Measuring cardiac output at the bedside.

PURPOSE OF REVIEW: Bedside cardiac output (CO) measurement is an important part of routine hemodynamic monitoring in the differential diagnosis of circulatory shock and fluid management. Different choices of CO measurement devices are available. The purpose of this review is to review the importance of CO [or stroke volume (SV)] measurement and to discuss the various methods (devices) used in determination of CO. RECENT FINDINGS: CO measurement devices can be classified into two types: those use simple physical principles with minimal assumptions, and those predicting CO via mathematical modelling with a number of assumptions. Both have pros and cons, with the former being more accurate but with limited continuous monitoring capability whereas the latter less accurate but usually equipped with continuous monitoring functionality. With frequent updates in mathematical models, research data constantly become outdated in this area. Recent data suggest devices based on mathematical modelling have limited accuracies and poor precisions. SUMMARY: Measurement of CO or SV is important in critically ill patients. Most devices have accuracy and reliability issues. The choice of device should depend on the purpose of measurement. For diagnostic purposes, devices based on simple physical principles, especially thermodilution and transthoracic echocardiography are more reliable due to accuracy.

The use of echocardiographic indices in defining and assessing right ventricular systolic function in critical care research.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Longitudinal wall fractional shortening: an M-mode index based on mitral annular plane systolic excursion (MAPSE) that correlates and predicts left ventricular longitudinal strain (LVLS) in intensive care patients.

BACKGROUND: Left ventricular longitudinal strain (LVLS) is a modern measurement for LV function. However, strain measurement is often difficult in critically ill patients. We sought to show LVLS can be estimated using M-mode-derived longitudinal wall fractional shortening (LWFS), which is less dependent on image quality and is easier to perform in critically ill patients. METHODS: Transthoracic echocardiographic records were retrospectively screened and 80 studies suitable for strain and M-mode measurements in the apical 4-chamber view were selected. Longitudinal wall fractional shortening was derived from conventional M-mode (LWFS) and curved anatomical M-mode (CAMMFS). The relationships between LVLS and mitral annular plane systolic excusion (MAPSE) and M-mode-derived fractional shortening were examined using univariate generalized linear model in a training set (n = 50) and was validated in a separate validation set (n = 30). RESULTS: MAPSE, CAMMFS, and LWFS demonstrated very good correlations with LVLS (r = 0.852, 0.875 and 0.909, respectively). LWFS was the best unbiased predictor for LVLS (LVLS = 1.180 x LWFS - 0.737, P < 0.001). Intra- and inter-rater agreement and reliability for LWFS measurement were good. CONCLUSIONS: LVLS can be estimated by LWFS in the critically ill patients. It provides a fast and accurate prediction of LVLS. LWFS is a reproducible and reliable measurement which can be used as a potential index in place of LVLS in the critically ill population.

Brain not processing: is finding a role for BNP in sepsis like fitting a square peg into a round hole?

Since its introduction to the intensive care setting a decade ago, B-type natriuretic peptide has been the focus of studies in different areas (in particular, sepsis). With this biomarker, as with many newly identified biomarkers, its diagnostic performance was pursued initially and then its ability to predict outcomes. Despite all the efforts, results have not been consistent and the applications of B-type natriuretic peptide in the intensive care setting remain by and large academic. Will such studies one day become clinical practice? Or are we too obsessed with finding a place for every biomarker?

Identifying key regulatory genes in the whole blood of septic patients to monitor underlying immune dysfunctions.

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.

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

INTRODUCTION: Reversible 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. METHODS: PubMed, 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. RESULTS: A 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. CONCLUSION: This 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.

From speckle tracking echocardiography to torsion: research tool today, clinical practice tomorrow.

PURPOSE OF REVIEW: Speckle tracking is the latest available technology in echocardiography. However, the technology is still mainly used as a research tool. The potential applications of speckle tracking are many, including cardiac synchronization, regional wall motion analysis, and in the areas of cardiac mechanic studies. This review presents the background theory of speckle tracking echocardiography (STE) and how this technology can be extended to velocity vector analysis, strain, and torsion measurements. The interpretations of these measurements are covered. We also present some potential applications in the critical care setting. RECENT FINDINGS: Speckle tracking is almost always available in high-end ultrasound machines. The technology has been applied to velocity vector analysis, strain and strain rate measurements, and twist and torsion analysis. Torsion analysis and velocity vector analyses are impossible without using speckle tracking. Speckle tracking-derived strain is superior to tissue Doppler strain because it is angle-independent. A number of studies demonstrated that STE is useful in left and right heart assessments and can be used in assessing preload and afterload. SUMMARY: Speckle tracking can be used to measure instantaneous myocardial contractility, strain, and left ventricular torsion. It is still a research tool at present, but shows the promise of being a clinical tool in the future.

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

INTRODUCTION: Diagnosis 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. METHODS: Whole-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. RESULTS: The 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. CONCLUSIONS: The 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.

Cardiac biomarkers in the intensive care unit.

