Sepsis-associated organ dysfunction involves multiple responses to inflammation, including endothelial and microvascular dysfunction, immune and autonomic dysregulation, and cellular metabolic reprogramming. The effect of targeting these mechanistic pathways on short- and long-term outcomes depends highly on the timing of therapeutic intervention. Furthermore, there is a need to understand the adaptive or maladaptive character of these mechanisms, to discover phase-specific biomarkers to guide therapy, and to conceptualize these mechanisms in terms of resistance and tolerance.Copyright © 2017 Elsevier Inc. All rights reserved.

Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. In sepsis, the immune response that is initiated by an invading pathogen fails to return to homeostasis, thus culminating in a pathological syndrome that is characterized by sustained excessive inflammation and immune suppression. Our understanding of the key mechanisms involved in the pathogenesis of sepsis has increased tremendously, yet this still needs to be translated into novel targeted therapeutic strategies. Pivotal for the clinical development of new sepsis therapies is the selection of patients on the basis of biomarkers and/or functional defects that provide specific insights into the expression or activity of the therapeutic target.

Sepsis is heterogeneous, and the optimal strategy for tailoring immunotherapy is uncertain.

Sepsis remains a major global health challenge, exerting a particularly severe toll in low- and middle-income countries. Despite advances in antimicrobial and supportive care, sepsis continues to defy effective control due to its complex pathophysiology and multi-organ involvement. Central to this complexity is a dysregulated host response, driven by hyperinflammation, immune suppression, and profound mitochondrial and metabolic dysfunction. A critical mediator of this dysregulation is oxidative stress, which exacerbates cellular injury through reactive oxygen and nitrogen species, disrupting mitochondrial integrity and redox balance. This review synthesizes current insights into the mechanistic interplay between oxidative stress, mitochondrial dysfunction, and immunopathology in sepsis. It further evaluates the therapeutic potential of endogenous antioxidants, such as superoxide dismutase, catalase, and glutathione, as well as exogenous agents including vitamins A, C, E, selenium, omega-3 fatty acids, melatonin, and carnosine. While translational gaps persist, particularly in dosing, timing, and patient stratification, emerging strategies including mitochondria-targeted antioxidants, nanotherapeutics, and biomarker-guided interventions hold promise for restoring redox homeostasis and improving clinical outcomes. This review aims to serve as a contemporary resource for researchers and clinicians striving to decode the oxidative basis of sepsis and accelerate the development of precision antioxidant therapies.

Sepsis is characterized by a dysregulated and excessive systemic inflammatory response to infection, associated with vascular and metabolic abnormalities that ultimately lead to organ dysfunction. In immune cells, both non-oxidative and oxidative metabolic rates are closely linked to inflammatory responses. Mitochondria play a central role in supporting these cellular processes by utilizing metabolic substrates and synthesizing ATP through oxygen consumption. To meet fluctuating cellular demands, mitochondria must exhibit adaptive plasticity underlying bioenergetic capacity, biogenesis, fusion, and fission. Given their role as a hub for various cellular functions, mitochondrial alterations induced by sepsis may hold significant pathophysiological implications and impact on clinical outcomes. In patients, mitochondrial DNA concentration, protein expression levels, and bioenergetic profiles can be accessed via tissue biopsies or isolated peripheral blood cells. Clinically, monocytes and lymphocytes serve as promising matrices for evaluating mitochondrial function. These mononuclear cells are highly oxidative, mitochondria-rich, routinely monitored in blood, easy to collect and process, and show a clinical association with immune status. Hence, mitochondrial assessments in immune cells could serve as biomarkers for clinical recovery, immunometabolic status, and responsiveness to oxygen and vasopressor therapies in sepsis. These characteristics underscore mitochondrial parameters in both tissues and immune cells as practical tools for exploring underlying mechanisms and monitoring septic patients in intensive care settings. In this article, we examine pathophysiological aspects, key methods for measuring mitochondrial function, and prominent studies in this field.© 2024. The Author(s).

