect bladder rupture, which is a fatal complication in the presence of signs such as oliguria, haematuria, anuria, abdominal pain, and syncope.

We have read with great interest the article by Pfortmueller et al. about fluid management in patients undergoing cardiac surgery [1]. This randomized double blind study showed equivalence between Ringer’s lactate solution and Ringer’s acetate solution in terms of hemodynamic stability, as well as the acid-base and ionic profiles of the two patient populations. However, they observed a higher prevalence of postoperative cardiac arrhythmia in the group receiving Ringer’s lactate solution without a change in the pH or electrolyte values. Previous work has shown that acetate-based dialysate solutions cause hemodynamic and rhythmic disruption. Acetate induces the production of cyclic adenosine monophosphate (cAMP) and cytokines that increase the synthesis of nitric oxide (NO). Studies have shown that acetate-induced NO production induces hypotension during dialysis. Noris et al. showed that the levels of NO and interleukin (IL)-1β are higher after dialysis with acetate than after dialysis with bicarbonate. They suggested that acetate-activated monocytes produce Il-1β that in turn stimulates endothelial cells to produce NO, which can result in hemodynamic instability and arrhythmias [2]. Regarding acid-base balance, it has been shown that Ringer’s lactate solution has a strong ion difference (SID) of 28 while acetate-based solutions have a SID of around 36. Infusion of Ringer’s lactate solution results in a larger reduction in pH when compared to acetate solutions. In vivo, regardless of whether a lactate- or acetate-based solution is infused, serum potassium levels do not change to a degree that could result in rhythm disturbances [3]. Pfortmueller et al. also observed a significant elevation of lactate in Ringer’s lactate solution group compared with Ringer’s acetate solution group (p = 0.0065). There is therefore a significant exogenous supply of lactate related to the type of infusion, especially when put into the complex metabolic, hemodynamic, and inflammatory context of cardiac surgery. This exogenous lactate alters the lactate to pyruvate ratio, with the consequent production of glucose at the expense of amino acids in hepatocytes [4]. In addition, the increase in lactate suggests a redox shift, with an increased nicotinamide adenine dinucleotide (reduced and oxidized forms) (NADH/NAD+) ratio in the blood and an increase in cytoplasmic pyruvate. Pyruvate uptake is closely linked to oxidative metabolism which requires adenosine triphosphate (ATP). The fall of ATP induces a leftward shift in the oxygen dissociation curve that can alter oxygen delivery and left ventricular function [5].We believe that these alterations could promote the occurrence of cardiac arrhythmias. Not applicable. cAMP: Cyclic adenosine monophosphate NO: Nitrous oxide IL-1β: Interleukin-1β SID: Strong ion difference ATP: Adenosine triphosphate NADH/NAD+: Nicotinamide adenine dinucleotide (reduced and oxidized forms) 1. Pfortmueller CA, Faeh L, Müller M, Eberle B, Jenni H, Zante B, et al. Fluid management in patients undergoing cardiac surgery: effects of an acetate- versus lactate-buffered balanced infusion solution on hemodynamic stability (HEMACETAT). Crit Care. 2019;23(1):159. https://doi.org/10.1186/s13054-019-2423-8. Article PubMed PubMed Central Google Scholar 2. Noris M, Todeschini M, Casiraghi F, Roccatello D, Martina G, Minetti L, et al. Effect of acetate, bicarbonate dialysis, and acetate-free biofiltration on nitric oxide synthesis: implications for dialysis hypotension. Am J Kidney Dis. 1998;32(1):115–24. https://doi.org/10.1053/ajkd.1998.v32.pm9669432. CAS Article PubMed Google Scholar 3. Hofmann-Kiefer KF, Chappell D, Kammerer T, Jacob M, Paptistella M, Conzen P, et al. Influence of an acetate- and a lactate-based balanced infusion solution on acid base physiology and hemodynamics: an observational pilot study. Eur J Med Res. 2012;17:21. https://doi.org/10.1186/2047-783X-17-21. CAS Article PubMed PubMed Central Google Scholar 4. Barenbrock M, Hausberg M, Matzkies F, de la Motte S, Schaefer RM. Effects of bicarbonate- and lactate-buffered replacement fluids on cardiovascular outcome in CVVH patients. Kidney Int. 2000;58(4):1751–7. CAS Article Google Scholar 5. Panichi V, Parrini M, Bianchi AM, Andreini B, Cirami C, Finato V, et al. Mechanisms of acid-base homeostasis in acetate and bicarbonate dialysis, lactate hemofiltration and hemodiafiltration. Int J Artif Organs. 