The Role of Transcriptomics in Redefining Critical Illness.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2023. Other selected articles can be found online at  https://www.biomedcentral.com/collections/annualupdate2023 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from  https://link.springer.com/bookseries/8901 .

The Sequential Organ Failure Assessment (SOFA) Score: has the time come for an update?

The Sequential Organ Failure Assessment (SOFA) score was developed more than 25 years ago to provide a simple method of assessing and monitoring organ dysfunction in critically ill patients. Changes in clinical practice over the last few decades, with new interventions and a greater focus on non-invasive monitoring systems, mean it is time to update the SOFA score. As a first step in this process, we propose some possible new variables that could be included in a SOFA 2.0. By so doing, we hope to stimulate debate and discussion to move toward a new, properly validated score that will be fit for modern practice.

The Role of Mitochondria in the Immune Response in Critical Illness.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2022. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2022 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .

Echocardiographic assessment of left ventricular diastolic pressure.

PURPOSE OF REVIEW: Knowledge of the left ventricular pressures throughout the cardiac cycle is of considerable assistance in managing a haemodynamically unstable patient. Invasive pressure measurement is the only accurate way to analyze ventricular diastolic pressures but this is not feasible outside the catheterization laboratory, whereas the use of a pulmonary artery catheter or Doppler echocardiography, using surrogate measurements, is available at the bedside. The ever-increasing trend toward noninvasive monitoring puts echocardiography at the forefront and considerable effort has been made to define its role in this setting. RECENT FINDINGS: Ongoing refinement of guidelines used to evaluate left ventricular diastolic function have provided a pathway for critical care physicians to better understand how to evaluate left ventricular end-diastolic pressure and/or left atrial pressures. A number of recent studies have investigated the accuracy of combined or single echocardiographic parameters in determining left ventricular diastolic pressures as compared to those obtained invasively. Specifically selected combined parameters have moderate accuracy. SUMMARY: The recent literature on the clinical application of echocardiography on the accuracy in determining left ventricular noninvasively demonstrates that although far from perfect, it can be a very useful tool.

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

OBJECTIVE: To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN: A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS: The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS: Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.

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.

Detecting impaired myocardial relaxation in sepsis with a novel tissue Doppler parameter (septal e'/s').

BACKGROUND: Left ventricular diastolic dysfunction is associated with mortality outcomes in severe sepsis and septic shock. There are ongoing issues with diagnosing diastolic dysfunction in this cohort, partly owing to the poor applicability of traditional parameters in the hyperdynamic circulation. In this feasibility study, we sought to assess the utility of a novel parameter (septal e'/s') to identify diastolic dysfunction in patients with severe sepsis and septic shock who had normal systolic function against the 2016 American Society Echocardiography and European Association of Cardiovascular Imaging (ASE/EACI) guidelines on diastolic dysfunction. METHODS: In this prospective observational pilot study, patients identified as having severe sepsis and septic shock underwent transthoracic echocardiography on day 1 and day 3 of their intensive care unit admission. In patients with normal systolic function, septal e'/s' was calculated using the peak modal velocity of the s' compared with the e' from the septal annulus tissue Doppler imaging and compared with their diastolic grade according to the 2016 ASE/EACI guidelines on diastolic dysfunction. RESULTS: On day 1 of admission, 44 of 62 patients with severe sepsis and septic shock had normal systolic function. There was a strong association of those with diastolic dysfunction having a reduced septal e'/s' compared with patients with normal diastolic function (AUC 0.91). A similar relationship was seen with patients who had indeterminate diastolic dysfunction. On day 3, 37 patients had normal systolic function. Again, there was a strong association of those with diastolic dysfunction and a reduced septal e'/s' (AUC 0.95). CONCLUSIONS: A reduction in septal e'/s' may indicate diastolic dysfunction in patients with severe sepsis and septic shock who have normal systolic function. As opposed to limited traditional measures of diastolic dysfunction, it is applicable in those with hyperdynamic systolic function.

Echocardiography in shock management.

