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Objectives To examine the effect of premorbid β-blocker exposure on mortality and organ dysfunction in sepsis. Design Retrospective observational study. Setting ICUs in Australia, the Czech Republic, and the United States. Patients Total of 4,086 critical care patients above 18 years old with sepsis between January 2014 and December 2018. Intervention Premorbid beta-blocker exposure. Measurements and main results One thousand five hundred fifty-six patients (38%) with premorbid β-blocker exposure were identified. Overall ICU mortality rate was 15.1%. In adjusted models, premorbid β-blocker exposure was associated with decreased ICU (adjusted odds ratio, 0.80; 95% CI, 0.66-0.97; p = 0.025) and hospital (adjusted odds ratio, 0.83; 95% CI, 0.71-0.99; p = 0.033) mortality. The risk reduction in ICU mortality of 16% was significant (hazard ratio, 0.84, 95% CI, 0.71-0.99; p = 0.037). In particular, exposure to noncardioselective β-blocker before septic episode was associated with decreased mortality. Sequential Organ Failure Assessment score analysis showed that premorbid β-blocker exposure had potential benefits in reducing respiratory and neurologic dysfunction. Conclusions This study suggests that β-blocker exposure prior to sepsis, especially to noncardioselective β blockers, may be associated with better outcome. The findings suggest prospective evaluation of β-blocker use in the management of sepsis.

Modern perioperative care is making steady advances in achieving optimal recovery for patients using the concept of early recovery after surgery (ERAS). Perioperative nutrition plays an important part in ERAS care and opportunities for nutritional interventions present for weeks up to hours before an operation, as well as in the postoperative period. Despite that malnutrition and suboptimal nutrition in surgical patients, particularly in those presenting with cancer, is very common.

Critical care echocardiography (CCE) is commonly performed in many intensive care units across Australia and New Zealand (ANZ). The scope of practice ranges from Basic CCE through to Advanced CCE and includes the use of transthoracic echocardiography and transoesophageal echocardiography. Many training and qualification pathways exist with no standardisation of education goals. This document defines different levels of CCE expertise and recommends minimum training standards for each level of adult CCE in ANZ. Guidelines committee of College of Intensive Care Medicine's Ultrasound Special Interest Group held multiple face to face meetings, organised teleconferences, conducted a survey of the Fellows of the college and reviewed the international CCE training pathways prior to writing these guidelines.

BackgroundRobust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness.MethodsWe conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients.FindingsWe show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression is associated with the presence of a high viral load. We further demonstrate that systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 severity. For clinical outcome prediction (e.g. respiratory failure), IFI27 expression displays a high positive (0.83) and negative (0.95) predictive value, outperforming all other known predictors of COVID-19 severity. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 swine influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients.InterpretationThese data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus.Research in contextEvidence before this studyWe searched the scientific literature using PubMed to identify studies that used the IFI27 biomarker to predict outcomes in COVID-19 patients. We used the search terms “IFI27”, “COVID-19, “gene expression” and “outcome prediction”. We did not identify any study that investigated the role of IFI27 biomarker in outcome prediction. Although ten studies were identified using the general terms of “gene expression” and “COVID-19”, IFI27 was only mentioned in passing as one of the identified genes. All these studies addressed the broader question of the host response to COVID-19; none focused solely on using IFI27 to improve the risk stratification of infected patients in a pandemic.Added value of this studyHere, we present the findings of a multi-cohort study of the IFI27 biomarker in COVID-19 patients. Our findings show that the host response, as reflected by blood IFI27 gene expression, accurately predicts COVID-19 disease progression (positive and negative predictive values; 0.83 and 0.95, respectively), outperforming age, comorbidity, C-reactive protein and all other known risk factors. The strong association of IFI27 with disease severity occurs not only in SARS-CoV-2 infection, but also in other respiratory viruses with pandemic potential, such as the influenza virus. These findings suggest that host response biomarkers, such as IFI27, could help identify high-risk COVID-19 patients - those who are more likely to develop infection complications - and therefore may help improve patient triage in a pandemic.Implications of all the available evidenceThis is the first systemic study of the clinical role of IFI27 in the current COVID-19 pandemic and its possible future application in other respiratory virus pandemics. The findings not only could help improve the current management of COVID-19 patients but may also improve future pandemic preparedness.

Objectives Hospitalized patients who presented within the last 24 h with a bacterial infection were recruited. Participants were assigned into sepsis and uncomplicated infection groups. In addition, healthy volunteers were recruited as controls. RNA was prepared from whole blood, depleted from beta-globin mRNA and sequenced. This dataset represents a highly valuable resource to better understand the biology of sepsis and to identify biomarkers for severe sepsis in humans. Data description The data presented here consists of raw and processed transcriptome data obtained by next generation RNA sequencing from 105 peripheral blood samples from patients with uncomplicated infections, patients who developed sepsis, septic shock patients, and healthy controls. It is provided as raw sequenced reads and as normalized log2 transformed relative expression levels. This data will allow performing detailed analyses of gene expression changes between uncomplicated infections and sepsis patients, such as identification of differentially expressed genes, co-regulated modules as well as pathway activation studies.

