Anthony S. McLean

Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis*

Objective:Controversy remains as to whether low-dose corticosteroids can reduce the mortality and morbidity of acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS) without increasing the risk of adverse reactions. We aimed to evaluate all studies investigating prolonged corticosteroids in low-to-moderate dose in ALI or ARDS. Data Sources:MEDLINE, EMBASE, Current Content, and Cochrane Central Register of Controlled Trials, and bibliographies of retrieved articles. Study Selection:Randomized controlled trials (RCTs) and observational studies reported in any language that used 0.5–2.5 mg·kg−1·d−1 of methylprednisolone or equivalent to treat ALI/ARDS. Data Extraction:Data were extracted independently by two reviewers and included study design, patient characteristics, interventions, and mortality and morbidity outcomes. Data Synthesis:Both cohort studies (five studies, n = 307) and RCTs (four trials, n = 341) showed a similar trend toward mortality reduction (RCTs relative risk 0.51, 95% CI 0.24–1.09; p = 0.08; cohort studies relative risk 0.66, 95% CI 0.43–1.02; p = 0.06). The overall relative risk was 0.62 (95% CI 0.43–0.91; p = 0.01). There was also improvement in length of ventilation-free days, length of intensive care unit stay, Multiple Organ Dysfunction Syndrome Score, Lung Injury Scores, and improvement in Pao2/Fio2. There was no increase in infection, neuromyopathy, or any major complications. There was significant heterogeneity in the pooled studies. Subgroup and meta-regression analyses showed that heterogeneity had minimal effect on treatment efficacy; however, these findings were limited by the small number of studies used in the analyses. Conclusion:The use of low-dose corticosteroids was associated with improved mortality and morbidity outcomes without increased adverse reactions. The consistency of results in both study designs and all outcomes suggests that they are an effective treatment for ALI or ARDS. The mortality benefits in early ARDS should be confirmed by an adequately powered randomized trial.

The confounding effects of age, gender, serum creatinine, and electrolyte concentrations on plasma B-type natriuretic peptide concentrations in critically ill patients.

ObjectiveTo investigate the confounding effects of age, gender, serum creatinine, and electrolyte concentrations on plasma B-type natriuretic peptide (BNP) concentrations in critically ill patients. DesignA prospective cross-sectional study. SettingA 20-bed general intensive care unit of a tertiary referral hospital. PatientsPatients were 121 patients admitted to the intensive care unit over a period of 9 wks. InterventionsIntravenous blood was collected for BNP measurements, and cardiac investigations including echocardiography were carried out for every patient on admission. Measurements and Main ResultsThe mean BNP concentration was 201 ± 317 pg/mL (n = 121). Thirty-five patients (28.9%), identified to have cardiac abnormalities, exhibited higher BNP concentrations than those without cardiac abnormalities (518 ± 394 vs. 60 ± 98 pg/mL, p < .001). The females exhibited higher concentrations of BNP than males in the noncardiac abnormality group (96 ± 132 pg/mL, n = 39 vs. 31 ± 38 pg/mL, n = 47, p = .016). BNP correlated significantly with age (r2 = .19) and creatinine (r2 = .084). The latter correlation became insignificant when patients with cardiac abnormality were excluded. No correlation was found between serum Na+ and K+ concentrations with BNP. Multivariate analyses demonstrated that the presence of cardiac abnormalities accounted for nearly 50% of the BNP variation. Addition of age and gender improved R2 to 60%. The contribution of creatinine was found to be insignificant. There was no association between BNP concentrations and serum Na+ and K+ concentrations. Logistic analysis confirmed that BNP is the strongest predictor for cardiac abnormalities in the critically ill patients. ConclusionThe current study demonstrated that plasma BNP concentrations increased with age and were higher in females than in males. Although the presence of cardiac disease was the most important determinant for BNP variations, age and gender also contributed significantly. The results suggest that age and gender need to be taken into account in the interpretation of BNP concentrations in critically ill patients.

Gene-expression profiling of peripheral blood mononuclear cells in sepsis.

Objectives:It has been shown that gene-expression profiling of circulating neutrophils could identify signature genes of sepsis. However, whether similar transcriptional changes occurred in peripheral blood mononuclear cells (PBMC) was not known. Using microarray technology, we performed gene-expression profiling of PBMC to identify signature genes that distinguish sepsis from noninfectious causes of systemic inflammatory response syndrome (SIRS), between Gram-positive and Gram-negative sepsis. Design:A cross-sectional, observational study. Setting:A 20-bed general intensive care unit of a tertiary referral hospital. Patients:Seventy critically ill patients (46 sepsis and 24 SIRS). Interventions:Intravenous blood was collected for leukocyte separation and RNA extraction. Gene-expression profiling was performed on PBMC using Affymetrix GeneChip microarrays with 54,675 transcripts. Data were divided into a training set (n = 35) and a validation set (n = 35). A molecular signature was developed in the training set using support vector machine and was then validated in the validation set. Measurements and Main Results:We identified a molecular signature of 138 genes that could differentiate between sepsis and SIRS patients with 91% and 80% accuracy in the training and validation sets, respectively. There were no signature genes that could differentiate between Gram-positive and Gram-negative sepsis. The expression of genes involved in inflammatory response and immune function was significantly reduced in septic patients when compared with those with SIRS. Genes involved in apoptosis, on the other hand, were more highly expressed in septic patients. Conclusion:There was evidence of sepsis-related immunosuppression and reduced inflammatory response in mononuclear cells on a transcriptome level. These characteristic transcriptional changes can be used to aid the diagnosis of sepsis.

