Sepsis in Burns—Lessons Learnt from Developments in the Management of Septic Shock

After surviving the acute phase of resuscitation, septic shock is the cause of death in the majority of burn patients. Therefore, the management of septic shock is a cornerstone in modern burn care. Whereas sepsis therapy in general has undergone remarkable developments in the past decade, the management of septic shock in burn patients still has a long way to go. Instead, the differences of burn patients with septic shock versus general patients have been emphasized and thus, burn patients were excluded in every sepsis study which are the basis for modern sepsis therapy. However, due to the lack of evidence in burn patients, the standards of procedure for general sepsis therapy have been adopted in burn care. This review identifies the differences of burn patients with sepsis versus other septic patients and summarizes the scientific basis for modern sepsis therapy in general ICU patients and burn patients. Consequently, the results in general sepsis research should be transferred to burn care, which means the implementation of effective screening, early resuscitation, and efficient antimicrobial treatment. Therefore, on the basis of past developments and in the light of the current update of the Surviving Sepsis Campaign guidelines, this review introduces the “Burn SOFA score” and the “3 H’s of burn sepsis” as a screening tool for early sepsis recognition in burn patients.

Effects of Thyroid Hormone on Tissue Hypoxia: Relevance to Sepsis Therapy

Tissue hypoxia occurs in various conditions such as myocardial or brain ischemia and infarction, sepsis, and trauma, and induces cellular damage and tissue remodeling with recapitulation of fetal-like reprogramming, which eventually results in organ failure. Analogies seem to exist between the damaged hypoxic and developing organs, indicating that a regulatory network which drives embryonic organ development may control aspects of heart (or tissue) repair. In this context, thyroid hormone (TH), which is a critical regulator of organ maturation, physiologic angiogenesis, and mitochondrial biogenesis during fetal development, may be of important physiological relevance upon stress (hypoxia)-induced fetal reprogramming. TH signaling has been implicated in hypoxic tissue remodeling after myocardial infarction and T3 prevents remodeling of the postinfarcted heart. Similarly, preliminary experimental evidence suggests that T3 can prevent early tissue hypoxia during sepsis with important physiological consequences. Thus, based on common pathways between different paradigms, we propose a possible role of TH in tissue hypoxia after sepsis with the potential to reduce secondary organ failure.

Therapeutic Modulation of the Host Defense by Hemoadsorption with CytoSorb®—Basics, Indications and Perspectives—A Scoping Review

The “normal” immune response to an insult triggers a highly regulated response determined by the interaction of various immunocompetent cells with pro- and anti-inflammatory cytokines. Under pathologic conditions, the massive elevation of cytokine levels (“cytokine storm”) could not be controlled until the recent development of hemoadsorption devices that are able to extract a variety of different DAMPs, PAMPs, and metabolic products from the blood. CytoSorb® has been approved for adjunctive sepsis therapy since 2011. This review aims to summarize theoretical knowledge, in vitro results, and clinical findings to provide the clinician with pragmatic guidance for daily practice. English-language and peer-reviewed literature identified by a selective literature search in PubMed and published between January 2016 and May 2021 was included. Hemoadsorption can be used successfully as adjunct to a complex therapeutic regimen for various conditions. To the contrary, this nonspecific intervention may potentially worsen patient outcomes in complex immunological processes. CytoSorb® therapy appears to be safe and useful in various diseases (e.g., rhabdomyolysis, liver failure, or intoxications) as well as in septic shock or cytokine release syndrome, although a conclusive assessment of treatment benefit is not possible and no survival benefit has yet been demonstrated in randomized controlled trials.

Synthetic hydrogel nanoparticles for sepsis therapy

Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. Currently, there is no direct treatment for sepsis. Here we report an abiotic hydrogel nanoparticle (HNP) as a potential therapeutic agent for late-stage sepsis. The HNP captures and neutralizes all variants of histones, a major inflammatory mediator released during sepsis. The highly optimized HNP has high capacity and long-term circulation capability for the selective sequestration and neutralization of histones. Intravenous injection of the HNP protects mice against a lethal dose of histones through the inhibition of platelet aggregation and migration into the lungs. In vivo administration in murine sepsis model mice results in near complete survival. These results establish the potential for synthetic, nonbiological polymer hydrogel sequestrants as a new intervention strategy for sepsis therapy and adds to our understanding of the importance of histones to this condition.