OBJECTIVE: To describe the recommended procedure and common ultrasonographic findings and present a framework for labelling, recording and reporting of images obtained during a focused lung ultrasound study. BACKGROUND: Lung ultrasound is a widely utilised point‐of‐care investigation in acute care, providing valuable diagnostic information in patients with dyspnoea or haemodynamic instability. It has a number of recognised advantages and has been incorporated into a variety of clinical algorithms. Recommendations for performing lung ultrasound and description of common artefacts are readily available; however, there is a lack of a recognised framework for labelling and reporting a lung ultrasound study. Standardised recording, labelling and reporting are important clinically, while promoting consistency, quality assurance, teaching and research opportunities. Documenting lung ultrasound also has potential medico‐legal implications. RESULTS: For focused lung ultrasound, an extended bilateral four‐quadrant approach is recommended. Acquired images and loops should be clearly labelled identifying left or right, anterior or lateral and inferior, superior or posterior locations. 2D loops should be of sufficient length to clearly demonstrate pleural sliding, complemented by M‐mode stills if required. Reports should provide information regarding the presence or absence of an intact pleural interface, the presence or absence and the size and nature of pleural collections as well as any parenchymal artefacts or consolidation, in all examined locations. It is important to use internationally accepted terminology to describe findings, and it is also recommended to conclude the report with a clear summary that can be interpreted by healthcare providers without specific training in lung ultrasound.

IntroductionAccurate triage is an important first step to effectively manage the clinical treatment of severe cases in a pandemic outbreak. In the current COVID-19 global pandemic, there is a lack of reliable clinical tools to assist clinicians to perform accurate triage. Host response biomarkers have recently shown promise in risk stratification of disease progression; however, the role of these biomarkers in predicting disease progression in patients with COVID-19 is unknown. Here, we present a protocol outlining a prospective validation study to evaluate the biomarkers’ performance in predicting clinical outcomes of patients with COVID-19.Methods and analysisThis prospective validation study assesses patients infected with COVID-19, in whom blood samples are prospectively collected. Recruited patients include a range of infection severity from asymptomatic to critically ill patients, recruited from the community, outpatient clinics, emergency departments and hospitals. Study samples consist of peripheral blood samples collected into RNA-preserving (PAXgene/Tempus) tubes on patient presentation or immediately on study enrolment. Real-time PCR (RT-PCR) will be performed on total RNA extracted from collected blood samples using primers specific to host response gene expression biomarkers that have been previously identified in studies of respiratory viral infections. The RT-PCR data will be analysed to assess the diagnostic performance of individual biomarkers in predicting COVID-19-related outcomes, such as viral pneumonia, acute respiratory distress syndrome or bacterial pneumonia. Biomarker performance will be evaluated using sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operating characteristic curve.Ethics and disseminationThis research protocol aims to study the host response gene expression biomarkers in severe respiratory viral infections with a pandemic potential (COVID-19). It has been approved by the local ethics committee with approval number 2020/ETH00886. The results of this project will be disseminated in international peer-reviewed scientific journals.

PurposeDysregulated immune response is a key driver of disease progression in sepsis and known to be associated with impaired cellular metabolism. This association has been studied mostly in the late stage sepsis patients. Here, we investigate whether such impairment in cellular metabolism is present in uncomplicated infection patients who do not develop sepsis.MethodsForty sepsis (fulfilled Sepsis-3 criteria) and 27 uncomplicated infection patients were recruited from the emergency department along with 20 healthy volunteers. Whole blood was collected for measurement of gene expression, cytokine levels and cellular metabolic functions (including mitochondrial respiration, oxidative stress and apoptosis).ResultsOur analysis revealed the impairment of mitochondrial respiration in uncomplicated infection and sepsis patients (p value ConclusionsThese findings suggest that impaired immune cell metabolism is present in infection patients without presenting sepsis, thereby opening potential window for early diagnosis and intervention (e.g. antioxidant therapy) in such patients.

The severe acute respiratory syndrome coronavirus 2 (COVID‐19) pandemic has placed an unprecedented challenge on healthcare systems across the globe. Rapid assessment of the cardiorespiratory function to monitor disease progression and guide treatment is essential. Therefore, we have designed the COVID‐US: a simplified cardiopulmonary ultrasound approach to use in suspected and confirmed COVID‐19 patients, to aid front‐line health workers in their decision‐making in a surge crisis.

BACKGROUND In patients with septic shock mortality is high, and survivors experience long-term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive versus (vs) standard-care intravenous (IV) fluid therapy. The hypothesis is that IV fluid restriction improves patient-important long-term outcomes. AIM To assess the predefined patient-important long-term outcomes in patients randomised into the CLASSIC trial. METHODS In this pre-planned follow-up study of the CLASSIC trial, we will assess all-cause mortality, Health-Related Quality of Life (HRQoL) and cognitive function one year after randomisation in the two intervention groups. The 1-year mortality will be collected from electronic patient records or central national registries in most participating countries. We will contact survivors and assess EuroQol 5-Dimension, -5-Level (EQ-5D-5L) and EuroQol-Visual Analogue Scale and Montreal Cognitive Assessment 5-minute protocol score. We will analyse mortality by logistic regression and use general linear models to assess HRQoL and cognitive function. DISCUSSION With this pre-planned follow-up study of the CLASSIC trial, we will provide patient-important data on long-term survival, HRQoL and cognitive function of restrictive vs standard-care IV fluid therapy in patients with septic shock.

