Emerging Paradigms in Sepsis Management: Critical Insights from Contemporary Clinical Trials

Expert consensus on the use of human serum albumin in critically ill patients.

Surviving Sepsis Campaign.

Use of Albumin as a Resuscitative Fluid in the Intensive Care Unit.

Severe sepsis (systemic inflammation secondary to infection combined with acute organ dysfunction) and septic shock (severe sepsis combined with hypotension not rectified by fluid resuscitation) are complex multifactorial medical conditions with significant associated morbidity and mortality, and are among the leading causes of death in the intensive care unit (ICU). Even with aggressive treatment, the mortality has been shown to be around 40 percent (Bernard et al., 1997) and in some studies has been reported to be as high as 71.9 percent (Sasse et al., 1995). In 2001, Angus et al conducted a study of the incidence, cost, and outcome of severe sepsis in the United States of America; the results showed an incidence of 3 cases per 1,000 population, a mortality rate of 28.6 percent, and a cost of $22,100 per case, giving an annual cost of $16.7 billion (Angus et al., 2001). The same study showed that the number of deaths per year associated with severe sepsis is equal to that of acute myocardial infarction, yet myocardial infarction has attracted far more attention and funding in terms of treatment and management research, leaving sepsis a relatively unacknowledged problem. With severe sepsis having such a high incidence, high and increasing mortality rate, and high annual cost, it is becoming a prime target for research into improving diagnosis, management, and survival. Reducing morbidity and mortality in severe sepsis and septic shock has been the primary goal of the Surviving Sepsis Campaign (SSC) – a global initiative developed by the European Society of Intensive Care Medicine (ESICM), the International Sepsis Forum (ISF), and the Society of Critical Care Medicine (SCCM) to raise awareness of sepsis among healthcare professionals and to improve and standardize the early diagnosis and treatment of sepsis (Welcome To The Surviving Sepsis Campaign Website,n.d.). Containing a number of the world’s experts on sepsis, this campaign attempts to tackle various challenges in the diagnosis and management of sepsis. Some of the challenges lie in the complexity of the condition and the variability in the presentation and course of sepsis, with many of the symptoms being of a general nature and easily attributable to a number of other conditions and etiologies. This makes it quite difficult to create a standard clinical definition of sepsis. This lack of definitive criteria for a diagnosis of sepsis makes it easily misdiagnosed, and consequently improperly treated. If, however, a diagnosis of sepsis is made, it is often still made late and treatment is less effective if delayed. As is discussed later in this chapter,

The challenge of sepsis

In 2002 and 2007, the American College of Critical Care Medicine (ACCCM) provided clinical guidelines for hemodynamic support of pediatric and neonatal patients in septic shock. In 2008 and 2013, the Surviving Sepsis Campaign (SSC) Guidelines Committee offered up-to-date clinical guidelines for the management of severe sepsis and septic shock in adults and in pediatric patients. The aim of this study was to assess the standard of care of neonates with severe sepsis and septic shock in German neonatal intensive care units (NICUs) with regard to variability in management and guideline conformity. 199 pediatric clinics in Germany were asked to describe their management of septic neonates in a telephone survey. The questionnaire that was used for the preliminary survey was designed based on the ACCCM and SSC clinical guidelines. A total of 90 (45%) surveys were completed and analyzed. Among all hospitals, the guidelines most commonly included in current practice patterns were obtaining cultures before administering antibiotics (100%), determining capillary refill time (99%), and using crystalloids for initial fluid therapy (97%). The guidelines least commonly included in current practice were determination of ammoniac to rule out inborn errors of metabolism (51%) and the use of dopamine as the first choice of hemodynamic support (48%). The management of sepsis, severe sepsis, and septic shock in neonates is not always guideline consistent, but quite a number of ACCCM and SSC guidelines were included in the current practice pattern.

Critical Care Nephrology: Core Curriculum 2009

Editorial I: Circulating volume and clinical assessment of the circulation

Sepsis Care Pathway 2019.