Nanocapsules modify membrane interaction of polymyxin B to enable safe systemic therapy of Gram-negative sepsis

Systemic therapy of Gram-negative sepsis remains challenging. Polymyxin B (PMB) is well suited for sepsis therapy due to the endotoxin affinity and antibacterial activity. However, the dose-limiting toxicity has limited its systemic use in sepsis patients. For safe systemic use of PMB, we have developed a nanoparticulate system, called D-TZP, which selectively reduces the toxicity to mammalian cells but retains the therapeutic activities of PMB. D-TZP consists of an iron-complexed tannic acid nanocapsule containing a vitamin D core, coated with PMB and a chitosan derivative that controls the interaction of PMB with endotoxin, bacteria, and host cells. D-TZP attenuated the membrane toxicity associated with PMB but retained the ability of PMB to inactivate endotoxin and kill Gram-negative bacteria. Upon intravenous injection, D-TZP protected animals from pre-established endotoxemia and polymicrobial sepsis, showing no systemic toxicities inherent to PMB. These results support D-TZP as a safe and effective systemic intervention of sepsis.

Acetate sensing by GPR43 alarms neutrophils and protects from severe sepsis

Bacterial sepsis is a major cause of mortality resulting from inadequate immune responses to systemic infection. Effective immunomodulatory approaches are urgently needed but it has remained elusive, which targets might be suitable for intervention. Increased expression of the G-protein-coupled receptor GPR43, which is known to govern intestinal responses to acetate, has been associated with sepsis patient survival but the mechanisms behind this observation have remained unclear. We show that elevated serum acetate concentrations prime neutrophils in a GPR43-dependent fashion, leading to enhanced neutrophil chemotaxis, oxidative burst, cytokine release and upregulation of phagocytic receptors. Consequently, acetate priming improved the capacity of human neutrophils to eliminate methicillin-resistant Staphylococcus aureus. Acetate administration increased mouse serum acetate concentrations and primed neutrophils. Notably, it rescued wild-type mice from severe S. aureus sepsis and reduced bacterial numbers in peripheral organs by several magnitudes. Acetate treatment improved the sepsis course even when applied several hours after onset of the infection, which recommends GPR43 as a potential target for sepsis therapy. Our study indicates that the severity of sepsis depends on transient neutrophil priming by appropriate blood acetate concentrations. Therapeutic interventions based on GPR43 stimulation could become valuable strategies for reducing sepsis-associated morbidity and mortality.

Ex Vivo Evaluation of the Sepsis Triple Therapy High-Dose Vitamin C in Combination with Vitamin B1 and Hydrocortisone in a Human Peripheral Blood Mononuclear Cells (PBMCs) Model

Sepsis is an extremely complex clinical syndrome, usually involving an excessive inflammatory response including an overshooting cytokine release that damages tissue and organs of the patient. Due to the severity of this condition, it is estimated that over 11 million people die from sepsis each year. Despite intensive research in the field, there is still no specific therapy for sepsis. Many sepsis patients show a marked deficiency of vitamin C. 9 out of 10 sepsis patients have a hypovitaminosis C, and every third patient even shows a clinical deficiency in the scurvy range. In addition, low vitamin C levels of intensive care sepsis patients correlate with a higher need for vasopressors, higher Sequential Organ Failure Assessment (SOFA) scores, and increased mortality. Based on this observation and the conducted clinical trials using vitamin C as sepsis therapy in intensive care patients, the aim of the present ex vivo study was to evaluate the effects of high-dose vitamin C alone and in a triple combination supplemented with vitamin B1 (thiamine) and hydrocortisone on the lipopolysaccharide (LPS)-induced cytokine response in peripheral blood mononuclear cells (PBMCs) from healthy human donors. We found that all corticosteroid combinations strongly reduced the cytokine response on RNA- and protein levels, while high-dose vitamin C alone significantly diminished the PBMC mediated secretion of the cytokines interleukin (IL)-10, IL-23, and monocyte chemo-attractant protein (MCP-1), which mediate the inflammatory response. However, vitamin C showed no enhancing effect on the secretion of further cytokines studied. This data provides important insights into the possible immunomodulatory function of vitamin C in an ex vivo setting of human PBMCs and the modulation of their cytokine profile in the context of sepsis. Since vitamin C is a vital micronutrient, the restoration of physiologically adequate concentrations should be integrated into routine sepsis therapy, and the therapeutic effects of supraphysiological concentrations of vitamin C in sepsis patients should be further investigated in clinical trials.