Echocardiography is pivotal in the diagnosis and management of the shocked patient. Important characteristics in the setting of shock are that it is non-invasive and can be rapidly applied.In the acute situation a basic study often yields immediate results allowing for the initiation of therapy, while a follow-up advanced study brings the advantage of further refining the diagnosis and providing an in-depth hemodynamic assessment. Competency in basic critical care echocardiography is now regarded as a mandatory part of critical care training with clear guidelines available. The majority of pathologies found in shocked patients are readily identified using basic level 2D and M-mode echocardiography. A more comprehensive diagnosis can be achieved with advanced levels of competency, for which practice guidelines are also now available. Hemodynamic evaluation and ongoing monitoring are possible with advanced levels of competency, which includes the use of colour Doppler, spectral Doppler, and tissue Doppler imaging and occasionally the use of more recent technological advances such as 3D or speckled tracking.The four core types of shock-cardiogenic, hypovolemic, obstructive, and vasoplegic-can readily be identified by echocardiography. Even within each of the main headings contained in the shock classification, a variety of pathologies may be the cause and echocardiography will differentiate which of these is responsible. Increasingly, as a result of more complex and elderly patients, the shock may be multifactorial, such as a combination of cardiogenic and septic shock or hypovolemia and ventricular outflow obstruction.The diagnostic benefit of echocardiography in the shocked patient is obvious. The increasing prevalence of critical care physicians experienced in advanced techniques means echocardiography often supplants the need for more invasive hemodynamic assessment and monitoring in shock.

Is a Single Entry Training Scheme for Intensive Care Medicine Both Inevitable and Desirable?

The development of Intensive Care Medicine as a recognizable branch of medicine has been underway for more than half a century, with delivery by a number of different service models. This delivery may be entirely by related medical specialties, such as anesthesiology or pulmonology; alternatively, it may be as a standalone-recognized specialty and frequently by a hybrid of these two extremes. A country may have a completely different delivery model from neighboring countries, and different models may exist within a single country. Debate about the most appropriate method of providing critical care services frequently centers around the training. However, an alternative perspective is that training regimes only follow on from another objective, namely to have Intensive Care Medicine represented in important forums by dedicated critical care physicians. A historical perspective of the development of critical care in two countries over a 40-year period is discussed, whereby a transition from a multiple specialty provision of critical care medicine to that of a single binational pathway occurred. The perceived advantages and disadvantages are outlined, offering insights into how possible future challenges in a highly complex medical specialty can be anticipated and strategies formulated.

The ideal fluid.

PURPOSE OF REVIEW: The characteristics of an ideal intravenous fluid in the critically ill patient are discussed. RECENT FINDINGS: Intravenous fluids are the most frequent drug administered to patients. Questioning the use of commonly administered intravenous fluids has resulted in an increased focus on their efficacy and safety. Discrimination between fluids currently in use has been the central theme of many recent large studies, and emerging from these findings is an understanding of characteristics that would make for an ideal fluid for critically ill patients. There is increased morbidity and mortality with high chloride-containing crystalloid solutions and hydroxyethyl starch preparations, with resultant international governmental agency warnings regarding hydroxyethyl starch . The ideal fluid is one which achieves the aim of administration while minimizing or negating adverse effects, is inexpensive, and sufficiently stable when stored to be used in a wide range of clinical settings. SUMMARY: The ideal fluid currently does not exist. Of existing options, use of hydroxyethyl starches and high chloride-containing crystalloid solutions should be discouraged. There is a lack of direct evidence that a balanced crystalloid solution confers benefit, however, the trend of recent data would support future investigation into the advantage of balanced solution over 0.9% saline.

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?

Blood content analysis for evaluating cardiopulmonary function.

PURPOSE OF REVIEW: To review the role of blood analysis in cardiac and pulmonary evaluation. RECENT FINDINGS: A comprehensive understanding of arterial blood gas analysis - often aided by venous blood gas analysis, to help determine the ideal levels of blood oxygenation and hemoglobin (Hb), is reviewed in light of the recent findings. Serum lactate plays an important role in assessing cardiopulmonary function; yet, with the exception of prognosis, as to exactly what an elevated lactate implies remains unclear. Despite considerable research into the pulmonary-specific biomarkers, none are currently sufficiently robust to use in daily practice. Of the cardiac biomarkers, the natriuretic peptides are yet to be established in critical care practice apart from a role in assisting weaning from a ventilator, and cardiac troponin (cTn) continues to be an essential tool. SUMMARY: The ongoing research on blood contents has not resulted in any new outstanding markers to the critical care physician to use in evaluating cardiopulmonary function, with the exception of high-sensitive cTn. Yet, many recent studies assist the clinician by providing a better understanding of how to use routine tools, like arterial and venous blood gas analysis, more effectively and offer guidance in optimizing Hb and lactate blood levels.

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.

Survey of the current status of teaching intensive care medicine in Australia and New Zealand medical schools.