Using ultrasonography to help diagnose, risk stratify and treat patients suffering from COVID-19 disease is therefore intuitive and imperative.

INTRODUCTION: Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the Conservative versus Liberal Approach to fluid therapy of Septic Shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock.METHODS: CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analyst-blinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events, serious adverse reactions, days alive at day 90 without life support, days alive and out of hospital at day 90, and mortality, health-related quality of life, and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat population.DISCUSSION: The CLASSIC trial results will provide important evidence to guide clinicians' choice regarding IV fluid therapy in adults with septic shock. This article is protected by copyright. All rights reserved.

Supplemental Digital Content is available in the text., Objectives: To examine the association between premorbid metformin exposure and mortality, hyperlactatemia, and organ dysfunction in sepsis. Data Sources: PubMed and EMBASE (with Medline via Ovid) databases were searched for all studies of premorbid metformin exposure and sepsis published between January 1974 and August 2018. Study Selection: Studies of at least 20 patients with sepsis that reported data on metformin use, mortality, and/or organ dysfunction were independently selected. Data Extraction: Two reviewers abstracted data on study design, settings, study quality, participants, metformin exposure, mortality, initial lactate levels, and organ dysfunction. Risk of bias was independently assessed. Data Synthesis: Eight observational studies fulfilled our criteria, comprising 4,144 patients with sepsis including 562 diabetics on metformin. Premorbid metformin exposure was associated with reduced mortality in sepsis (odds ratio, 0.57; 95% CI, 0.40–0.80). Between studies heterogeneity was low (i2 = 43%; τ2 = 0.1; p = 0.09). Premorbid metformin exposure was not significantly associated with initial lactate levels (mean difference, 0.39 [–0.50 to 1.28]; i2 = 72%; p = 0.39). Conclusions: The meta-analysis suggests that premorbid metformin exposure is associated with decreased mortality in sepsis but not with hyperlactatemia. What are the potential mechanisms and whether there is any effect on organ dysfunction remain unclear.

Open lung ventilation with a recruitment maneuver could be beneficial for acute respiratory distress syndrome patients. However, the increased airway pressures resulting from the recruitment maneuver may induce cardiac dysfunction, limiting the benefit of this maneuver. We analyzed the effect of a recruitment maneuver and decremental positive end-expiratory pressure titration on cardiac function.Medical ICU Amiens, France.Twenty patients with moderate to severe acute respiratory distress syndrome INTERVENTIONS:: Patients underwent a stepwise recruitment maneuver with respiratory evaluation and echocardiography assessment of cardiac function including longitudinal strain at baseline, peak positive end-expiratory pressure of recruitment maneuver (positive end-expiratory pressure 40 cm H2O), and at "optimal" positive end-expiratory pressure. The patients were divided into two groups based on change on the PaO2/FIO2 ratio (nonresponders50%; responders ≥ 50%).At peak positive end-expiratory pressure during the recruitment maneuver, the arterial pressure, cardiac output, left ventricular size decreased and right ventricular size increased. The left ventricular ejection fraction decreased from 60% ± 13% to 48% ± 18% (p = 0.05). Both left and right ventricular global longitudinal strain were impaired (-15.8% ± 4.5% to -11% ± 4.7% and -19% ± 5% to -14% ± 6% [p = 0.05] respectively). Fifty percent of patients were nonresponders and demonstrated a lower hemodynamic tolerance to the recruitment maneuver than responders. Optimal positive end-expiratory pressure was 14 ± 5 cm H2O (vs 11 ± 4 cm H2O at baseline), and PaO2/FIO2 ratio increased from 111 ± 25 to 197 ± 89 mm Hg (p0.0001). All hemodynamic variables returned to their baseline value after the recruitment maneuver despite a higher positive end-expiratory pressure.An open lung strategy with a stepwise recruitment maneuver permitted a higher positive end-expiratory pressure and improved oxygenation without any cardiac impairment. The recruitment maneuver was associated with mild and transient, cardiac dysfunction, with nonresponders demonstrating poorer tolerance.