1994;17(6):315–21. CAS Article Google Scholar Download references We wish to thank a lot Dr. Melissa Jackson for a complete review and editing process of this letter. Funding None. Affiliations ICU Department, Centre Hospitalier Universitaire Brugmann, Brugmann University Hospital, Place Van Gehuchtenplein, 4, 1020, Brussels, Belgium Sébastien Redant , Yael Langman , David De Bels , Rachid Attou  & Patrick M. HonoreAuthors Search for Sébastien Redant in: PubMed • Google Scholar Search for Yael Langman in: PubMed • Google Scholar Search for David De Bels in: PubMed • Google Scholar Search for Rachid Attou in: PubMed • Google Scholar Search for Patrick M. Honore in: PubMed • Google Scholar Contributions SR and PMH designed the paper. All authors participated in drafting and reviewing. All authors read and approved the final version of the manuscript. Corresponding author Correspondence to Patrick M. Honore. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This comment refers to the article available at https://doi.org/10.1186/s13054-019-2423-8. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Redant, S., Langman, Y., De Bels, D. et al. Mechanism of arrhythmias during the infusion of Ringer’s acetate and Ringer’s lactate solutions during cardiac surgery: new insights. Crit Care 23, 413 (2019) doi:10.1186/s13054-019-2696-y Download citation Received 04 November 2019 Accepted 06 December 2019 Published 18 December 2019 DOI https://doi.org/10.1186/s13054-019-2696-y

In ICU patients, digestive tract colonization by multidrug-resistant (MDR) Gram-negative (G−) bacteria is a significant risk factor for the development of infections. In patients undergoing extracorporeal membrane oxygenation (ECMO), colonization by MDR bacteria and risk of subsequent nosocomial infections (NIs) have not been studied yet. The aim of this study is to evaluate the incidence, etiology, risk factors, impact on outcome of gastrointestinal colonization by MDR G− bacteria, and risk of subsequent infections in patients undergoing ECMO.

There is a compelling unmet medical need for biomarker-based models to risk-stratify patients with acute respiratory distress syndrome. Effective stratification would optimize participant selection for clinical trial enrollment by focusing on those most likely to benefit from new interventions. Our objective was to develop a prognostic, biomarker-based model for predicting mortality in adult patients with acute respiratory distress syndrome. This is a secondary analysis using a cohort of 252 mechanically ventilated subjects with the diagnosis of acute respiratory distress syndrome. Survival to day 7 with both day 0 (first day of presentation) and day 7 sample availability was required. Blood was collected for biomarker measurements at first presentation to the intensive care unit and on the seventh day. Biomarkers included cytokine-chemokines, dual-functioning cytozymes, and vascular injury markers. Logistic regression, latent class analysis, and classification and regression tree analysis were used to identify the plasma biomarkers most predictive of 28-day ARDS mortality. From eight biologically relevant biomarker candidates, six demonstrated an enhanced capacity to predict mortality at day 0. Latent-class analysis identified two biomarker-based phenotypes. Phenotype A exhibited significantly higher plasma levels of angiopoietin-2, macrophage migration inhibitory factor, interleukin-8, interleukin-1 receptor antagonist, interleukin-6, and extracellular nicotinamide phosphoribosyltransferase (eNAMPT) compared to phenotype B. Mortality at 28 days was significantly higher for phenotype A compared to phenotype B (32% vs 19%, p = 0.04). An adult biomarker-based risk model reliably identifies ARDS subjects at risk of death within 28 days of hospitalization.

