Publications

Increased awareness of the signs and symptoms of sepsis and an emphasis on the importance of early treatment have helped to improve survival rates from this serious and frequent condition in recent years. With no specific, effective anti-sepsis therapies available, management focuses on early source control with adequate and appropriate antibiotics and removal of any source of infection, rapid resuscitation, hemodynamic stabilization and organ support. Use of dedicated teams to care for patients with sepsis can help optimize early management.

Le tableau I reprend les différents signes de sepsis. Il faut noter qu’aucune de ces altérations n’est entièrement spécifique. Bien que la fièvre soit un signe important de sepsis, elle peut accompagner tout état de stress (même l’œadème pulmonaire cardiogénique ou l’infarctus myocardique). En outre, les altérations de perfusion peuvent empêcher l’apparition de fièvre. Dans environ 10 % des cas, le sepsis peut même être accompagné d’hypothermie : ces cas sont de plus mauvais pronostic.

Sepsis, a word of Greek origin initially used by Hippocrates to refer to putrefaction, has become the term used to describe a serious infection, i.e., an infection complicated by organ dysfunction. The word sepsis is more appropriate than the term 'septicemia' which has been widely used but implies the presence of microorganisms in the blood whereas blood cultures are positive in scarcely 50% of patients with sepsis.Sepsis is a global disease, responsible for some 20% of total annual deaths and designated a worldwide health priority by the World Health Organization (World Health Organization 2020). It is difficult to estimate the full individual and societal burden of sepsis, especially as there are limited data available from low and middle income countries, yet these populations are likely to be disproportionately affected given the general poorer hygiene and resource availability for sepsis prevention and treatment in these areas (Schultz et al. 2017). Moreover, in addition to its high mortality rates, sepsis is also responsible for considerable short and long-term morbidity with associated high economic impact in terms of costs of hospitalization and treatment, of long-term care if needed, and of lost workforce productivity.The impact of sepsis on the emotional, psychological, and social well-being of affected individuals and their families is also substantial. Recent initiative such as the Global Sepsis Alliance (https://globalsepsisalliance.org), the International Sepsis Forum (https://sepsisforum.org), and World Sepsis Day (https://www.worldsepsisday.org) have raised awareness of sepsis, but many challenges remain to address and reduce the huge burden of this condition worldwide.The current management of sepsis relies on hemodynamic stabilization and infection control.Hemodynamic stabilization requires the administration of intravenous fluids, vasopressor agents (primarily norepinephrine and sometimes vasopressin), and inotropic agents (primarily dobutamine) when required. Infection control requires adequate antibiotic therapy and source control. Nevertheless, these measures are not, and will never be, fully effective. It is now recognized that not even the most effective antibiotic therapy can control all cases of sepsis.Being able to modulate the sepsis response is a tantalizing prospect but is currently limited to corticosteroid administration in severe cases and is a subject of ongoing debate and controversy (Bode et al. 2023).The critical care community assumed for far too long that sepsis was a homogeneous, primarily hyperinflammatory host response to infection. This influenced our approach to developing potential therapies, focusing on agents with anti-inflammatory or immunosuppressive effects. We now consider that the basic underlying mechanism is better described as a "dysregulation" of the host response (Singer et al. 2016). Understanding the different facets of this dysregulation will help in the development of more specific, targeted sepsis therapeutics. These recent concepts and the possible systems immunology approaches that can be used to improve our understanding of the complexities of the sepsis response and thus move towards more precision-based treatments are beautifully presented by Hancock and colleagues in their lead article (Hancock et al. 2025). Important aspects to remember include, first, that the underlying immune alterations of sepsis are highly complex and need to be better characterized in each individual patient, which is now becoming possible, especially with the assistance of artificial intelligence-based models. And, second, these alterations can change rapidly over time, implying the need for regular, repeated assessments of the host response.We can thus identify a path towards real progress in this field. After many years of negative trials trying to identify sepsis drugs that would be effective for all patients with sepsis, we have come to recognize that this was an oversimplistic illusion. Patients with sepsis are so different in terms of demographics, comorbidities, genetics, causative microorganisms, stage of disease at presentation, prior treatments, and degree of host response, among other factors, that identifying a single agent that would work for all was never going to be realistic. It has become obvious that more specific interventions are needed. Better characterization of individual patients will help determine which therapy is most likely to be of benefit in which patient. Hancock et al. (Hancock et al. 2025) excellently describe some of the tools available to achieve this, focusing on endotypes, in which patients are characterized according to underlying pathophysiological mechanisms, such as degree or type of immune response. A recent roundtable conference held in Brussels proposed focusing also on patient subphenotypes or treatable traits, which characterize patients more according to specific clinical features or outcomes rather than biological mechanisms (Gordon et al. 2024). The development of theranostics, combining diagnostic approaches (using biomarkers, endotypes, phenotypes, etc, to characterize patients) with appropriate therapeutic choices, has been used to guide the selection of the most relevant medication for individual patients in clinical trials in sepsis. For example, Vincent et al. selected only patients with sepsis-associated coagulopathy for inclusion in a randomized trial of thrombomodulin versus placebo (Vincent et al. 2019) and Francois et al. assessed response to nangibotide, which modulates triggering receptor expressed on myeloid cells (TREM)-1, according to concentrations of soluble TREM-1-a known sepsis biomarker (Francois et al. 2023). It has even been suggested that we may no longer need the word "sepsis" to describe a patient's condition, and this could be replaced using methods that more precisely evaluate and define the immune status.Nevertheless, several hurdles remain. One is that a patient's characteristics may change rapidly over time, and the trend is not predictable or identical in each individual. The specific moment of onset of sepsis is also generally not known with precision; sepsis may have developed before the admission to the intensive care unit (ICU) or even before admission to the hospital. Second, different types of response may coexist: some cells may be in a hyperinflammatory state at the same time as others are immunosuppressed (van Vught et al. 2017). Third, we usually assess the host response in the blood, but any alterations may be different in the tissues. To overcome some of these challenges, new studies need to investigate not only mortality outcomes but also other patient-relevant benefits, including limiting the development of organ failure and facilitating an uncomplicated recovery with shorter ICU and hospital stays. Even if a therapeutic strategy is not demonstrated to increase survival, effects on other outcomes can be clinically meaningful. Trial designs other than the traditional randomized controlled trial may also help in identifying and assessing new interventions (Gordon et al. 2024). For example, adaptive clinical trial designs, in which multiple trial arms are initially included and those showing promise are continued while others are rapidly discontinued. With the improved patient characterization methods highlighted by Hancock et al. (Hancock et al. 2025), clinical trials could also focus not so much on the presence of an infection, which is sometimes difficult to establish definitely (Maraolo et al. 2025), but on a particular pattern, characterized by a specific marker, endotype, phenotype and so on. So-called 'basket trials' are now used in oncology to test whether a new drug can be effective in patients who have a certain abnormality regardless of the type of cancer. Likewise, critically ill patients could be enrolled in a trial when they have a particular profile, regardless of documented presence of infection.As new therapies become available assisted by these novel approaches, a reasonable management option, based on current knowledge, may be to initially use an intervention that could reduce the inflammatory response when present, and then to immunostimulate the host in the later phase of immunosuppression. Limitations to this approach are that the proinflammatory response may be quite short (van Amstel et al. 2024), the two phases may be present simultaneously in some patients, and the immunosuppressive phase may not contribute markedly to mortality (van Vught et al. 2016). The better characterization of patients now becoming possible, as Hancock et al. (Hancock et al. 2025) discuss, will facilitate appropriate treatment choices for individual patients.In conclusion, better characterization of the host response over time in individual patients with sepsis will help advance research in this field, allowing potential therapies to be trialed in more precisely defined populations who are most likely to benefit. This in turn will enable the host response to be controlled more precisely and thus more effectively. Global collaboration of multiple stakeholders-research scientists, clinicians, industry, healthcare managers, politicians, and governments-is needed to help overcome the remaining challenges and obstacles, including the high associated costs, and drive the incorporation of precision medicine into clinical practice to help improve sepsis outcomes.

