Publications

The optimal type of fluid for intravascular volume resuscitation in critically ill patients remains a matter of debate. With their higher molecular weight, colloids remain in the intravascular space longer, and, therefore, provide more rapid hemodynamic stabilization than crystalloids, which extravasate to a greater degree so that more fluids are required to achieve the same end points. However, colloids are more expensive than crystalloids, in particular albumin, so that other colloids have been developed, including gelatins, dextrans, and hydroxyethyl starch (HES) solutions. Hydroxyethyl starch solutions have evolved since they were first developed in the Unite States in the 1970s. The first HES solutions included HES molecules of relatively high molecular weight and high degree of substitution, in an attempt to prolong their vascular persistence. These solutions were associated with an increased risk of bleeding (1,2) and renal failure (3–5). Prolonged persistence in the body also raised concern (6), and there are numerous reports of delayed itching in the dermatologic literature (7). Lower molecular weight HES solutions and solutions with lesser degrees of substitution have since been developed that may have an improved pharmacological profile, with fewer negative effects on coagulation and renal function, and more rapid tissue clearance (8,9). Importantly, in addition to their effects as intravascular volume expanders, HES solutions may have other properties. As early as the 1980s, Zikria et al. (10,11) reported that HES solutions could reduce microvascular permeability, leading to the concept that they could “plug” the leaks created in the endothelium during various disease processes, including sepsis and burns (12). In this issue of Anesthesia & Analgesia, Feng et al. (13) show that, in a model of cecal ligation and perforation, rats that received HES or gelatin solutions had reduced pulmonary capillary leakage compared with those that received normal saline. In addition, HES administration was associated with reduced expression of various proinflammatory mediators, including tumor necrosis factor and interleukin-1, while gelatin administration was not. In their present study, these authors have extended their previous data in rats, which showed that HES significantly reduced lipopolysaccharide-induced increases in lung capillary permeability, and inhibited lung neutrophil accumulation, cytokine-induced neutrophil chemoattractant protein, and nuclear factor-κ B activation (14). Their results also agree with experimental studies from other groups demonstrating the antiinflammatory effects of HES solutions (15–19). Hydroxyethyl starch has been shown to restore macrophage integrity and prevent the increase in interleukin-6 in mice after trauma-hemorrhage (15), to alter the interaction of neutrophils with activated endothelium (16,17), to decrease the neutrophil respiratory burst induced by Escherichia coli (18), and to attenuate hypoxia-induced increases in vascular leakage and acute inflammation (19). Boldt et al. (20), in patients undergoing major abdominal surgery, reported that the administration of HES was associated with reduced markers of inflammation and endothelial activation compared with crystalloid. The Feng et al. data (13) thus seem consistent with previous studies, but interpretation remains difficult. An important question is whether the observed effects are due to the solution itself or, rather, due to the effectiveness of the fluid resuscitation. In in vivo studies it is difficult to separate the specific effects of the individual fluids on the vessels from the general effects of fluid resuscitation. These difficulties are well illustrated by Marx et al. (21) in their study in a porcine model, where the early administration of HES solution restored tissue oxygenation better than Ringer’s lactate solution; however, there were no differences in the albumin escape rate, suggesting that the changes observed were due more to hemodynamic than to specific antiinflammatory effects. Prolonged tissue hypoperfusion with regional tissue hypoxia can increase the inflammatory response. Even in the absence of inflammation, prolonged severe hypoxia results in increased endothelial permeability, believed to be a key factor in the development of organ failure (22); thus, the longer a shock state persists, the greater the likelihood that the patient will develop organ failure. In patients with severe sepsis, we (23) recently showed that the duration of vasopressor requirement was directly related to the risk of subsequent organ failure. Intravascular fluid resuscitation has been shown to reduce the inflammatory response. For example, improved resuscitation after hemorrhage is associated with reduced pulmonary dysfunction and lung inflammation (24,25), and preemptive intravascular volume administration prevents lipopolysaccharide-induced microcirculatory changes (26). In other septic models, intravascular fluid resuscitation attenuated the release of cytokines or platelet activating factor (27,28). Logically, therefore, rapid reversal of acute circulatory failure should result in a shorter and less intense inflammatory reaction, with fewer permeability alterations and less edema formation. In the study by Feng et al. (13), the effects of HES were compared with those of an identical amount of gelatin, a colloid with a molecular weight only half that of albumin. Hence, the intravascular volume effects may have been greater in the HES group than in the other group. Arterial blood pressure was similar in the various groups, but this provides only a rough estimate of hemodynamic stability. Even measurements of cardiac output would not be entirely reassuring. Indeed, macrohemodynamic variables can be restored while the microhemodynamic status remains altered (29). Studies in rats, like that by Feng et al. (13), cannot explore these differences reliably, and one would like to see similar experiments in larger animals, or even in humans, and with a more effective colloid (such as albumin) for comparison. In summary, the intensity of the intravascular fluid resuscitation may be more important than the type of fluid itself, and HES solutions have very effective vascular effects. In the meantime, if the evidence is strong enough to support the antiinflammatory effects of HES, the question then becomes, Do these antiinflammatory properties give HES solutions a definitive advantage over other fluids? Perhaps not. First, a reduced inflammatory response does not necessarily translate into clinical benefit. Decreased capillary leak may be globally beneficial, but decreased neutrophil activation may have unwanted, as well as wanted, consequences. Second, assuming that the antiinflammatory effects are beneficial, other fluids may have similar advantages. Albumin, for example, has been shown to have antiinflammatory and antioxidant effects (30–33). Hydroxyethyl starch solutions may have other drawbacks, including the risk of altered hemostasis and the persistence of HES molecules in the body. In addition, there is new concern about the increased risks of renal failure associated with HES administration. A recent multicenter German study, the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis study, indicates that HES administration in patients with severe sepsis may be associated with an increased risk of acute renal failure. (Data presented at the 27th International Symposium of Intensive Care and Emergency Medicine, Brussels, March 2006.) So, where does this leave us in the big fluid debate? The present results are interesting and add another little piece to the big puzzle, but much more work is needed before we will be able to see the full picture and to better determine where each fluid fits. Although we use these fluids every day, we still know surprisingly little about them.

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.