Memory gaps in intensive care unit (ICU) survivors are associated with psychiatric disorders. The ICU diaries improve the patient’s factual memory of the ICU, but it is not clear if they reduce the incidence of psychiatric disorders in patients and relatives after hospital discharge. The aim of this study is to evaluate the literature on the effect of ICU diaries for patients admitted in ICU and their relatives. Two authors independently searched the online databases PubMed, OVID, Embase, EBSCO host, and PsycINFO from inception to July 2019. Studies were included if the intervention group (ICU diary) was compared with a group with no diaries and the sample was comprised patients ≥ 18 years old admitted in the ICU for more than 24 h and their relatives. Randomized clinical trials, observational studies, letter with original data, and abstracts were included, irrespective of the language. The search was not limited by any specific outcome. Review articles, commentaries, editorials, and studies without a control group were excluded. Structured tools were used to assess the methodological quality (“Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I)” for cohort studies and the “Cochrane Risk of Bias tool” for included RCTs and before/after studies). A random-effects model was employed considering the anticipated variability between the studies. Seven hundred eighty-five titles were identified for screening. Two additional studies were selected after a reference search, and after a full-text review, a total of 12 studies were included. When pooling the results, ICU diary was associated with lower risk of depression (RR 0.41, 95% CI 0.23–0.75) and better quality of life (10.3 points higher in SF-36 general health score, 95% CI 0.79–19.8), without a decrease in anxiety or post-traumatic stress disorder (PTSD). For the relatives receiving an ICU diary, there was no difference in the incidence of PTSD, anxiety, or depression. This systematic review and meta-analysis supports the use of ICU diaries to reduce the risk of depression and preserve the quality of life of patients after ICU admission. ICU diaries do not seem to have any beneficial effect on the relatives of the patients. PROSPERO, CRD42019136639

Positive end-expiratory pressure (PEEP) is a cornerstone treatment for critically ill patients, with beneficial effects for acute respiratory distress syndrome (ARDS). In ARDS, PEEP prevents alveolar collapse during expiration and counteracts increased surface tension due to surfactant impairment, alveolar over-deflation, and superimposed pressure. These mechanisms contribute to a reduction in intrapulmonary shunting. Furthermore, alveolar recruitment maintained through PEEP may translate into a higher end-expiratory lung volume (EELV), which often leads to better compliance of the respiratory system (CRS) and therefore a reduction in the driving pressure (DP), both of which are associated with higher survival rates [1]. Moreover, alveolar stability protects against intra-tidal recruitment/derecruitment (i.e., atelectrauma) [2] and imposed mechanical stresses and inflammation (i.e., biotrauma) [3], and it reduces ventilation heterogeneity [4]. Advantages of PEEP should be balanced against its potential disadvantages, namely, a reduction in cardiac output, an increase in pulmonary vascular resistance and alveolar dead space, and the risk of regional over-inflation [5]. Current guidelines concerning moderate or severe ARDS recommend using higher rather than lower PEEP levels [6]. This recommendation is based on meta-analysis of individual patient data [7]. Furthermore, a subsequent ancillary analysis of LUNG SAFE reported that higher PEEP levels are associated with improved survival [8]. We present a PEEP titration strategy that relies heavily on physiological considerations, which is applied at our center. This opinion-based editorial is based on our interpretation of the evidence-based medical literature and on clinical experience, without presumptions of exhaustiveness or superiority to other strategies. For moderate and severe ARDS, the guidelines [6] recommend higher PEEP levels without specifying absolute values or, more importantly, what methodology to apply. Therefore, for patients with moderate or severe ARDS, we typically aim to increase PEEP levels, if hemodynamic conditions allow it, through closely monitoring the individual response and focusing on two main targets: driving pressure and oxygenation (Fig. 1). Fig. 1 Evidence-based decision-making flow chart for patients with ARDS requiring treatment using PEEP, according to patient physiological readouts. The approach we use to set up PEEP is applied either to patients in a supine position or to those with moderate-to-severe ARDS and prone positioning. Each step lasts normally 10 to 30 min. The area in light blue indicates that FiO2 remains constant throughout the steps. After PEEP titration FiO2 can be decreased (or increased) to target normoxia. Pre-existing barotrauma and (according to some authors) elevated intracranial pressure should discourage from application of high PEEP. Abbreviations and symbols: ARDS, acute respiratory distress syndrome; CRS, compliance of the respiratory system; CW, chest wall; EIT, electrical impedance tomography; FiO2, inspiratory