The determination of oxygen consumption (VO2) in critically ill patients is useful to evaluate metabolic expenditure, to calculate cardiac output and to assess the adequacy of oxygen supply to the tissues by the relationship between oxygen delivery (DO2) and VO2. Only the last application requires a high degree of accuracy in measurement. Highly accurate devices have been developed over the last few years although there are still problems with their use during spontaneous ventilation, mechanical ventilation with high FiO2, and treatment with inhaled nitric oxide (NO). Due to Haldane's transformation and the body's large CO2 stores, VO2 should only be measured in steady-state conditions, avoiding changes in ventilatory conditions or cardiac output. Air leaks should be carefully avoided since measurements would be erroneous. There is generally good agreement between Fick-derived VO2 and VO2 obtained by indirect calorimetry; discrepancies between the two methods in the study of changes in VO2 in response to changes in DO2 could be due to errors in both techniques. There is no strong evidence that mathematical coupling of data alone can account for VO2/DO2 dependency, which can sometimes be observed in critically ill patients.

Because the formation of platelet thrombi has been incriminated in the development of the adult respiratory distress syndrome (ARDS), we tested the hypothesis that early administration of antiplatelet agents might protect the lungs in patients at risk to develop ARDS after circulatory shock. This double-blinded study included 40 patients treated with either 3 mg/kg . 24 h of dipyridamole or a corresponding dose of placebo after an episode of hemorrhagic, traumatic, or septic shock. Each patient also received 100 mg of aspirin daily. Arterial blood gases and chest x-rays were not significantly different between dipyridamole and placebo groups. Moreover, two patients receiving dipyridamole but none receiving placebo developed ARDS. This pilot study does not support a beneficial effect of dipyridamole in the prevention of ARDS after circulatory shock.

The revised Surviving Sepsis Campaign (SSC) guidelines for the management of severe sepsis and septic shock have recently been published. These guidelines represent the end product of an intense process and provide a template approach to the early resuscitation and support of patients with sepsis, based on a synthesis of evidence that has been shown to improve the outcome of the septic patient. The SSC guidelines arose from a recognition that care of the septic patient was suboptimal for at least three reasons. First, the entity of sepsis was frequently not diagnosed in a timely fashion, allowing the process to evolve into a life-threatening syndrome of major physiologic organ system dysfunction. Secondly, even when sepsis was recognized, the urgency of treatment was underappreciated - and so haemodynamic resuscitation was tentative, and the administration of effective antibiotic therapy was often delayed. Finally, treatment was often suboptimal, and failed to take advantage of emerging insights into optimal approaches to patient management. The revised guidelines are far from perfect, but they represent the best available synthesis of contemporary knowledge in this area and as such should be promoted.