Sepsis is a life-threatening syndrome characterized by a dysregulated immune response to infection, frequently leading to multiorgan failure and high mortality. Inflammasomes—cytosolic multiprotein complexes of the innate immune system—serve as critical platforms for sensing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs). Key sensors such as NLRP3, AIM2, and IFI16 initiate caspase-1 activation, IL-1β and IL-18 maturation, and gasdermin D–mediated pyroptosis. In sepsis, excessive inflammasome activation drives oxidative stress, endothelial dysfunction, immunothrombosis, and immune exhaustion. This maladaptive cascade is further aggravated by the release of DAMPs and procoagulant factors, compromising vascular integrity and immune homeostasis. Prolonged activation contributes to immunoparalysis, lymphopenia, and increased susceptibility to secondary infections. Inflammasome signaling also intersects with necroptosis and ferroptosis, amplifying systemic inflammation and tissue injury. Additionally, various pathogens exploit immune evasion strategies to modulate inflammasome responses and enhance virulence. Therapeutic interventions under investigation include selective NLRP3 inhibitors, IL-1 blockers, gasdermin D antagonists, and extracorporeal cytokine hemoadsorption. Emerging approaches emphasize biomarker-guided immunomodulation to achieve personalized therapy. While preclinical studies have shown promising results, clinical translation remains limited. Targeting inflammasomes may offer a path toward precision immunotherapy in sepsis, with potential to reduce organ dysfunction and improve survival.

Septic shock typically requires the administration of vasopressors. Adrenergic agents remain the first choice, namely norepinephrine. However, their use to counteract life-threatening hypotension comes with potential adverse effects, so that non-adrenergic vasopressors may also be considered. The use of agents that act through different mechanisms may also provide an advantage. Nitric oxide (NO) is the main driver of the vasodilation that leads to hypotension in septic shock, so several agents have been tested to counteract its effects. The use of non-selective NO synthase inhibitors has been of questionable benefit. Methylene blue, an inhibitor of soluble guanylate cyclase, an important enzyme involved in the NO signaling pathway in the vascular smooth muscle cell, has also been proposed. However, more than 25 years since the first clinical evaluation of MB administration in septic shock, the safety and benefits of its use are still not fully established, and it should not be used routinely in clinical practice until further evidence of its efficacy is available.

Sepsis and septic shock are leading causes of maternal morbidity and mortality. Sepsis complicates an estimated 1 in 1,000 pregnancies and is responsible for 24% of in-hospital maternal deaths. Because most cases occur outside of the hospital, it is crucial to educate patients about warning signs to seek early medical care and for clinicians to engage in critical listening and evaluation of patient concerns. In the hospital, screening patients for vital sign aberrancy, followed by bedside and laboratory evaluation for signs of end-organ injury, prompt antibiotic therapy, and restoration of perfusion (through fluid resuscitation and vasopressor administration), is critical for optimal outcomes. Long-term sequelae are common and include psychological sequelae, cognitive dysfunction, and weakness. Screening for these long-term effects and referrals for treatment are key to patient recovery.

Pregnant and postnatal women are a high-risk population particularly prone to rapid progression to sepsis with significant morbidity and mortality worldwide. Moreover, severe maternal infections can have a serious detrimental impact on neonates with almost 1 million neonatal deaths annually attributed to maternal infection or sepsis. In this review we discuss the susceptibility of pregnant women and their specific physiological and immunological adaptations that contribute to their vulnerability to sepsis, the implications for the neonate, as well as the issues with antimicrobial stewardship and the challenges this poses when attempting to reach a balance between clinical care and urgent treatment. Finally, we review advancements in the development of pregnancy-specific diagnostic and therapeutic approaches and how these can be used to optimize the care of pregnant women and neonates.© 2023 The Author(s).

Respiratory failure may affect up to 1 in 500 pregnancies, due to pregnancy-specific conditions, conditions aggravated by the pregnant state, or other causes. Management during pregnancy is influenced by altered maternal physiology, and the presence of a fetus influencing imaging, and drug therapy choices. Few studies have addressed the approach to invasive mechanical ventilatory management in pregnancy. Hypoxemia is likely harmful to the fetus, but precise targets are unknown. Hypocapnia reduces uteroplacental circulation, and some degree of hypercapnia may be tolerated in pregnancy. Delivery of the fetus may be considered to improve maternal respiratory status but improvement does not always occur.Copyright © 2024 Elsevier Inc. All rights reserved.