oxygen fraction; PEEP, positive end-expiratory pressure; Pes, esophageal pressure; RM, recruitment maneuver; RV, right ventricle; US, ultrasound; ↑, increase; ↓, decrease; =, equalFull size image Driving pressure CRS is proportional to the “baby lung” size [9]; therefore, as a good proxy of EELV (albeit possibly influenced by other factors, such as chest-wall compliance), CRS tends to increase with recruitment but decreases again once over-inflation begins. For this reason, changes in CRS are a key element for PEEP titration. At the same tidal volume (VT), any change in CRS will be reflected in the driving pressure (DP) [10], or if pressure control is used, VT increases for the same DP. We increase PEEP levels aiming to observe a decrease in DP at the same VT, likely indicating recruitment (not necessarily to a fully open lung). To facilitate this process, we could use a moderate recruitment maneuver (RM) (e.g., 40 cmH2O for 20 s) before increasing PEEP. An RM (rather than to correct hypoxemia) might work as a diagnostic tool (diagnostic RM) to explore the potential for lung recruitability, leading to an increase in PEEP levels in responders compared with non-responders. Simultaneously, if CRS decreases when PEEP is increased, indicating overdistension, we reduce either PEEP or VT (if feasible in terms of CO2 elimination and respiratory rate). For a safe plateau pressure (Pplat), one size (i.e., 30 cmH2O) does not fit all, and if overdistension is an issue, our safety threshold for Pplat is decreased. Oxygenation We always verify the response to gas exchange, primarily, an increase in PaO2 at a constant inspiratory FiO2, with constant or decreasing PaCO2. Although PaO2/FiO2 is a poor proxy for alveolar recruitment, patients who have responded to an increased PEEP with improved oxygenation have been reported to have a reduced risk of death [11]. As such, we prefer to uncouple the PEEP and FiO2 settings. Patients do not always show an improvement in oxygenation with higher PEEP levels. In this scenario, a strategy that mandates simultaneous increase of these parameters (e.g., PEEP/FiO2 tables) would recommend a further PEEP increase combined with FiO2. Finally, an increase in PaCO2 levels in relation to a PEEP increase should be an immediate alert for a risk of overdistension. Of late, and more frequently, we are taking advantage of bedside electrical impedance tomography (EIT) to corroborate our PEEP titration procedure. We propose a 2-step strategy. First, we perform a diagnostic RM to evaluate the potential for lung recruitment. Second, we increase the PEEP level in small increments (e.g., 2 cmH2O) until it is sufficient to maintain EELV stability, according to the end-expiratory lung impedance signal. This approach leads to an improvement in arterial oxygenation and a reduction in the DP and provides regional information concerning the balance between alveolar overdistension and collapse [12]. We typically confine the measurement of esophageal pressure to selected clinical conditions (Fig. 1). The described approach might appear to be contradictory to the recent literature [13] reporting that patients receiving an RM followed by a decremental PEEP trial, according to CRS, have increased mortality rates. However, we consider that this study does not invalidate the concept of higher PEEP levels being associated with a lower DP, as it combined other procedures that might have contributed to the higher mortality, such as an aggressive RM of up to 60 cmH2O (reduced to 50 cmH2O after 50% enrollment) and lasting several minutes overall, which required important fluid expansion, neuromuscular blocking agents, and an additional RM performed after PEEP titration. Furthermore, the decision to set PEEP at 2 cmH2O above the best CRS likely led to regional overdistension of the non-dependent lung. It is known that a high PEEP level does not fit all; therefore, innovative concepts such as the different responses of hypo- and hyper-inflammatory ARDS phenotypes to PEEP [14] and the use of population enrichment for inclusion in trials [15] are encouraging. In the meantime, we set PEEP levels for patients with moderate or severe ARDS that aim for a moderate reasonable recruitment, given the challenges of full lung recruitment, according to incremental PEEP steps (possibly interspersed with short diagnostic RMs) and seek improvements in functional and physiologic readouts, such as CRS, gas exchange, and EIT. Not applicable ARDS: Acute respiratory distress syndrome CRS : Compliance of the respiratory system DP: Driving pressure EELV: End-expiratory lung volume EIT: Electrical impedance tomography FiO2 : Inspiratory fraction of oxygen PaCO2 : Arterial pressure of carbon dioxide PaO2 : Arterial pressure of oxygen PEEP: Positive end-expiratory pressure P plat : Plateau pressure RM: Recruitment maneuver V T : Tidal volume 1. Sahetya SK, Goligher EC, Brower RG. Fifty years of research in ARDS. Setting positive end-expiratory pressure in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017;195(11):1429–38. Google Scholar 2. Caironi P, Cressoni M, Chiumello D, Ranieri M, Quintel M, Russo SG, Cornejo R, Bugedo G, Carlesso E, Russo R, Caspani L, Gattinoni L. Lung opening and closing during ventilation of acute respiratory distress syndrome. Am J Respir Crit Care Med. 2010;181(6):578–86. Google Scholar 3. Tremblay LN, Slutsky AS. Ventilator-induced injury: from barotrauma to biotrauma. Proc Assoc Am Physicians. 