To investigate the metabolic and cardiac effects of intravenous administration of two hypertonic solutions - 3% saline (SAL) and 0.5M sodium lactate (LAC).A randomised, doubleblind, crossover study in ten human volunteers. Intravenous bolus of either SAL or LAC at 3 mL/kg over 20 min followed by a 2 mL/kg infusion over 60 min.Acid base parameters and echocardiographic indices of cardiac function, cardiac output (CO), left ventricular ejection fraction (LVEF) and mitral annular peak systolic velocity (Sm) before and after infusion of SAL or LAC.Despite haemodilution, we observed an increase in sodium (139 ± 2 mmol/L to 142 ± 2 mmol/L in both groups) and respective anions, chloride (106 ± 2 mmol/L to 112 ± 3 mmol/L) and lactate (1.01 ± 0.28 mmol/L to 2.38 ± 0.38 mmol/L) with SAL and LAC, respectively. The pH (7.37 ± 0.03 to 7.45 ± 0.03; P0.01) and simplified strong ion difference (SID) (36.3 ± 4.6 mmol/L to 39.2 ± 3.6 mmol/L; P0.01) increased during the LAC infusion. The pH was unchanged, but SID decreased during SAL infusion (36.3 ± 2.5 mmol/L to 33.9 ± 3.1 mmol/L; P = 0.01). Both solutions led to an increase in preload and cardiac function, CO (4.36 ± 0.79 L/min to 4.98 ± 1.37 L/ min v 4.62 ± 1.30 L/min to 5.13 ± 1.44 L/min), LVEF (61 ± 6% to 63 ± 8% v 64 ± 6% to 68 ± 7%). The averaged Sm improved in the LAC group as compared with the SAL group (0.088 ± 0.008 to 0.096 ± 0.016 v 0.086 ± 0.012 to 0.082 ± 0.012; P = 0.032).The administration of SAL or LAC has opposing effects on acid base variables such as SID. Hypertonic fluid infusion lead to increased cardiac preload and performance with Sm, suggesting better left ventricular systolic function during LAC as compared with SAL. Lactated hypertonic solutions should be evaluated as resuscitation fluids.

High plasma lactate is a useful indicator of shock, a canary in the coal mine, that is associated with increased mortality in sepsis. But instead of a harmful molecule per se, lactate is a central molecule in the intra and interorgan exchange of carbon and redox potential. (1) The study by Gattinoni et al., who presented a novel approach to the analysis of data from the ALBIOS study, adds to the required change of paradigm concerning lactate metabolism in sepsis. (2) The authors nicely demonstrated that there are multiple reasons for hyperlactataemia in sepsis and that the increased snapshot value we measure, reflects an imbalance between increased production and reduced consumption...

Many echocardiographic indices (or methods) for assessing right ventricular (RV) function are available, but each has its strengths and limitations. In some cases, there might be discordance between the indices. We conducted a systematic review to audit the echocardiographic RV assessments in critical care research to see if a consistent pattern existed. We specifically looked into the kind and number of RV indices used, and how RV dysfunction was defined in each study. Studies conducted in critical care settings and reported echocardiographic RV function indices from 1997 to 2017 were searched systematically from three databases. Non-adult studies, case reports, reviews and secondary studies were excluded. These studies’ characteristics and RV indices reported were summarized. Out of 495 non-duplicated publications found, 81 studies were included in our systematic review. There has been an increasing trend of studying RV function by echocardiography since 2001, and most were conducted in ICU. Thirty-one studies use a single index, mostly TAPSE, to define RV dysfunction; 33 used composite indices and the combinations varied between studies. Seventeen studies did not define RV dysfunction. For those using composite indices, many did not explain their choices. TAPSE seemed to be the most popular index in the last 2–3 years. Many studies used combinations of indices but, apart from cor pulmonale, we could not find a consistent pattern of RV assessment and definition of RV dysfunction amongst these studies.

To describe the technique and review the utility of bedside lung ultrasound in acute care.Lung ultrasound is a useful point-of-care investigation in acute care, especially in patients with dyspnoea or haemodynamic instability. Although normal lung parenchyma is not accessible to ultrasound, distinctive artefacts arising from parietal and visceral pleura indirectly imply the presence of normal lung. As aeration of lung tissue reduces with disease process, visual assessment of several pathologic entities by ultrasound becomes possible. Ultrasound can be used for qualitative and quantitative assessment as well as to guide intervention. Compared with supine anteroposterior chest x-rays, lung ultrasound is faster and superior at ruling out pneumothorax and diagnosing lung consolidation, pleural effusions or pulmonary oedema. It is a logical and highly valuable extension of echocardiography and can be incorporated into diagnostic algorithms for assessment of dyspnoea, hypotension, chest pain or trauma. It provides rapid information about potentially reversible pathology in cardiac arrest scenarios. Other advantages include bedside availability, repeatability, provision of dynamic diagnostic information, ease of use and the absence of radiation exposure.