Genome-wide transcription profiling of human sepsis: a systematic review

IntroductionSepsis is thought to be an abnormal inflammatory response to infection. However, most clinical trials of drugs that modulate the inflammatory response of sepsis have been unsuccessful. Emerging genomic evidence shows that the host response in sepsis does not conform to a simple hyper-inflammatory/hypo-inflammatory model. We, therefore, synthesized current genomic studies that examined the host response of circulating leukocytes to human sepsis.MethodsElectronic searches were performed in Medline and Embase (1987 to October 2010), supplemented by additional searches in multiple microarray data repositories. We included studies that (1) used microarray, (2) were performed in humans and (3) investigated the host response mediated by circulating leukocytes.ResultsWe identified 12 cohorts consisting of 784 individuals providing genome-wide expression data in early and late sepsis. Sepsis elicited an immediate activation of pathogen recognition receptors, accompanied by an increase in the activities of signal transduction cascades. These changes were consistent across most cohorts. However, changes in inflammation related genes were highly variable. Established inflammatory markers, such as tumour necrosis factor-α (TNF-α), interleukin (IL)-1 or interleukin-10, did not show any consistent pattern in their gene-expression across cohorts. The finding remains the same even after the cohorts were stratified by timing (early vs. late sepsis), patient groups (paediatric vs. adult patients) or settings (clinical sepsis vs. endotoxemia model). Neither a distinctive pro/anti-inflammatory phase nor a clear transition from a pro-inflammatory to anti-inflammatory phase could be observed during sepsis.ConclusionsSepsis related inflammatory changes are highly variable on a transcriptional level. We did not find strong genomic evidence that supports the classic two phase model of sepsis.

Prognostic values of B-type natriuretic peptide in severe sepsis and septic shock.

Objective: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. Design:Prospective observational study. Setting:General intensive care unit. Patients:Forty patients with severe sepsis or septic shock. Interventions:None. Measurements and Main Results: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. Conclusion: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.

International consensus statement on training standards for advanced critical care echocardiography

Endorsed by the European Society of Intensive Care Medicine (ESICM), American College of Chest Physicians (ACCP), American Thoracic Society (ATS), Société de Réanimation de Langue Française (SRLF), Asia Pacific Association of Critical Care Medicine, Canadian Critical Care Society, College of Intensive Care Medicine of Australia and New Zealand, Hong Kong College of Anaesthesiologists, Hong Kong Society of Critical Care Medicine. All authors certify that they endorse all parts of the published manuscript. The expert round table participants and the authors as a group are listed in the Appendix.

Development and validation of a novel molecular biomarker diagnostic test for the early detection of sepsis

IntroductionSepsis is a complex immunological response to infection characterized by early hyper-inflammation followed by severe and protracted immunosuppression, suggesting that a multi-marker approach has the greatest clinical utility for early detection, within a clinical environment focused on Systemic Inflammatory Response Syndrome (SIRS) differentiation. Pre-clinical research using an equine sepsis model identified a panel of gene expression biomarkers that define the early aberrant immune activation. Thus, the primary objective was to apply these gene expression biomarkers to distinguish patients with sepsis from those who had undergone major open surgery and had clinical outcomes consistent with systemic inflammation due to physical trauma and wound healing.MethodsThis was a multi-centre, prospective clinical trial conducted across four tertiary critical care settings in Australia. Sepsis patients were recruited if they met the 1992 Consensus Statement criteria and had clinical evidence of systemic infection based on microbiology diagnoses (n = 27). Participants in the post-surgical (PS) group were recruited pre-operatively and blood samples collected within 24 hours following surgery (n = 38). Healthy controls (HC) included hospital staff with no known concurrent illnesses (n = 20). Each participant had minimally 5 ml of PAXgene blood collected for leucocyte RNA isolation and gene expression analyses. Affymetrix array and multiplex tandem (MT)-PCR studies were conducted to evaluate transcriptional profiles in circulating white blood cells applying a set of 42 molecular markers that had been identified a priori. A LogitBoost algorithm was used to create a machine learning diagnostic rule to predict sepsis outcomes.ResultsBased on preliminary microarray analyses comparing HC and sepsis groups, a panel of 42-gene expression markers were identified that represented key innate and adaptive immune function, cell cycling, WBC differentiation, extracellular remodelling and immune modulation pathways. Comparisons against GEO data confirmed the definitive separation of the sepsis cohort. Quantitative PCR results suggest the capacity for this test to differentiate severe systemic inflammation from HC is 92%. The area under the curve (AUC) receiver operator characteristics (ROC) curve findings demonstrated sepsis prediction within a mixed inflammatory population, was between 86 and 92%.ConclusionsThis novel molecular biomarker test has a clinically relevant sensitivity and specificity profile, and has the capacity for early detection of sepsis via the monitoring of critical care patients.