Recent large-scale randomized controlled trials (RCTs) challenged current beliefs about the potential role of micronutrients to attenuate the inflammatory response and improve clinical outcomes of critically ill patients. The purpose of this narrative review is to provide an overview and critical discussion about most recent clinical trials, which evaluated the clinical significance of a vitamin C, vitamin D, or selenium administration in critically ill patients. None of the most recent large-scale RCTs could demonstrate any clinical benefits for a micronutrient administration in ICU patients, whereas a recent RCT indicated harmful effects, if high dose vitamin C was administered in septic patients. Following meta-analyses could not confirm harmful effects for high dose vitamin C in general critically ill patients and indicated benefits in the subgroup of general ICU patients with higher mortality risk. For vitamin D, the most recent large-scale RCT could not demonstrate clinical benefits for critically ill patients, whereas another large-scale RCT is still ongoing. The aggregated and meta-analyzed evidence highlighted a potential role for intravenous vitamin D administration, which encourages further research. In high-risk cardiac surgery patients, a perioperative application of high-dose selenium was unable to improve patients' outcome. The observed increase of selenium levels in the patients' blood did not translate into an increase of antioxidative or anti-inflammatory enzymes, which illuminates the urgent need for more research to identify potential confounding factors. Current data received from most recent large-scale RCTs could not demonstrate clinically meaningful effects of an intervention with either vitamin C, vitamin D, or selenium in critically ill patients. More attention is needed to carefully identify potential confounding factors and to better evaluate the role of timing, duration, and combined strategies.

BackgroundEarly assessment and management of patients with sepsis can significantly reduce its high mortality rates and improve patient outcomes and quality of life.ObjectivesThe purposes of this review are to: (1) explore nurses’ knowledge, attitude, practice, and perceived barriers and facilitators related to early recognition and management of sepsis, (2) explore different interventions directed at nurses to improve sepsis management.MethodsA systematic review method according to the PRISMA guidelines was used. An electronic search was conducted in March 2021 on several databases using combinations of keywords. Two researchers independently selected and screened the articles according to the eligibility criteria.ResultsNurses reported an adequate of knowledge in certain areas of sepsis assessment and management in critically ill adult patients. Also, nurses’ attitudes toward sepsis assessment and management were positive in general, but they reported some misconceptions regarding antibiotic use for patients with sepsis, and that sepsis was inevitable for critically ill adult patients. Furthermore, nurses reported they either were not well-prepared or confident enough to effectively recognize and promptly manage sepsis. Also, there are different kinds of nurses’ perceived barriers and facilitators related to sepsis assessment and management: nurse, patient, physician, and system-related. There are different interventions directed at nurses to help in improving nurses’ knowledge, attitudes, and practice of sepsis assessment and management. These interventions include education sessions, simulation, decision support or screening tools for sepsis, and evidence-based treatment protocols/guidelines.DiscussionOur findings could help hospital managers in developing continuous education and staff development training programs on assessing and managing sepsis in critical care patients.ConclusionNurses have poor to good knowledge, practices, and attitudes toward sepsis as well as report many barriers related to sepsis management in adult critically ill patients. Despite all education interventions, no study has collectively targeted critical care nurses’ knowledge, attitudes, and practice of sepsis management.

Sepsis remains a major contributor to mortality among critically ill patients, with sepsis-induced metabolic dysfunction significantly worsening outcomes. As metabolic dysfunction plays a key role in the pathogenesis of sepsis, recent interest has grown around metabolic resuscitation therapies as potential adjuncts to traditional fluid resuscitation strategies. This narrative review evaluates current evidence regarding the role of vitamin C, thiamine, and corticosteroids in improving sepsis outcomes. Early studies suggested that vitamin C may reduce organ dysfunction and vasopressor requirements; however, more recent randomized trials have produced inconsistent results, with some findings even indicating potential harm in certain patient groups. Similarly, the use of corticosteroids in sepsis management has shown mixed outcomes. Thiamine has demonstrated possible renal protective effects and improved lactate clearance, although its impact on mortality and vasopressor needs remains inconclusive. Combination therapy with hydrocortisone, vitamin C, and thiamine (the HAT protocol) has been associated with reduced vasopressor duration but has not consistently improved survival or other major clinical endpoints, despite its apparent safety. Overall, while vitamin C, corticosteroids, and thiamine present a theoretically attractive strategy in sepsis management, clinical results remain debated. Corticosteroids currently have the strongest supporting evidence for use in septic shock, while vitamin C and thiamine remain investigational therapies and are not recommended for routine use outside clinical trials. Future research should explore biomarker-guided, precision-medicine approaches to better identify patients who might benefit most from metabolic resuscitation, and large-scale randomized controlled trials are needed to clarify optimal timing and dosing strategies.