Supplemental Digital Content is available in the text., Objectives: We performed a meta-analysis to assess whether the newly introduced quick Sequential Organ Failure Assessment score could predict sepsis outcomes and compared its performance to systematic inflammatory response syndrome, the previously widely used screening criteria for sepsis. Data Sources: We searched multiple electronic databases including MEDLINE, the Cochrane Library, Embase, Web of Science, and Google Scholar (up to March 1, 2019) that evaluated quick Sequential Organ Failure Assessment score, systemic inflammatory response syndrome, or both (International Prospective Register of Systematic Reviews [PROSPERO]: CRD42018103327). Study Selection: Studies were included if the outcome was mortality, organ dysfunction, admission to ICU, ventilatory support, or prolonged ICU stay and if prediction performance was reported as either area under the curve, odds ratio, sensitivity, or specificity. Data Extraction: The criterion validity of the quick Sequential Organ Failure Assessment score and systemic inflammatory response syndrome criteria were assessed by measuring its predictive validity for primary (mortality) and secondary outcomes in pooled metrics as mentioned. The data were analyzed using random effects model, and heterogeneity was explored using prespecified subgroups analyses. Data Synthesis: We screened 1,340 studies, of which 121 studies (including data for 1,716,017 individuals) were analyzed. For mortality prediction, the pooled area under the curve was higher for quick Sequential Organ Failure Assessment score (0.702; 95% CI, 0.685–0.718; I2 = 99.41%; p < 0.001) than for systemic inflammatory response syndrome (0.607; 95% CI, 0.589–0.624; I2 = 96.49%; p < 0.001). Quick Sequential Organ Failure Assessment score consistently outperformed systemic inflammatory response syndrome across all subgroup analyses (area under the curve of quick Sequential Organ Failure Assessment vs. area under the curve of systemic inflammatory response syndrome p < 0.001), including patient populations (emergency department vs ICU), study design (retrospective vs prospective), and countries (developed vs resource-limited). Quick Sequential Organ Failure Assessment score was more specific (specificity, 74.58%; 95% CI, 73.55–75.61%) than systemic inflammatory response syndrome (specificity, 35.24%; 95% CI, 22.80–47.69%) but less sensitive (56.39%; 95% CI, 50.52–62.27%) than systemic inflammatory response syndrome (78.84%; 95% CI, 74.48–83.19%). Conclusions: Overall, quick Sequential Organ Failure Assessment score outperforms systemic inflammatory response syndrome in predicting sepsis outcome, but quick Sequential Organ Failure Assessment score has relative strengths/weaknesses (more specific but less sensitive) compared with systemic inflammatory response syndrome.

There is currently no reliable tool available to measure immune dysfunction in septic patients in the clinical setting. This proof-of-concept study assesses the potential of gene expression profiling of whole blood as a tool to monitor immune dysfunction in critically ill septic patients. Whole-blood samples were collected daily for up to 5 days from patients admitted to the intensive care unit with sepsis. RNA isolated from whole-blood samples was assayed on Illumina HT-12 gene expression microarrays consisting of 48,804 probes. Microarray analysis identified 3,677 genes as differentially expressed across 5 days between septic patients and healthy controls. Of the 3,677 genes, biological pathway analysis identified 86 genes significantly downregulated in the sepsis patients were present in pathways relating to immune response. These 86 genes correspond to known immune pathways implicated in sepsis, including lymphocyte depletion, reduced T-lymphocyte activation, and deficient antigen presentation. Furthermore, expression levels of these genes correlated with clinical severity, with a significantly greater degree of downregulation found in nonsurvivors compared with survivors. The results show that whole-blood gene expression analysis can capture systemic immune dysfunctions in septic patients. Our study provides an experimental basis to support further study on the use of a gene expression-based assay, to assess immunosuppression, and to guide immunotherapy in future clinical trials.

Cardiac output (CO) is dependent on a number of factors, in particular, the systolic function of the heart. Tissue Doppler (TD) is a modality in echocardiography that measures myocardial velocity and is related to contractility. TD can therefore be used to measure the systolic function of the heart. This study sought to establish whether the systolic component of TD can be used to estimate CO in critically ill patients. Retrospective data was obtained from a total of 80 patients: 29 patients with a normal echocardiogram, and 51 intensive care unit patients; 28 septic and 23 with heart failure. The mean TD peak systolic velocity (Sm) was significantly lower in the heart failure patients (P

The current trend to treat hypotension in critically ill patients is to place a greater emphasis on inotropic support and less on fluid resuscitation in order to limit the potential harm from fluid overload. This combination may trigger left ventricular outflow tract obstruction (LVOTO) in susceptible patients. Although LVOTO is classically described in patients with hypertrophic cardiomyopathy it has been reported in other conditions including septic shock, apical ballooning syndrome, myocardial infarction, respiratory failure, and post valvular surgery. It is more common in the elderly, females, and in patients with hypertension, diabetes, and chronic vascular disease because of predisposing anatomical conditions such as left ventricular hypertrophy, small left ventricle size, sigmoid septum and alterations in the positions of the aortic and mitral valve annular planes. The onset of LVOTO is largely unpredictable due to a complex interplay between preload, afterload, heart rhythm and rate in susceptible patients. The consequences of missing this treatable condition may lead to life-threatening hypotension refractory to, or exacerbated by, a further increase in inotropic support. Dynamic LVOTO should be considered in any hypotensive intensive care patient. Echocardiography is perhaps the best tool to assess LVOTO and its underlying pathophysiology in the critically ill. Detection of LVOTO is a relatively simple task using a combination of two-dimensional, M-mode and spectral Doppler imaging by an operator alert to the possible diagnosis.

