Bench-to-bedside review: Chloride in critical illness

Chloride is the principal anion in the extracellular fluid and is the second main contributor to plasma tonicity. Its concentration is frequently abnormal in intensive care unit patients, often as a consequence of fluid therapy. Yet chloride has received less attention than any other ion in the critical care literature. New insights into its physiological roles have emerged together with progress in understanding the structures and functions of chloride channels. In clinical practice, interest in a physicochemical approach to acid-base physiology has directed renewed attention to chloride as a major determinant of acid-base status. It has also indirectly helped to generate interest in other possible effects of disorders of chloraemia. The present review summarizes key aspects of chloride physiology, including its channels, as well as the clinical relevance of disorders of chloraemia. The paper also highlights current knowledge on the impact of different types of intravenous fluids on chloride concentration and the potential effects of such changes on organ physiology. Finally, the review examines the potential intensive care unit practice implications of a better understanding of chloride.     

Bench-to-bedside review: Erythropoietin and its derivatives as therapies in critical care

ABSTRACT: Erythropoietin (EPO) is known to have numerous biological functions. Its primary function in the body is to increase red blood cell numbers by way of preventing the apoptosis of erythroid progenitor cells via the homodimeric EPO receptor. The discovery that the local production of EPO within the brain in response to hypoxia or ischemia protects neurons against injury via an anti-apoptotic effect formed the basis of the hypothesis that the local generation of EPO limits the extent of injury. Although the hypothesis proved to be true in pre-clinical models of ischemia/reperfusion injury and inflammation, the randomized, controlled clinical trials that followed demonstrated serious adverse events of EPO due to activation of the hematopoietic system. Consequently, derivatives of EPO that lacked erythropoietic activity were discovered to reduce injury in many pre-clinical models associated with ischemia and inflammation. Unfortunately, there are no published clinical trials to determine the efficacy of non-erythropoietic derivatives of EPO in humans.     

Bench-to-bedside review: humanism in pediatric critical care medicine - a leadership challenge

A humanistic approach to leadership is especially important in the case of children in the technology-rich intensive care unit (ICU) environment. Leaders should create a humanistic milieu in which the needs of critically ill children, their families and staff are never overlooked. Humanistic leaders are tactful, accessible, approachable and versatile, and have a sense of humour. Humanness in the ICU environment has many faces and poses a challenge to many in leadership positions. Humanistic leaders treat others as they hope they will become. They are constantly questioning themselves, seeking awareness of themselves and others, but most importantly they are constantly learning and evolving. Ultimately, humanistic leadership creates an ICU culture that supports all, is conducive to enriching lives, and is sensitive to the needs of patients and their families.     

Bench-to-bedside review: Ethical challenges for those in directing roles in critical care units

Though much attention in the medical literature has focused on the ethics of critical care, it seems to be disproportionately weighted toward clinical issues. On the presumption that the operational management of an intensive care unit (ICU) also requires ethical considerations, it would be useful to know what these are. This review undertook to identify what literature exists with regard to the non-clinical issues of ethical importance in the ICU as encountered by clinician-managers. We found that in addition to issues of resource allocation, there exist many areas of ethical importance to clinician-managers in the ICU that have been described only superficially. We argue that a renewed focus on ICU ethics is merited to shed light on these other, non-clinical, issues.     

Bench-to-bedside review: Microdialysis in intensive care medicine

Microdialysis is a technique used to measure the concentrations of various compounds in the extracellular fluid of an organ or in a body fluid. It is a form of metabolic monitoring that provides real-time, continuous information on pathophysiological processes in target organs. It was introduced in the early 1970s, mainly to measure concentrations of neurotransmitters in animal experiments and clinical settings. Using commercial equipment it is now possible to conduct analyses at the bedside by collecting interstitial fluid for measurement of carbohydrate and lipid metabolites. Important research has been reported in the field of neurosurgery in recent decades, but use of metabolic monitoring in critical care medicine is not yet routine. The present review provides an overview of findings from clinical studies using microdialysis in critical care medicine, focusing on possible indications for clinical biochemical monitoring. An important message from the review is that sequential and tissue-specific metabolic monitoring, in vivo, is now available.     