1998;110:482–8. Google Scholar 4. Cressoni M, Cadringher P, Chiurazzi C, et al. Lung inhomogeneity in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2014;189(2):149–58. Google Scholar 5. Luecke T, Pelosi P. Clinical review: positive end-expiratory pressure and cardiac output. Crit Care. 2005;9(6):607–21. Google Scholar 6. Fan E, Del Sorbo L, Goligher EC, et al. American Thoracic Society, European Society of Intensive Care Medicine, and Society of Critical Care Medicine. An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline: mechanical ventilation in adult patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017;195(9):1253–63. Google Scholar 7. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010;303(9):865–73. Google Scholar 8. Laffey JG, Bellani G, Pham T, et al. LUNG SAFE Investigators and the ESICM Trials Group. Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study. Intensive Care Med. 2016;42(12):1865–76. Google Scholar 9. Gattinoni L, Pesenti A. The concept of “baby lung”. Intens Care Med. 2005;31(6):776–84. Google Scholar 10. Amato MB, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372(8):747–55. Google Scholar 11. Goligher EC, Kavanagh BP, Rubenfeld GD, et al. Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. A secondary analysis of the LOVS and ExPress trials. Am J Respir Crit Care Med. 2014;190(1):70–6. Google Scholar 12. Eronia N, Mauri T, Maffezzini E, et al. Bedside selection of positive end-expiratory pressure by electrical impedance tomography in hypoxemic patients: a feasibility study. Ann Intensive Care. 2017;7(1):76. Google Scholar 13. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura ÉA, Laranjeira LN, et al. Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2017;318(14):1335–45. Google Scholar 14. Calfee CS, Delucchi K, Parsons PE, et al. NHLBI ARDS Network. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med. 2014;2(8):611–20. Google Scholar 15. Shankar-Hari M, Rubenfeld GD. Population enrichment for critical care trials: phenotypes and differential outcomes. Curr Opin Crit Care. 2019;25(5):489–97. Download references We are grateful to Prof. Antonio Pesenti and Prof. Giacomo Grasselli for their invaluable suggestions in reviewing this manuscript. Funding The study was supported by Institutional funds. Affiliations Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy Emanuele Rezoagli  & Giacomo Bellani Department of Emergency and Intensive Care, San Gerardo Hospital, Monza, Italy Giacomo Bellani Authors Search for Emanuele Rezoagli in: PubMed • Google Scholar Search for Giacomo Bellani in: PubMed • Google Scholar Contributions ER and GB conceived the study, reviewed the literature, wrote the manuscript, critically revised it, and read and approved the final manuscript. Corresponding author Correspondence to Giacomo Bellani. Ethics approval and consent to participate Not applicable Consent for publication Not applicable Competing interests G.B. received lecturing fees from Draeger. E.R. declares that he has no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Rezoagli, E., Bellani, G. How I set up positive end-expiratory pressure: evidence- and physiology-based!. Crit Care 23, 412 (2019) doi:10.1186/s13054-019-2695-z Download citation Received 13 September 2019 Accepted 06 December 2019 Published 16 December 2019 DOI https://doi.org/10.1186/s13054-019-2695-z

Volume expansion is aimed at increasing cardiac output (CO), but this variable is not always directly measured. We assessed the ability of changes in arterial pressure, pulse pressure variation (PPV) and heart rate (HR) or of a combination of them to detect a positive response of cardiac output (CO) to fluid administration.

During spontaneous breathing trial, low-pressure support is thought to compensate for endotracheal tube resistance, but it actually should provide overassistance. Automatic tube compensation is an option available in the ventilator to compensate for flow-resistance of endotracheal tube. Its effects on patient effort have been poorly investigated. We aimed to compare the effects of low-pressure support and automatic tube compensation during spontaneous breathing trial on breathing power and lung ventilation distribution.

Pulmonary embolism (PE) is responsible for ~ 3% of Out-of-Hospital Cardiac Arrest (OHCA) and is associated with unfavorable prognoses [1]. We have recently shown that thrombolysis during resuscitation was associated with a better survival in the event of a proven pulmonary embolism [2]. The challenge is thus to identify, from the beginning of resuscitation, PE-related OHCA in order to deliver the proper treatment to the patient. This issue is highlighted by the premature stoppage of the TROICA trial [1], which showed no benefit of using thrombolysis in medical cardiac arrests. Our aim was to identify the factors associated with PE-related OHCA. We selected adults from the French National OHCA Registry, admitted to the hospital. This registry and the OHCA management by a mobile medical team have been previously described [3]. The present study was approved by the French