To compare lung ultrasonography (LUS), chest xray (CXR) and physical examination (Ex) for the detection of pathological abnormalities in the lungs of critically ill patients.A prospective cohort study of 145 patients in the intensive care unit of a tertiary teaching hospital who were undergoing echocardiography for a clinical indication.Each patient was independently assessed by Ex, CXR and LUS on the same day. Examiners were asked to comment on the presence or absence and severity of pleural effusion, lung consolidation and alveolar interstitial syndrome (AIS). Independent expert examiners performed the LUS and an independent radiologist reported on the CXR.Ex, CXR and LUS were in fair agreement with each other in detecting a pulmonary abnormality (CXR v LUS, κ = 0.31; CXR v Ex, κ = 0.29; LUS v Ex, κ = 0.22). LUS detected more abnormalities than did CXR (16.2%; χ(2) = 64.1; P0.001) or Ex (23.5%; χ(2) = 121.9; P0.001). CXR detected more pleural effusions than LUS (9.3%; χ(2) = 7.6; κ = 0.39), but LUS detected more pleural effusions than Ex (22.8%; χ(2) = 36.4; κ = 0.18). There was no significant difference in the performance of LUS and CXR in quantifying the size of a pleural effusion (Z = -1.2; P = 0.23). Ex underestimated size compared with CXR or LUS. LUS detected more consolidation than CXR (17%; χ(2) = 115.9; P0.001) and Ex (16.2%; χ(2) = 90.3; P0.001). We saw no difference in performance between CXR and Ex in detecting lung consolidation (0.9%; χ(2) = 0.51; P0.48). LUS detected more cases of AIS than CXR (5.5%; χ(2) = 7.9; P = 0.005) and Ex (13%; χ(2) = 25.8; P0.001).There was only fair-to-moderate agreement between LUS, CXR and Ex in detecting pulmonary abnormalities, including pleural effusion, lung consolidation and AIS. The higher rate of detection from LUS, combined with its ease of use and increasing accessibility, makes for a powerful diagnostic tool in the ICU.

Host response biomarkers can accurately distinguish between influenza and bacterial infection. However, published biomarkers require the measurement of many genes, thereby making it difficult to implement them in clinical practice. This study aims to identify a single-gene biomarker with a high diagnostic accuracy equivalent to multi-gene biomarkers.In this study, we combined an integrated genomic analysis of 1071 individuals with

Activation of the poly(ADP-ribose)polymerase (PARP), a highly energy-consuming DNA-repairing enzyme, plays a crucial role in the pathogenesis of multiorgan failure. Most results, however, were derived from experiments with hypodynamic shock states characterized by a markedly decreased cardiac output (CO) and/or using a pretreatment approach. Therefore, we investigated the effects of the novel potent and selective PARP-1 inhibitor PJ34 in a posttreatment model of long-term, volume-resuscitated porcine endotoxemia. Anesthetized, mechanically ventilated and instrumented pigs received continuous intravenous (i.v.) lipopolysaccharide (LPS) over 24 h. Hydroxyethyl starch was administered to maintain a mean arterial pressure > 65 mmHg. After 12 h of LPS infusion, the animals were randomized to receive either vehicle (Control, n = 9) or i.v. PJ34 (n = 6; 10 mg/kg over 1 h followed by 2 mg/kg/h until the end of the experiment). Measurements were performed before as well as at 12, 18, and 24 h of LPS infusion. In all animals CO increased because of reduced systemic vascular resistance (SVR) and fluid resuscitation. PJ34 further raised CO (P < 0.05 vs. control group) as the result of a higher stroke volume indicating its positive inotropic effect. In addition, it diminished the rise in the ileal mucosal-arterial PCO 2 gap, which returned to baseline levels at 24 h of LPS, and improved the gut lactate balance (P = 0.093 PJ34 vs. control) together with significantly lower portal venous lactate/pyruvate ratios. By contrast, it failed to influence the LPS-induced derangements of liver metabolism. Incomplete PARP inhibition because of dilutional effects and/or an only partial efficacy when used in post-treatment approaches may account for this finding.

Objective. To determine the mechanisms of improved gut mucosal acidosis associated with selective inducible nitric oxide synthase (iNOS) inhibition. Design. Prospective, controlled experimental study. Setting. Animal research laboratory. Animals. Fourteen domestic pigs. Interventions. Anesthetized and mechanically ventilated pigs received continuous i.v. endotoxin for 24 h. A selective iNOS-inhibitor (1400W, n=8) or vehicle (control, n=6) was started at 12 h of endotoxin and infused until the end of the experiment. Measurements and results. Before as well as at 12 and 24 h of endotoxin, portal venous flow (ultrasound probe), intestinal oxygen (O2) extraction, portal venous-arterial carbon dioxide (CO2) content difference and ileal mucosal-arterial PCO2 gap (fiberoptic sensor) were assessed together with video recordings of the villous microcirculation (number of perfused/unperfused villi) using orthogonal polarization spectral imaging via an ileostomy. The gut wall microvascular blood flow (units) and hemoglobin O2 saturation (µHb-O2) were assessed with a combined laser Doppler flow and remission spectrophotometry probe. 1400W blunted the otherwise progressive rise in the PCO2 gap without affecting portal venous flow, regional O2 and CO2 exchange or the number of unperfused villi. While endotoxin markedly aggravated the heterogeneity of the microvascular blood flow and oxygenation, 1400W had no further effect. Conclusions. Given the uninfluenced parameters of the ileal mucosal microcirculation in our model of long-term porcine endotoxemia, selective iNOS inhibition probably improved the PCO2 gap due to a redistribution of the microvascular perfusion within the gut wall and/or an amelioration of the cellular respiration.