SOMANZ (Society of Obstetric Medicine Australia and New Zealand) has written a guideline to provide evidence-based guidance for the investigation and care of women with sepsis in pregnancy or the postpartum period. The guideline is evidence-based and incorporates recent changes in the definition of sepsis. The etiology, investigation and treatment of bacterial, viral and non-infective causes of sepsis are discussed. Obstetric considerations relevant to anaesthetic and intensive care treatment in sepsis are also addressed. A multi-disciplinary group of clinicians with experience in all aspects of the care of pregnant women have contributed to the development of the guidelines. This is an executive summary of the guidelines.© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

In normal pregnancy, there is a marked increase in the procoagulant activity in maternal blood characterized by elevation of factors VII, X, VIII, fibrinogen and von Willebrand factor, which is maximal around term. This is associated with an increase in prothrombin fragments (PF1+2) and thrombin-antithrombin complexes. There is a decrease in physiological anticoagulants manifested by a significant reduction in protein S activity and by acquired activated protein C (APC) resistance. The overall fibrinolytic activity is impaired during pregnancy, but returns rapidly to normal following delivery. This is largely due to placental derived plasminogen activator inhibitor type 2 (PAI-2), which is present in substantial quantities during pregnancy. D-dimer, a specific marker of fibrinolysis resulting from breakdown of cross-linked fibrin polymer by plasmin, increases as pregnancy progresses. Overall, there is a 4- to 10-fold increased thrombotic risk throughout gestation and the postpartum period. Local haemostasis at the placental throphoblast level is characterized by increased tissue factor (TF) expression and low expression of the inhibitor TFPI. Microparticles derived from maternal endothelial cells and platelets, and from placental throphoblasts may contribute to the procoagulant effect. Local anticoagulant mechanisms on placental throphoblasts are important for counterbalance of the procoagulant milieu. Disruption of anticoagulant mechanisms, for example, autoantibodies, to annexin V may increase pregnancy complications in patients with antiphospholipid antibodies (APLA).

Disseminated intravascular coagulation (DIC) is a life-threatening situation that can arise from a variety of obstetrical and nonobstetrical causes. Obstetrical DIC has been associated with a series of pregnancy complications including the following: (1) acute peripartum hemorrhage (uterine atony, cervical and vaginal lacerations, and uterine rupture); (2) placental abruption; (3) preeclampsia/eclampsia/hemolysis, elevated liver enzymes, and low platelet count syndrome; (4) retained stillbirth; (5) septic abortion and intrauterine infection; (6) amniotic fluid embolism; and (7) acute fatty liver of pregnancy. Prompt diagnosis and understanding of the underlying mechanisms of disease leading to this complication in essential for a favorable outcome. In recent years, novel diagnostic scores and treatment modalities along with bedside point-of-care tests were developed and may assist the clinician in the diagnosis and management of DIC. Team work and prompt treatment are essential for the successful management of patients with DIC. Copyright © 2015 Elsevier Inc. All rights reserved.

This Position Paper aims to review and discuss the available data on therapeutic drug monitoring (TDM) of antibacterials, antifungals and antivirals in critically ill adult patients in the intensive care unit (ICU). This Position Paper also provides a practical guide on how TDM can be applied in routine clinical practice to improve therapeutic outcomes in critically ill adult patients.Literature review and analysis were performed by Panel Members nominated by the endorsing organisations, European Society of Intensive Care Medicine (ESICM), Pharmacokinetic/Pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Association for Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and International Society of Antimicrobial Chemotherapy (ISAC). Panel members made recommendations for whether TDM should be applied clinically for different antimicrobials/classes.TDM-guided dosing has been shown to be clinically beneficial for aminoglycosides, voriconazole and ribavirin. For most common antibiotics and antifungals in the ICU, a clear therapeutic range has been established, and for these agents, routine TDM in critically ill patients appears meritorious. For the antivirals, research is needed to identify therapeutic targets and determine whether antiviral TDM is indeed meritorious in this patient population. The Panel Members recommend routine TDM to be performed for aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin and voriconazole in critically ill patients.Although TDM should be the standard of care for most antimicrobials in every ICU, important barriers need to be addressed before routine TDM can be widely employed worldwide.