Cardiac biomarkers (CB) were first developed for assisting the diagnosis of cardiac events, especially acute myocardial infarction. The discoveries of other CB, the better understanding of cardiac disease process and the advancement in detection technology has pushed the applications of CB beyond the 'diagnosis' boundary. Not only the measurements of CB are more sensitive, the applications have now covered staging of cardiac disease, timing of cardiac events and prognostication. Further, CB have made their way to the intensive care setting where their uses are not just confined to cardiac related areas. With the better understanding of the CB properties, CB can now help detecting various acute processes such as pulmonary embolism, sepsis-related myocardial depression, acute heart failure, renal failure and acute lung injury. This article discusses the properties and the uses of common CB, with special reference to the intensive care setting. The potential utility of "multimarkers" approach and microRNA as the future CB are also briefly discussed.

Appreciating the strengths and weaknesses of transthoracic echocardiography in hemodynamic assessments.

Transthoracic echocardiography (TTE) is becoming the choice of hemodynamic assessment tool in many intensive care units. With an ever increasing number of training programs available worldwide, learning the skills to perform TTE is no longer a limiting factor. Instead, the future emphasis will be shifted to teach the users how to recognize measurement errors and artefacts (internal validity), to realize the limitations of TTE in various applications, and finally how to apply the information to the patient in question (external validity). This paper aims to achieve these objectives in a common area of TTE application-hemodynamic assessments. We explore the strengths and weaknesses of TTE in such assessments in this paper. Various methods of hemodynamic assessments, such as cardiac output measurements, estimation of preload, and assessment of fluid responsiveness, will be discussed.

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

INTRODUCTION: Sepsis 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. METHODS: Electronic 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. RESULTS: We 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. CONCLUSIONS: Sepsis 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.

Do we need a critical care ultrasound certification program? Implications from an Australian medical-legal perspective.

Medical practitioners have a duty to maintain a certain standard of care in providing their services. With critical care ultrasound gaining popularity in the ICU, it is envisaged that more intensivists will use the tool in managing their patients. Ultrasound, especially echocardiography, can be an 'easy to learn, difficult to manage' skill, and the competency in performing the procedure varies greatly. In view of this, several recommendations for competency statements have been published in recent years to advocate the need for a unified approach to training and certification. In this paper, we take a slightly different perspective, from an Australian medical-legal viewpoint, to argue for the need to implement a critical care ultrasound certification program. We examine various issues that can potentially lead to a breach of the standard of care, hence exposing the practitioners and/or the healthcare institutions to lawsuits in professional negligence or breach of contract. These issues, among others, include the failure to use ultrasound in appropriate situations, the failure of hospitals to ensure practitioners are properly trained in the skills, the failure of practitioners to perform an ultrasound study that is of a reasonable standard, and the failure of practitioners to keep themselves abreast of the latest developments in treatment and management. The implications of these issues and the importance of having a certification process are discussed.

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.

Bench-to-bedside review: the value of cardiac biomarkers in the intensive care patient.

The use of cardiac biomarkers in the intensive care setting is gaining increasing popularity. There are several reasons for this increase: there is now the facility for point-of-care biomarker measurement providing a rapid diagnosis; biomarkers can be used as prognostic tools; biomarkers can be used to guide therapy; and, compared with other methods such as echocardiography, the assays are easier and much more affordable. Two important characteristics of the ideal biomarker are disease specificity and a linear relationship between the serum concentration and disease severity. These characteristics are not present, however, in the majority of biomarkers for cardiac dysfunction currently available. Those clinically useful cardiac biomarkers, which naturally received the most attention, such as troponins and B-type natriuretic peptide, are not as specific as was originally thought. In the intensive care setting, it is important for the user to understand the degree of specificity of these biomarkers and that the interpretation of the results should always be guided by other clinical information. The present review summarizes the available biomarkers for different cardiac conditions. Potential biomarkers under evaluation are also briefly discussed.

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.

The use of gene-expression profiling to identify candidate genes in human sepsis.

RATIONALE: Our understanding of the pathophysiology of sepsis remains incomplete. Genomewide study offers an unbiased, system biology approach to examine the expression patterns of circulating leukocytes and may reveal novel insights into the host response to sepsis. OBJECTIVES: We examined whether gene-expression profiling of neutrophils could identify signature genes and important pathways in the clinical syndrome of sepsis. METHODS: Gene-expression profiling was performed using oligonucleotide microarrays on peripheral blood samples of 94 critically ill patients (71 septic and 23 nonseptic). Using a supervised learning algorithm based on support vector machine, a molecular signature of sepsis was generated from a training set of 44 samples and validated in an independent set of 50 samples. The diagnostic performance of the signature genes was assessed against a reference standard based on the International Sepsis Forum Consensus Conference definition of infection. MEASUREMENTS AND MAIN RESULTS: A set of 50 signature genes correctly identified sepsis with a prediction accuracy of 91 and 88% in the training and validation sets, respectively. The diagnostic performance remained high regardless of patient's age, comorbidities, or prior antibiotic treatment. Compared with controls, genes involved in immune modulation and inflammatory response had reduced expression in patients with sepsis. In particular, the activation of nuclear factor-kappaB pathway was reduced, whereas its inhibitor gene, NFKBIA, was significantly up-regulated. CONCLUSIONS: The signature genes reflect suppression of neutrophils' immune and inflammatory function by sepsis. Gene-expression profiling therefore provides a novel approach to advance our understanding of the host response in 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.