Objective: The impact of the start of continuous veno-venous haemodiafiltration (CVVHDF) on gastric mucosal carbon dioxide concentration (PiCO2) - a marker of gastric mucosal perfusion and CO2 production - was studied. Design: Prospective observational study. Setting: University hospital medical intensive care unit (ICU). Subjects: Sixteen critically ill haemodynamically stable patients (APACHE II on admission 30±7) with multiple organ dysfunction syndrome, in whom CVVHDF was started because of acute renal failure were studied. Two patients were excluded from the analysis because of major haemodynamic instability during the study period. Interventions: Initiation of CVVHDF, placement of gastric tonometer. Measurements and main results: PiCO2 was measured using saline tonometry in 13 patients, and air tonometry in one patient at baseline and then at 1,2,3 and 6 h after starting CVVHDF. A gastric-arterial CO2 gap of > 15 torr (2 kPa) was chosen asa cut-off value of the presence of gastric musocal acidosi...

Host response biomarkers can accurately distinguish between influenza and bacterial infection. However, published biomarkers require the measurement of many genes, thereby making it difficult to implement them in clinical practice. This study aims to identify a single-gene biomarker with a high diagnostic accuracy equivalent to multi-gene biomarkers.In this study, we combined an integrated genomic analysis of 1071 individuals with in vitro experiments using well-established infection models.We identified a single-gene biomarker, IFI27, which had a high prediction accuracy (91%) equivalent to that obtained by multi-gene biomarkers. In vitro studies showed that IFI27 was upregulated by TLR7 in plasmacytoid dendritic cells, antigen-presenting cells that responded to influenza virus rather than bacteria. In vivo studies confirmed that IFI27 was expressed in influenza patients but not in bacterial infection, as demonstrated in multiple patient cohorts (n=521). In a large prospective study (n=439) of patients presented with undifferentiated respiratory illness (aetiologies included viral, bacterial and non-infectious conditions), IFI27 displayed 88% diagnostic accuracy (AUC) and 90% specificity in discriminating between influenza and bacterial infections.IFI27 represents a significant step forward in overcoming a translational barrier in applying genomic assay in clinical setting; its implementation may improve the diagnosis and management of respiratory infection.

Seven healthy volunteers and nine stable intensive care unit (ICU) patients with poor tolerance of gastric feeding were investigated. In volunteers, postpyloric feeding does not interfere with gastric tonometry measurement and gastric bolus leads to a PiCO2 decrease. The impact of postpyloric and gastric feeding on gastric tonometry in ICU patients with compromised gut is variable.

We examined if a loss-of-function polymorphism in the P2X(7) receptor (1513C) corresponded with circulating interleukin(IL)-18 concentrations in heart failure (HF) patients. IL-18 values were significantly elevated in HF subjects compared to healthy control subjects. No association was seen between the polymorphism and IL-18 concentrations in HF patients. In HF patients, IL-18 values had an inverse relationship with ejection fraction, mean arterial pressure and body mass index, while high IL-18 concentrations were associated with increased mortality.

Influenza A infection is a global disease that has been responsible for four pandemics over the last one hundred years. However, it remains poorly understood as to why some infected individuals succumb to life threatening complications whilst others recover and are relatively unaffected. Using gene-expression analysis of circulating leukocytes, here we show that the progression towards severe influenza A infection is characterised by an abnormal transcriptional reprogramming of cell cycle and apoptosis pathways. In severely infected humans, leukocyte gene-expression profiles display opposing cell cycle activities; an increased aberrant DNA replication in the G(1)/S phase yet delayed progression in the G(2)/M phase. In mild infection, cell cycle perturbations are fewer and are integrated with an efficient apoptotic program. Importantly, the loss of integration between cell cycle perturbations and apoptosis marks the transition from a mild viral illness to a severe, life threatening infection. Our findings suggest that circulating immune cells may play a significant role in the evolution of the host response. Further study may reveal alternative host response factors previously unrecognized in the current disease model of influenza.