Bench-to-bedside review: the effects of hyperoxia during critical illness

Oxygen administration is uniformly used in emergency and intensive care medicine and has life-saving potential in critical conditions. However, excessive oxygenation also has deleterious properties in various pathophysiological processes and consequently both clinical and translational studies investigating hyperoxia during critical illness have gained increasing interest. Reactive oxygen species are notorious by-products of hyperoxia and play a pivotal role in cell signaling pathways. The effects are diverse, but when the homeostatic balance is disturbed, reactive oxygen species typically conserve a vicious cycle of tissue injury, characterized by cell damage, cell death, and inflammation. The most prominent symptoms in the abundantly exposed lungs include tracheobronchitis, pulmonary edema, and respiratory failure. In addition, absorptive atelectasis results as a physiological phenomenon with increasing levels of inspiratory oxygen. Hyperoxia-induced vasoconstriction can be beneficial during vasodilatory shock, but hemodynamic changes may also impose risk when organ perfusion is impaired. In this context, oxygen may be recognized as a multifaceted agent, a modifiable risk factor, and a feasible target for intervention. Although most clinical outcomes are still under extensive investigation, careful titration of oxygen supply is warranted in order to secure adequate tissue oxygenation while preventing hyperoxic harm.     

Role of theories in school-based diabetes care interventions: A critical review

BACKGROUNDDiabetes is one of the most common chronic diseases of childhood. School plays an essential role in the management of student diabetes, which reduces the risk of short- and long-term diabetes complications and ensures that students are well-positioned for optimal academic performance and growth.AIMThe aim of this review was to systematically identify and synthesize the literature concerning theory-based diabetes care interventions in K-12 schools in the United States. It critically assessed the specific role of theories and associated essential constructs in intervention design, implementation, outcome measurement, and evaluation.METHODSRelevant literature was identified by keyword searches of the Cochrane Library, PubMed, and Web of Science.RESULTSFour interventions met the eligibility criteria and were included in the review. Of those, two evaluated online diabetes education programs for school personnel and the other two assessed in-person interventions. Three studies adopted a one-group pre-post study design, and the remaining one adopted a one-shot case-study design. Three of the interventions adopted social cognitive theory, and the remaining one was guided by the diffusion of innovations theory. Three studies identified core constructs of a theory as predictors of behavioral change. Two used theory to select or develop intervention techniques. Two studies used theory to customize participant intervention techniques. Two studies discussed their findings in the context of theory. No study used theory to select potential intervention participants.CONCLUSIONIn conclusion, despite the value of theory in intervention design and evaluation, theory-based diabetes interventions at school remain scarce. Future research may seek ways to better integrate theory and empirical research.     

Bench-to-bedside review: High-mobility group box 1 and critical illness

High-mobility group box 1 (HMGB1) is a DNA-binding protein that also exhibits proinflammatory cytokine-like activity. HMGB1 is passively released by necrotic cells and also is actively secreted by immunostimulated macrophages, dendritic cells, and enterocytes. Although circulating HMGB1 levels are increased relative to healthy controls in patients with infections and severe sepsis, plasma or serum HMGB1 concentrations do not discriminate reliably between infected and uninfected critically ill patients. Nevertheless, administration of drugs that block HMGB1 secretion or of anti-HMGB1 neutralizing antibodies has been shown to ameliorate organ dysfunction and/or improve survival in numerous animal models of critical illness. Because HMGB1 tends to be released relatively late in the inflammatory response (at least in animal models of endotoxemia or sepsis), this protein is an attractive target for the development of new therapeutic agents for the treatment of patients with various forms of critical illness.     

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.     

Bench-to-bedside review: Hydrogen sulfide – the third gaseous transmitter: applications for critical care

Hydrogen sulfide (H₂S), a gas with the characteristic odor of rotten eggs, is known for its toxicity and as an environmental hazard, inhibition of mitochondrial respiration resulting from blockade of cytochrome c oxidase being the main toxic mechanism. Recently, however, H₂S has been recognized as a signaling molecule of the cardiovascular, inflammatory and nervous systems, and therefore, alongside nitric oxide and carbon monoxide, is referred to as the third endogenous gaseous transmitter. Inhalation of gaseous H₂S as well as administration of inhibitors of its endogenous production and compounds that donate H₂S have been studied in various models of shock. Based on the concept that multiorgan failure secondary to shock, inflammation and sepsis may represent an adaptive hypometabolic reponse to preserve ATP homoeostasis, particular interest has focused on the induction of a hibernation-like suspended animation with H₂S. It must be underscored that currently only a limited number of data are available from clinically relevant large animal models. Moreover, several crucial issues warrant further investigation before the clinical application of this concept. First, the impact of hypothermia for any H₂S-related organ protection remains a matter of debate. Second, similar to the friend and foe character of nitric oxide, no definitive conclusions can be made as to whether H₂S exerts proinflammatory or anti-inflammatory properties. Finally, in addition to the question of dosing and timing (for example, bolus administration versus continuous intravenous infusion), the preferred route of H₂S administration remains to be settled – that is, inhaling gaseous H₂S versus intra-venous administration of injectable H₂S preparations or H₂S donors. To date, therefore, while H₂S-induced suspended animation in humans may still be referred to as science fiction, there is ample promising preclinical data that this approach is a fascinating new therapeutic perspective for the management of shock states that merits further investigation.     