First Evaluation of a New Dynamic Scoring System Intended to Support Prescription of Adjuvant CytoSorb Hemoadsorption Therapy in Patients with Septic Shock

Introduction: Despite advances in critical care medicine, adjunctive approaches in sepsis therapy have failed to prove their efficacy. Notwithstanding promising results using hemoadsorption (CytoSorb), questions remain concerning timing and dosing. We created a dynamic scoring system (DSS) to assess patients with early septic shock and performed a first evaluation of the system in this patient population. Methods: Data from 502 patients with septic shock according to Sepsis-3 criteria were retrospectively analyzed. Score parameters were documented at the time of diagnosis (T0) and 6 h later (T6) to calculate a dynamic score. Survival on day 7 and 56 as well as ICU and hospital mortality were analyzed in regard to the score as well as the delay of hemoadsorption therapy. Results: Of the 502 patients analyzed, 198 received adjunctive CytoSorb treatment and 304 received standard therapy. Septic shock was typically represented by 5 points, while >6 points indicated a situation refractory to standard therapy with the worst outcome in patients shown by >8 points. The differences in mortality between the score groups (<6, 6–8, >8 points) were significant. Analysis further showed a significant 56-day, ICU and hospital survival advantage in CytoSorb patients when therapy was started early. Conclusion: We created a scoring system allowing for the assessment of the clinical development of patients in the early phase of septic shock. Applying this approach, we were able to detect populations with a distinct mortality pattern. The data also showed that an early start of CytoSorb therapy was associated with significantly improved survival. As a next step, this easy-to-apply scoring system would require validation in a prospective manner to learn whether patients to be treated with hemoadsorption therapy in the course of septic shock could thereby be identified.

Pharmacokinetics of meropenem during advanced organ support (ADVOS®) and continuous renal replacement therapy

The advanced organ support (ADVOS) system allows to eliminate water-soluble as well as protein-bound molecules. Despite its clinical features, to date nothing is known about the elimination of clinically relevant drugs such as antiinfectives. Therefore, we report a case treated with ADVOS, continuous renal replacement therapy (CRRT), and meropenem (1 g 8-hourly) for empiric sepsis therapy monitored by meropenem drug levels. ADVOS showed more efficient elimination of meropenem compared to CRRT which has to be considered when evaluating dosing regimens.

Astaxanthin Protects Dendritic Cells from Lipopolysaccharide-Induced Immune Dysfunction

Astaxanthin, originating from seafood, is a naturally occurring red carotenoid pigment. Previous studies have focused on its antioxidant properties; however, whether astaxanthin possesses a desired anti-inflammatory characteristic to regulate the dendritic cells (DCs) for sepsis therapy remains unknown. Here, we explored the effects of astaxanthin on the immune functions of murine DCs. Our results showed that astaxanthin reduced the expressions of LPS-induced inflammatory cytokines (TNF-α, IL-6, and IL-10) and phenotypic markers (MHCII, CD40, CD80, and CD86) by DCs. Moreover, astaxanthin promoted the endocytosis levels in LPS-treated DCs, and hindered the LPS-induced migration of DCs via downregulating CCR7 expression, and then abrogated allogeneic T cell proliferation. Furthermore, we found that astaxanthin inhibited the immune dysfunction of DCs induced by LPS via the activation of the HO-1/Nrf2 axis. Finally, astaxanthin with oral administration remarkably enhanced the survival rate of LPS-challenged mice. These data showed a new approach of astaxanthin for potential sepsis treatment through avoiding the immune dysfunction of DCs.