OBJECTIVE Critical illness is associated with tissue damage, inflammation and the development of immune dysfunction. Leukocyte reprogramming occurs leading to insufficient production of pro-inflammatory cytokines upon subsequent stimulation. Cellular nucleotides released during tissue damage act via purinergic receptors to modulate immune function. We hypothesized that extracellular nucleotides in concentrations similar to those found near injured and ischemic tissues will modulate cytokine secretion. DESIGN AND PARTICIPANTS Bench study in 28 healthy human volunteers using standardized lipopolysaccharide (LPS) stimulated ex vivo whole blood cultures (ILCS). SETTING The Nepean Hospital Laboratories, University of Sydney. INTERVENTIONS Nucleotides ATP, ADP and other P2 purinergic receptor agonists ATPgammaS, BzATP, UTP and P1 agonist CV1808 were injected into the ILCS, and cultured for 6, 12 and 24 h as indicated. MEASUREMENTS AND RESULTS ATP (100 muM) reduced the LPS stimulated secretion of TNFalpha at 6 and 12 h, as well as IL-12(p70) and IFNgamma at 24 h of incubation. ADP, ATPgammaS, BzATP, and CV1808, but not UTP displayed IL-12(p70) and IFNgamma reducing effect similar to ATP. Higher ATP concentration (500 muM) had even more pronounced immunosuppressive effect. Nucleotides had variable effect on stimulated IL-10 secretion. CONCLUSIONS ATP and ADP at high-micromolar concentrations reduce secretion of the main Th1 cytokines TNFalpha, IL-12(p70) and IFNgamma in LPS stimulated human blood. As immune dysfunction associated with critical illness is characterized by decreased TNFalpha, IL-12 and IFNgamma production by leukocytes, extracellular nucleotides might contribute to its pathogenesis [corrected]

To investigate the changes in B-type natriuretic peptide concentrations in patients with severe sepsis and septic shock and to investigate the value of B-type natriuretic peptide in predicting intensive care unit outcomes.Prospective observational study.General intensive care unit.Forty patients with severe sepsis or septic shock.None.B-type natriuretic peptide measurements and echocardiography were carried out daily for 10 consecutive days. In-hospital mortality and length of stay were recorded. The admission B-type natriuretic peptide concentrations were generally increased (747 +/- 860 pg/mL). B-type natriuretic peptide levels were elevated in patients with normal left ventricular systolic function (568 +/- 811 pg/mL), with sepsis-related reversible cardiac dysfunction (630 +/- 726 pg/mL), and with chronic cardiac dysfunction (1311 +/- 1097 pg/mL). There were no significance changes in B-type natriuretic peptide levels over the 10-day period. The daily B-type natriuretic peptide concentrations for the first 3 days neither predicted in-hospital mortality nor correlated with length of intensive care unit or hospital stay.B-type natriuretic peptide concentrations were increased in patients with severe sepsis or septic shock regardless of the presence or absence of cardiac dysfunction. Neither the B-type natriuretic peptide levels for the first 3 days nor the daily changes in B-type natriuretic peptide provided prognostic value for in-hospital mortality and length of stay in this mixed group of patients, which included patients with chronic cardiac dysfunction.

A 72-year-old patient with multiple myeloma was admitted to the intensive care unit because of hypercalcemic crisis and acute renal failure. After 7 days of comprehensive therapy including diuretics steroids, calcitonin, and intermittent hemodialysis (IHD) with low-calcium dialysate, calcium still reached high levels between IHD treatments and thrombocytopenia developed after chemotherapy. CVVHDF with calcium-free bicarbonate dialysate was started. Anticoagulation with 2.2% citrate was performed in order to chelate calcium, and thus treat the hypercalcemia, and to provide regional anticoagulation, and thus reduce the risk of bleeding due to thrombocytopenia. CVVHDF with citrate anticoagulation was continued for 6 days, and standard heparin anticoagulation was started when the hypercalcemia and thrombocytopenia abated.

Introduction Tracheostomy is one of the more commonly performed procedures in critically ill patients yet the optimal method of performing tracheostomies in this population remains to be established. The aim of this study was to systematically review and quantitatively synthesize all randomized clinical trials (RCTs), comparing elective percutaneous dilatational tracheostomy (PDT) and surgical tracheostomy (ST) in adult critically ill patients with regards to major short and long term outcomes. Methods MEDLINE, EMBASE, CINAHL and the Cochrane Controlled Clinical Trials Register databases were searched to identify relevant studies. Additionally, bibliographies and selected conference proceedings were reviewed, and experts in the field and manufacturers of two PDT kits were contacted. Randomized clinical trials comparing any method of elective PDT to ST that included critically ill adults and reported at least one clinically relevant outcome were included. Data extracted included trial characteristics, measures of study validity, and clinically relevant outcomes. Results Seventeen RCTs involving 1,212 patients were included. Most PDTs used a multiple dilator technique and were performed in the intensive care unit (ICU). The pooled odds ratio (OR) for wound infection was 0.28 (95% confidence interval (CI), 0.16 to 0.49, p < 0.0005), indicating a significant reduction with PDT compared to ST. Overall, PDT was equivalent to ST for bleeding, major peri-procedural and long-term complications; however, subgroup analysis suggested PDT resulted in a lower incidence of bleeding (OR = 0.29 (95% CI 0.12 to 0.75, p = 0.01)) and death (OR = 0.71 (95% CI 0.50 to 1.0, p = 0.05)) when the STs were performed in the operating theatre. Conclusion PDT reduces the overall incidence of wound infection and may further reduce clinical relevant bleeding and mortality when compared with ST performed in the operating theatre. PDT, performed in the ICU, should be considered the procedure of choice for performing elective tracheostomies in critically ill adult patients.