Gene-expression profiling of gram-positive and gram-negative sepsis in critically ill patients.

Objective:It is unclear whether the host response of Gram-positive sepsis differs from Gram-negative sepsis at a transcriptome level. Using microarray technology, we compared the gene-expression profiles of Gram-positive sepsis and Gram-negative sepsis in critically ill patients. Design:A prospective cross-sectional study. Setting:A 20-bed general intensive care unit of a tertiary referral hospital. Patients:Seventy-two patients admitted to the intensive care unit. Interventions:Intravenous blood was collected for leukocyte separation and RNA extraction. Microarray experiments were then performed examining the expression level of 18,664 genes in each sample. Measurements and Main Results:There was no difference in the expression profile between Gram-positive and Gram-negative sepsis. The finding remained unchanged even when genes with lower expression level were included or after statistical stringency was lowered. There were, however, 94 genes differentially expressed between sepsis and control patients. These genes included those involved in immune regulation, inflammation, and mitochondrial function. Hierarchical cluster analysis confirmed that the difference in gene expression profile existed between sepsis and control patients but not between Gram-positive and Gram-negative patients. Conclusions:Gram-positive sepsis and Gram-negative sepsis share a common host response at a transcriptome level. These findings support the hypothesis that the septic response is nonspecific and is designed to provide a more general response that can be elicited by a wide range of different microorganisms.

Is early ventricular dysfunction or dilatation associated with lower mortality rate in adult severe sepsis and septic shock? A meta-analysis

IntroductionReversible myocardial depression occurs early in severe sepsis and septic shock. The question of whether or not early ventricular depression or dilatation is associated with lower mortality in these patients remains controversial. Most studies on this topic were small in size and hence lacked statistical power to answer the question. This meta-analysis attempted to answer the question by increasing the sample size via pooling relevant studies together.MethodsPubMed, Embase (and Medline) databases and conference abstracts were searched to July 2012 for primary studies using well-defined criteria. Two authors independently screened and selected studies. Eligible studies were appraised using defined criteria. Additional information was sought the corresponding authors if necessary. Study results were pooled using random effects models. Standardized mean differences (SMD) between survivor and non-survivor groups were used as the main effect measures.ResultsA total of 62 citations were found. Fourteen studies were included in the analysis. The most apparent differences between the studies were sample sizes and exclusion criteria. All studies, except four pre-1992 studies, adopted the Consensus definition of sepsis. Altogether, there were >700 patients available for analysis of the left ventricle and >400 for the right ventricle. There were no significant differences in left ventricular ejection fractions, right ventricular ejection fractions, and right ventricular dimensions between the survivor and non-survivor groups. When indexed against body surface area or body height, the survivors and non-survivors had similar left ventricular dimensions. However, the survivors had larger non-indexed left ventricular dimensions.ConclusionThis meta-analysis failed to find any evidence to support the view that the survivors from severe sepsis or septic shock had lower ejection fractions. However, non-indexed left ventricular dimensions were mildly increased in the survivor group but the indexed dimensions were similar between the groups. Both survivors and non-survivors had similar right ventricular dimensions.

A distinct influenza infection signature in the blood transcriptome of patients with severe community-acquired pneumonia

IntroductionDiagnosis of severe influenza pneumonia remains challenging because of a lack of correlation between the presence of influenza virus and clinical status. We conducted gene-expression profiling in the whole blood of critically ill patients to identify a gene signature that would allow clinicians to distinguish influenza infection from other causes of severe respiratory failure, such as bacterial pneumonia, and noninfective systemic inflammatory response syndrome.MethodsWhole-blood samples were collected from critically ill individuals and assayed on Illumina HT-12 gene-expression beadarrays. Differentially expressed genes were determined by linear mixed-model analysis and overrepresented biological pathways determined by using GeneGo MetaCore.ResultsThe gene-expression profile of H1N1 influenza A pneumonia was distinctly different from those of bacterial pneumonia and systemic inflammatory response syndrome. The influenza gene-expression profile is characterized by upregulation of genes from cell-cycle regulation, apoptosis, and DNA-damage-response pathways. In contrast, no distinctive gene-expression signature was found in patients with bacterial pneumonia or systemic inflammatory response syndrome. The gene-expression profile of influenza infection persisted through 5 days of follow-up. Furthermore, in patients with primary H1N1 influenza A infection in whom bacterial co-infection subsequently developed, the influenza gene-expression signature remained unaltered, despite the presence of a superimposed bacterial infection.ConclusionsThe whole-blood expression-profiling data indicate that the host response to influenza pneumonia is distinctly different from that caused by bacterial pathogens. This information may speed the identification of the cause of infection in patients presenting with severe respiratory failure, allowing appropriate patient care to be undertaken more rapidly.