INTRODUCTION: The place of Intensive Care Medicine education within Medical Schools in Australia and New Zealand was investigated by survey in 2009. MATERIALS AND METHODS: All intensive care units in Australia and New Zealand were invited to take part in the survey. The survey included commitment to intensive care medicine training, teaching methods, curriculum content, assessment, and hours of student contact. All university teaching hospitals were identified and results analyzed. INTERVENTIONS: None. RESULTS: From recognized tertiary referral teaching hospitals, the response was 60%. A mandatory teaching program was offered by 56%, with a further 22% offering an optional program. The medical school curricula were primarily a mix of problem-based learning and traditional, lecture-based courses. Intensive care experience was usually undertaken in the latter years of the course. Contact hours allocated under the curriculum was less than 1 wk in the great majority. Assessment of students, where it existed, was undemanding. Intensive care medicine, although growing in stature within medical schools, still appears to occupy only a small place in the overall curriculum. CONCLUSION: A survey was undertaken to determine the extent of intensive care medicine training undertaken in medical student courses in Australia and New Zealand. A small majority of university hospitals had mandatory programs, with nearly a quarter having neither a mandatory or optional program. This is a higher proportion than identified in previous international surveys, but the results indicate considerable deficits requiring ongoing development within the undergraduate program.

Down but not out: myocardial depression in sepsis.

Myocardial depression in septic patients is well recognized yet still poorly understood. The prognostic significance in terms of overall mortality when it is identified, remains in dispute. Parameters of left ventricular function measured by tissue Doppler imaging may assist in resolving whether dysfunction identified early in the course of sepsis is a good prognostic sign.

Identification of sepsis subtypes in critically ill adults using gene expression profiling.

INTRODUCTION: Sepsis is a syndromic illness that has traditionally been defined by a set of broad, highly sensitive clinical parameters. As a result, numerous distinct pathophysiologic states may meet diagnostic criteria for sepsis, leading to syndrome heterogeneity. The existence of biologically distinct sepsis subtypes may in part explain the lack of actionable evidence from clinical trials of sepsis therapies. We used microarray-based gene expression data from adult patients with sepsis in order to identify molecularly distinct sepsis subtypes. METHODS: We used partitioning around medoids (PAM) and hierarchical clustering of gene expression profiles from neutrophils taken from a cohort of septic patients in order to identify distinct subtypes. Using the medoids learned from this cohort, we then clustered a second independent cohort of septic patients, and used the resulting class labels to evaluate differences in clinical parameters, as well as the expression of relevant pharmacogenes. RESULTS: We identified two sepsis subtypes based on gene expression patterns. Subtype 1 was characterized by increased expression of genes involved in inflammatory and Toll receptor mediated signaling pathways, as well as a higher prevalence of severe sepsis. There were differences between subtypes in the expression of pharmacogenes related to hydrocortisone, vasopressin, norepinephrine, and drotrecogin alpha. CONCLUSIONS: Sepsis subtypes can be identified based on different gene expression patterns. These patterns may generate hypotheses about the underlying pathophysiology of sepsis and suggest new ways of classifying septic patients both in clinical practice, and in the design of clinical trials.

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.

Echocardiography findings in COVID-19 patients admitted to intensive care units: a multi-national observational study (the ECHO-COVID study).

PURPOSE: Severely ill patients affected by coronavirus disease 2019 (COVID-19) develop circulatory failure. We aimed to report patterns of left and right ventricular dysfunction in the first echocardiography following admission to intensive care unit (ICU). METHODS: Retrospective, descriptive study that collected echocardiographic and clinical information from severely ill COVID-19 patients admitted to 14 ICUs in 8 countries. Patients admitted to ICU who received at least one echocardiography between 1st February 2020 and 30th June 2021 were included. Clinical and echocardiographic data were uploaded using a secured web-based electronic database (REDCap). RESULTS: Six hundred and seventy-seven patients were included and the first echo was performed 2 [1, 4] days after ICU admission. The median age was 65 [56, 73] years, and 71% were male. Left ventricle (LV) and/or right ventricle (RV) systolic dysfunction were found in 234 (34.5%) patients. 149 (22%) patients had LV systolic dysfunction (with or without RV dysfunction) without LV dilatation and no elevation in filling pressure. 152 (22.5%) had RV systolic dysfunction. In 517 patients with information on both paradoxical septal motion and quantitative RV size, 90 (17.4%) had acute cor pulmonale (ACP). ACP was associated with mechanical ventilation (OR > 4), pulmonary embolism (OR > 5) and increased PaCO2. Exploratory analyses showed that patients with ACP and older age were more likely to die in hospital (including ICU). CONCLUSION: Almost one-third of this cohort of critically ill COVID-19 patients exhibited abnormal LV and/or RV systolic function in their first echocardiography assessment. While LV systolic dysfunction appears similar to septic cardiomyopathy, RV systolic dysfunction was related to pressure overload due to positive pressure ventilation, hypercapnia and pulmonary embolism. ACP and age seemed to be associated with mortality in this cohort.