Bench-to-bedside review: Angiopoietin signalling in critical illness – a future target?

Multiple organ dysfunction syndrome (MODS) occurs in response to major insults such as sepsis, severe haemorrhage, trauma, major surgery and pancreatitis. The mortality rate is high despite intensive supportive care. The pathophysiological mechanism underlying MODS are not entirely clear, although several have been proposed. Overwhelming inflammation, immunoparesis, occult oxygen debt and other mechanisms have been investigated, and – despite many unanswered questions – therapies targeting these mechanisms have been developed. Unfortunately, only a few interventions, usually those targeting multiple mechanisms at the same time, have appeared to be beneficial. We clearly need to understand better the mechanisms that underlie MODS. The endothelium certainly plays an active role in MODS. It functions at the intersection of several systems, including inflammation, coagulation, haemodynamics, fluid and electrolyte balance, and cell migration. An important regulator of these systems is the angiopoietin/Tie2 signalling system. In this review we describe this signalling system, giving special attention to what is known about it in critically ill patients and its potential as a target for therapy.     

Bench-to-bedside review: Genetics and proteomics: deciphering gene association studies in critical illness

There is considerable interest in understanding genetic determinants of critical illness to improve current risk stratification models, provide individualized therapies, and improve our current understanding of disease mechanisms. This review provides a broad overview of genetic nomenclature, different study designs, and problems unique to each of these study designs in critical illnesses. Well designed genetic studies with careful attention to these issues during the planning phase, use of rigorous statistical methods during analysis, and replication of these results in different cohorts will lead to more robust results and improved understanding of genetics of critical care.     

Bench-to-bedside review: The role of C1-esterase inhibitor in sepsis and other critical illnesses

The purpose of this bench-to-bedside review is to summarize the literature relating to complement activation in sepsis and other critical illnesses and the role of C1-esterase inhibitor (C1 INH) as a potential therapy.     

Bench-to-bedside review: Leadership and conflict management in the intensive care unit

In the management of critical care units, leadership and conflict management are vital areas for the successful performance of the unit. In this article a practical approach to define competencies for leadership and principles and practices of conflict management are offered. This article is, by lack of relevant intensive care unit (ICU) literature, not evidence based, but it is the result of personal experience and a study of literature on leadership as well on conflicts and negotiations in non-medical areas. From this, information was selected that was recognisable to the authors and, thus, also seems to be useful knowledge for medical doctors in the ICU environment.     

Bench-to-bedside review: Glucose and stress conditions in the intensive care unit

The physiological response to blood glucose elevation is the pancreatic release of insulin, which blocks hepatic glucose production and release, and stimulates glucose uptake and storage in insulin-dependent tissues. When this first regulatory level is overwhelmed (that is, by exogenous glucose supplementation), persistent hyperglycaemia occurs with intricate consequences related to the glucose acting as a metabolic substrate and as an intracellular mediator. It is thus very important to unravel the glucose metabolic pathways that come into play during stress as well as the consequences of these on cellular functions. During acute injuries, activation of serial hormonal and humoral responses inducing hyperglycaemia is called the 'stress response'. Central activation of the nervous system and of the neuroendocrine axes is involved, releasing hormones that in most cases act to worsen the hyperglycaemia. These hormones in turn induce profound modifications of the inflammatory response, such as cytokine and mediator profiles. The hallmarks of stress-induced hyperglycaemia include 'insulin resistance' associated with an increase in hepatic glucose output and insufficient release of insulin with regard to glycaemia. Although both acute and chronic hyperglycaemia may induce deleterious effects on cells and organs, the initial acute endogenous hyperglycaemia appears to be adaptive. This acute hyperglycaemia participates in the maintenance of an adequate inflammatory response and consequently should not be treated aggressively. Hyperglycaemia induced by an exogenous glucose supply may, in turn, amplify the inflammatory response such that it becomes a disproportionate response. Since chronic exposure to glucose metabolites, as encountered in diabetes, induces adverse effects, the proper roles of these metabolites during acute conditions need further elucidation.