Advisory Committee on Information Processing in Health Research. It was approved as a medical assessment registry without a requirement for patient consent. We assessed characteristics associated with PE-related OHCA with a univariable analysis (χ2 test, Fisher’s exact test or Student’s t test). A multivariate logistic regression model was then developed to identify the factors associated with PE with a P value < 0.20. Statistical analyses were performed using R software v3.6.1. From July 2011 to March 2018, 14,253 patients were admitted to the hospital. We excluded OHCAs whose cause was obvious from the beginning of the resuscitation (n = 2341) or where data was incomplete (n = 1150). The final analysis included 10,402 subjects. Two hundred sixty subjects (2%) were diagnosed with PE upon hospital admission by computed tomography pulmonary angiography (CTPA) or echocardiogram. The results of the univariate and multivariate analyses are presented in Table 1. The prevalence of PE was 22% among the population with nonshockable rhythm and history of thromboembolism. These two factors had a sensitivity of 22% (95% CI [10–39]), a specificity of 98% (95% CI [97–98]) to detect PE. When an age limitation of < 50 years was added to these two factors, the probability of PE was 44% (Fig. 1). Table 1 Factors associated with OHCA caused by PEFull size table Fig. 1 Tree representation of the frequency of pulmonary embolism according to risk factorsFull size image In summary, this study found two factors strongly associated with PE: initial nonshockable rhythm and prior thromboembolism. These factors had already been described by Bouguoin et al. [4] as the two major factors associated with the diagnosis of PE-related OHCA. Moreover, in our study, young age was a risk factor for PE, and this population has a lower risk of major bleeding in the case of thrombolysis, as shown in the PEITHO trial (lower risk if ≤ 75 years) [5]. Our study had some limitations such as the lack of completeness of data which may have resulted in the selection of the population not being completely exhaustive. Moreover, the method of confirming PE either by CTPA or echocardiogram was not known for each patient, which may have underestimated the number of PE cases due to the lack of sensitivity for the ultrasound. In addition, autopsy results were not included in the data. Finally, we were unable to include subjects who died on site and were not admitted to hospital because of a lack of confirmation of the etiology of OHCA. In conclusion, we recommend that for cases of OHCA for which a cause is not obvious, suspect a pulmonary embolism if the initial rhythm is nonshockable and there is a medical history of thromboembolism. In accordance with the guidelines of the American Heart Association (AHA) [6], these subjects should be treated by thrombolysis during resuscitation, especially when they are young. All data that were collected where listed in an anonymous database. The dataset is not available but can be requested from the corresponding author. OHCA: Out-of-hospital cardiac arrest PE: Pulmonary embolism RéAC: French National OHCA Registry 95% CI: 95% confidence interval CTPA: Computed tomography pulmonary angiography AHA: American Heart Association 1. Böttiger BW, Arntz H-R, Chamberlain DA, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med. 2008;359(25):2651–62. Article Google Scholar 2. Javaudin F, Lascarrou J-B, Le Bastard Q, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest caused by pulmonary embolism increases 30-day survival: findings from the French National Cardiac Arrest Registry. Chest. 2019. https://doi.org/10.1016/j.chest.2019.07.015. Article Google Scholar 3. Javaudin F, Desce N, Le Bastard Q, et al. Impact of pre-hospital vital parameters on the neurological outcome of out-of-hospital cardiac arrest: results from the French National Cardiac Arrest Registry. Resuscitation. 2018;133:5–11. Article Google Scholar 4. Bougouin W, Marijon E, Planquette B, et al. Factors associated with pulmonary embolism-related sudden cardiac arrest. Circulation. 2016;134(25):2125–7. Article Google Scholar 5. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402–11. CAS Article Google Scholar 6. Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(Suppl 2):S444–64. Article Google Scholar Download references We thank all the prehospital emergency medical service units in France investigated in RéAC. Funding The RéAC registry is supported by the French Society of Emergency Medicine (SFMU), a patient foundation—Fédération Française de Cardiologie, the Mutuelle Générale de l’Education Nationale (MGEN), the University of Lille, and the Institute of Health Engineering of Lille. The authors declare that the funding sources had no role in the conduct, analysis, interpretation, or writing of this manuscript. Affiliations Department of Emergency Medicine, University Hospital of Nantes, Nantes, France François Javaudin  & Hyacinthe Esquina Microbiotas Hosts Antibiotics and bacterial Resistances (MiHAR), University of Nantes, Nantes, France François Javaudin  & Brice Leclère Medical Intensive Care Unit, University Hospital of Nantes, Nantes, France Jean-Baptiste Lascarrou Public Health Department EA 2694, Lille University Hospital, University of Lille, Lille, France