Despite numerous advances in medicine, the mortality rate of severe sepsis and septic shock remains high, 30-50%. New therapy strategies include: early goal-directed therapy, fluid replacement, early and appropriate antimicrobials, source of infection control, use of corticosteroids, vasopressors and inotropic therapy, use of recombinant activated protein C, tight glucose control, low-tidal-volume mechanical ventilation. They have been shown to improve the outcomes. The adequacy and speed of treatment influence the outcome, too. The objective was to evaluate if new therapy strategies had been integrated in our routine practice. Patients with severe sepsis or septic shock, who were treated in the Intensive Care Unit (ICU) over a ten-month period, were analysed retrospectively. The descriptive epidemiological method was applied. Central venous catheterization, central venous pressure, antibiotics, fluid resuscitation, mechanical ventilation, vasopressors, corticosteroids, blood administration, deep vein thrombosis prophylaxis, stress ulcer prophylaxis, glucose control, were evaluated. 27 patients were analysed. Patient characteristics were: age, 49.9 years (18-77) with 30-day in-hospital mortality rate of 48.1%. All patients received broad-spectrum antibiotics. Blood cultures were obtained in 85.2% patients. Adequate antimicrobial treatment was applied to 59.3% and 74.1% patients had central venous pressure monitoring. Average central venous pressure was 8.47 +/- 5.6 mm Hg (-2-20). Aggressive fluid therapy was given to 33.3% of the cases and 66.7% of the patients with septic shock received vasoactive drugs while 29.6% received corticosteroids. Red blood cell transfusions were applied in 59.3% of patients. All patients received stress ulcer prophylaxis, and 37% of them deep vein thrombosis prophylaxis. The average value of morning glucose was 9.11 +/- 5.03 mmol/l (3.7-22.0). 63% of patients were mechanically ventilated. Blood lactate was not determined. Evidence-based clinical guidelines for management of severe sepsis and septic shock have not been implemented in a widespread, systematic way in the ICU of the Clinical Centre, Kragujevac. Institutional acceptance of this protocol, and education of clinicians may improve survivability for patients with sepsis.

: Sepsis is one of the leading causes of mortality among children worldwide. Although the diagnosis and management of sepsis in infants and children is largely influenced by studies done in adults, there are important considerations relevant for pediatrics and we wanted to highlights pediatric-specific issues related to the definition of sepsis and its epidemiology and management. The definition of pediatric sepsis is currently in a state of evolution. For the past two decades, sepsis has been defined as “systemic inflammatory response syndrome (SIRS) caused by infection” both for adults and children. International pediatric sepsis consensus conference in 2015 revised the adult SIRS criteria for children. New sepsis criteria were advocated as “Sepsis-3” in 2017, which redefined “as life-threatening organ dysfunction caused by a dysregulated host response to infection”. Unfortunately, this change in the definition of sepsis is applied to adult population at this moment, consensus definition in children are not well established. The epidemiology of pediatric sepsis varies from study to study probably because of their different era, population, and diagnostic criteria. Sepsis is often diagnosed too late, because the clinical symptoms and laboratory signs that are currently used for the diagnosis of sepsis, like raised temperature, increased pulse or breathing rate, or white blood cell count are unspecific. In children, the signs and symptoms may be subtle and deterioration rapid. Early sepsis treatment is cost effective, reducing hospital and Critical Care bed days for patients. The current management of pediatric sepsis is largely based on adaptations from adult sepsis treatment. New knowledge was added regarding the hemodynamic management and the timely use of antimicrobials. The early administration of antibiotics and hemodynamic stabilization with fluid resuscitation and inotropic/vasopressor support are like both wheels of a vehicle for the initial management of sepsis. The management of pediatric sepsis must be tailored to the child’s age and immune capacity, and to the site, severity, and source of the infection. The management of pediatric sepsis would be expected to make further progress.

Rebuttal From Dr Jones