Valentine Baert  & Hervé Hubert Department of Epidemiology and Medical Evaluation, University Hospital of Nantes, Nantes, France Brice Leclère Authors Search for François Javaudin in: PubMed • Google Scholar Search for Jean-Baptiste Lascarrou in: PubMed • Google Scholar Search for Hyacinthe Esquina in: PubMed • Google Scholar Search for Valentine Baert in: PubMed • Google Scholar Search for Hervé Hubert in: PubMed • Google Scholar Search for Brice Leclère in: PubMed • Google Scholar Consortia on behalf of GR-RéAC François Javaudin , Jean-Baptiste Lascarrou , Hyacinthe Esquina , Valentine Baert , Hervé Hubert  & Brice Leclère Contributions FJ and BL developed the analysis plan. FJ undertook the main analysis with supervision from BL. FJ wrote the first draft of the paper, with all other authors making important critical revisions. All authors have read and approved the final version of the manuscript. Corresponding author Correspondence to François Javaudin. Ethics approval and consent to participate The present study was approved by the French Advisory Committee on Information Processing in Health Research and the French National Data Protection Commission (authorization no. 910946). It was approved as a medical assessment registry without a requirement for patient consent. Consent for publication The study was approved as a medical assessment registry without a requirement for patient consent. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Javaudin, F., Lascarrou, J., Esquina, H. et al. Improving identification of pulmonary embolism-related out-of-hospital cardiac arrest to optimize thrombolytic therapy during resuscitation. Crit Care 23, 409 (2019) doi:10.1186/s13054-019-2672-6 Download citation Received 04 November 2019 Accepted 13 November 2019 Published 13 December 2019 DOI https://doi.org/10.1186/s13054-019-2672-6 Keywords Out-of-hospital cardiac arrest Thrombolytic therapy Pulmonary embolism Cardiopulmonary resuscitation

We read the recent report by Aguilar et al., who concluded that among patients with nosocomial peritonitis who are on continuous renal replacement therapy (CRRT), ceftolozane-tazobactam (C/T) at a dose of 3 g every 8 h is safe [1]. This finding was additional information following the notion that CRRT was an independent predictor of clinical failure when C/T was administered at 1.5 g every 8 h [2]. The Aguilar et al. protocol included a short infusion time, i.e., 1 h [1]. Previously described extended-infusion over 4 h was found to reach above the minimal inhibitory concentration (MIC), given that beta-lactam antibiotics exhibit time-dependent antibacterial activity [3]. This might prevent underdosing during CRRT [3]. Besides, the C/T elimination was explained by diffusion [1]. However, adsorption was not assessed. The acrylonitrile 69 Multiflow (AN-69-M) membrane, used in this study, has a lower adsorptive capacity compared with the AN69 surface-treated (AN69-ST) membrane, which is considered a highly adsorptive membrane (HAM). In a recent comparison of polysulphone versus AN-69-M for C/T extraction by CRRT in an ex vivo model [4], there was no difference in adsorption. In a case report, a continuous infusion (CI) of 6 g in 24 h of C/T was used in a cystic fibrosis patient with a multidrug-resistant (MDR) Pseudomonas aeruginosa and augmented renal clearance to optimize time-dependent antibacterial activity [5]. In this patient, therapeutic drug monitoring (TDM) confirmed adequate exposure [5]. CI and TDM are two critical parameters when using C/T for patients receiving CRRT especially when MICs of bacteria like MDR P. aeruginosa are considered very high. Not applicable. AN-69-M: Acrylonitrile 69 Multiflow AN-69-ST: AN69-surface treated C/T: Ceftolozane-tazobactam CI: Continuous infusion CRRT: Continuous renal replacement therapy HAM: Highly adsorptive membranes MDR: Multi-drug resistant MIC: Minimal inhibitory concentration 1. Aguilar G, Ferriols R, Martínez-Castro S, Ezquer C, Pastor E, Carbonell JA, Alós M, Navarro D. Optimizing ceftolozane-tazobactam dosage in critically ill patients during continuous venovenous hemodiafiltration. Crit Care. 2019;23(1):145. https://doi.org/10.1186/s13054-019-2434-5. Article PubMed PubMed Central Google Scholar 2. Mussini C, Righi E, Tascini C, et al. Ceftolozane/tazobactam for the treatment of serious P. aeruginosa infections: a multicenter nationwide clinical experience. Int J Antimicrob Agents. 2018;53(4):408–15. https://doi.org/10.1016/j.ijantimicag.2018.11.001 Epub 2018 Nov 8. CAS Article PubMed Google Scholar 3. Oliver WD, Heil EL, Gonzales JP, Mehrotra S, Robinett K, Saleeb P, Nicolau DP. Ceftolozane-tazobactam pharmacokinetics in a critically ill patient on continuous venovenous hemofiltration. Antimicrob Agents Chemother. 2015;60(3):1899–901. https://doi.org/10.1128/AAC.02608-15. CAS Article PubMed PubMed Central Google Scholar 4. Chaijamorn W, Shaw AR, Lewis SJ, Mueller BA. Ex vivo ceftolozane/tazobactam clearance during continuous renal replacement therapy. Blood Purif. 2017;44(1):16–23. https://doi.org/10.1159/000455897 Epub 2017 Feb 25. CAS Article PubMed Google Scholar 5. Elizabeth Davis S, Ham J, Hucks J, Gould A, Foster R, Ann Justo J, Nicolau DP, Bookstaver PB. Use of continuous infusion ceftolozane-tazobactam with therapeutic drug monitoring in a patient with cystic fibrosis. Am J Health Syst Pharm. 2019;76(8):501–4. https://doi.org/10.1093/ajhp/zxz011. Article PubMed Google Scholar Download references We would like to thank Prof. Kianoush Kashani, MD, PhD, FCCP (Mayo Clinic, Rochester, USA) for critically reviewing the manuscript. Funding None. Affiliations ICU Department, Centre Hospitalier Universitaire Brugmann, Place Van Gehuchtenplein 4, 1020, Brussels, Belgium Patrick M. Honore , Aude Mugisha , Leonel Barreto Gutierrez , Sebastien Redant , Keitiane Kaefer , Andrea Gallerani  & David De Bels Authors Search for Patrick M. Honore in: PubMed • Google Scholar Search for Aude Mugisha in: PubMed • Google Scholar Search for Leonel Barreto Gutierrez in: PubMed • Google Scholar Search for Sebastien Redant in: PubMed • Google Scholar Search for Keitiane Kaefer in: PubMed • Google Scholar Search for Andrea Gallerani in: PubMed • Google Scholar Search for David De Bels in: PubMed • Google Scholar Contributions PMH and DDB designed the paper. All authors participated in the drafting and reviewing. All authors read and approved the final version of the manuscript. Corresponding author Correspondence to Patrick M. Honore. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This comment refers to the article available at https://doi.org/10.1186/s13054-019-2434-5. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Reprints and Permissions Cite this article Honore, P.M., Mugisha, A., Barreto Gutierrez, L. et al. Optimizing ceftolozane-tazobactam dosage during continuous renal replacement therapy: additional insights. Crit Care 23, 406 (2019) doi:10.1186/s13054-019-2692-2 Download citation Received 05 October 2019 Accepted 29 November 2019 Published 12 December 2019 DOI https://doi.org/10.1186/s13054-019-2692-2

Vitamin C is a well-documented antioxidant that reduces oxidative stress and fluid infusion in high doses; however, the association between high-dose vitamin C and reduced mortality remains unclear. This study evaluates the effect of high-dose vitamin C in severe burn patients under two varying thresholds. We enrolled adult patients with severe burns (burn index ≥ 15) who were registered in the Japanese Diagnosis Procedure Combination national inpatient database from 2010 to 2016. Propensity score matching was performed between patients who received high-dose vitamin C within 1 day of admission (vitamin C group) and those who did not (control group). High-dose vitamin C was defined as a dosage in excess of 10 g or 24 g within 2 days of admission. The primary outcome was in-hospital mortality. Eligible patients (n = 2713) were categorized into the vitamin C group (n = 157) or control group (n = 2556). After 1:4 propensity score matching, we compared 157 and 628 patients who were administered high-dose vitamin C (> 10-g threshold) and controls, respectively. Under this particular threshold, high-dose vitamin C therapy was associated with reduced in-hospital mortality (risk ratio, 0.79; 95% confidence interval, 0.66–0.95; p = 0.006). In contrast, in-hospital mortality did not differ between the control and high-dose vitamin C group under the > 24-g threshold (risk ratio, 0.83; 95% confidence interval, 0.68–1.02; p = 0.068). High-dose vitamin C therapy was associated with reduced mortality in patients with severe burns when used under a minimum threshold of 10 g within the first 2 days of admission. While “high-dose” vitamin C therapy lacks a universal definition, the present study reveals that different “high-dose” regimens may yield improved outcomes.

To develop a mathematical model to estimate daily evolution of disease severity using routinely available parameters in patients admitted to the intensive care unit (ICU). Over a 3-year period, we prospectively enrolled consecutive adults with sepsis and categorized patients as (1) being at risk for developing (more severe) organ dysfunction, (2) having (potentially still reversible) limited organ failure, or (3) having multiple-organ failure. Daily probabilities for transitions between these disease states, and to death or discharge, during the first 2 weeks in ICU were calculated using a multi-state model that was updated every 2 days using both baseline and time-varying information. The model was validated in independent patients. We studied 1371 sepsis admissions in 1251 patients. Upon presentation, 53 (4%) were classed at risk, 1151 (84%) had limited organ failure, and 167 (12%) had multiple-organ failure. Among patients with limited organ failure, 197 (17%) evolved to multiple-organ failure or died and 809 (70%) improved or were discharged alive within 14 days. Among patients with multiple-organ failure, 67 (40%) died and 91 (54%) improved or were discharged. Treatment response could be predicted with reasonable accuracy (c-statistic ranging from 0.55 to 0.81 for individual disease states, and 0.67 overall). Model performance in the validation cohort was similar. This prediction model that estimates daily evolution of disease severity during sepsis may eventually support clinicians in making better informed treatment decisions and could be used to evaluate prognostic biomarkers or perform in silico modeling of novel sepsis therapies during trial design. ClinicalTrials.gov NCT01905033