Calcification following tongue necrosis induced by vasopressor use in a nonintubated patient with septic shock: a case report.

BACKGROUND: Tongue necrosis is a rare and relatively uncommon condition, usually caused by vasculitis, thrombosis, severe hypotension due to septic or cardiogenic shock, vasopressor use, or intubation. Following damage such as necrosis, dystrophic calcification, a type of soft tissue calcification, can occur. CASE PRESENTATION: Herein, we present a unique case of bilateral tongue necrosis in a patient with nonintubated septic shock. A 70-year-old East Asian man with no significant medical history presented to the emergency department with postprandial epigastric pain. The patient was admitted to the intensive care unit with hypotension due to septic shock and disseminated intravascular coagulation. After a short course of vasopressors, the patient developed tongue discoloration and swelling without limb ischemia. Computed tomography was performed to observe the tongue necrosis, and calcification of the tongue was found. The patient was successfully treated by wiping the area with a hexamidine-soaked gauze. CONCLUSION: Tongue necrosis remains a rare finding, and its occurrence as a complication of vasopressor use is even rarer. Therefore, even with relatively short courses of vasopressors in the intensive care unit, daily visualization of the tongue to check for discoloration, along with daily inspection and pulse checks of the limbs, can help identify vasospasms. These measures allow for prompt intervention, minimizing permanent damage and shortening the recovery time.

[2, 6-dimethoxy-1, 4-benzoquinone alleviates septic shock in mice by inhibiting NLRP3 inflammasome activation].

OBJECTIVE: To investigate the mechanism of 2, 6-dimethoxy-1, 4-benzoquinone (DMQ), an active ingredients in fermented wheat germ extract, for inhibiting NLRP3 inflammasome activation and alleviating septic shock in mice. METHODS: Cultured murine bone marrow-derived macrophages (BMDM) stimulated with lipopolysaccharide (LPS) were treated with DMQ, followed by treatment with Nigericin, ATP, and MSU for activating the canonical NLRP3 inflammasome; the noncanonical NLRP3 inflammasome was activated by intracellular transfection of LPS, and AIM2 inflammasome was activated using Poly A: T.In human monocytic THP-1 cells, the effect of Nigericin on inflammasome activation products was examined using Western blotting and ELISA.Co-immunoprecipitation was performed to explore the mechanism of DMQ-induced blocking of NLRP3 inflammasome activation.In a male C57BL/6J mouse model of LPS-induced septic shock treated with 20 and 40 mg/kg DMQ, the levels of IL-1ß and TNF-α in the serum and peritoneal lavage fluid were determined using ELISA, and the survival time of the mice within 36 h was observed. RESULTS: Treatment with DMQ effectively inhibited LPS-induced activation of canonical NLRP3 inflammasome in mouse BMDM and human THP-1 cells and also inhibited non-canonical NLRP3 inflammasome activation in mouse BMDM, but produced no significant effect on AIM2 inflammasome activation.DMQ significantly blocked the binding between ASC and NLRP3.In the mouse models of septic shock, DMQ treatment significantly reduced the levels of IL-1ß in the serum and peritoneal fluid and obviously prolonged survival time of the mice. CONCLUSION: DMQ can effectively block ASC-NLRP3 interaction to inhibit NLRP3 inflammasome activation and alleviate LPSinduced septic shock in mice.

Antimicrobial peptide 2K4L inhibits the inflammatory response in macrophages and Caenorhabditis elegans and protects against LPS-induced septic shock in mice.

2K4L is a rationally designed analog of the short α-helical peptide temporin-1CEc, a natural peptide isolated and purified from the skin secretions of the Chinese brown frog Rana chensinensis by substituting amino acid residues. 2K4L displayed improved and broad-spectrum antibacterial activity than temporin-1CEc in vitro. Here, the antibacterial and anti-inflammatory activities of 2K4L in macrophages, C. elegans and mice were investigated. The results demonstrated that 2K4L could enter THP-1 cells to kill a multidrug-resistant Acinetobacter baumannii strain (MRAB 0227) and a sensitive A. baumannii strain (AB 22933), as well as reduce proinflammatory responses induced by MRAB 0227 by inhibiting NF-κB signaling pathway. Similarly, 2K4L exhibited strong bactericidal activity against A. baumannii uptake into C. elegans, extending the lifespan and healthspan of the nematodes. Meanwhile, 2K4L alleviated the oxidative stress response by inhibiting the expression of core genes in the p38 MAPK/PMK-1 signaling pathway and downregulating the phosphorylation level of p38, thereby protecting the nematodes from damage by A. baumannii. Finally, in an LPS-induced septic model, 2K4L enhanced the survival of septic mice and decreased the production of proinflammatory cytokines by inhibiting the signaling protein expression of the MAPK and NF-κB signaling pathways and protecting LPS-induced septic mice from a lethal inflammatory response. In conclusion, 2K4L ameliorated LPS-induced inflammation both in vitro and in vivo.

EVALUATION OF VASOPRESSOR INFLECTION POINT FOR SHORT-TERM PROGNOSIS OF PATIENTS WITH SEPTIC SHOCK.

ABSTRACT: Objective: The goal of this study is to investigate the clinical value of vasopressor inflection points in the evaluation of short-term prognosis among individuals afflicted with septic shock. Methods: A retrospective analysis was conducted on a cohort comprising 56 patients diagnosed with septic shock and receiving treatment at the department of critical care medicine of the hospital between January 2021 and March 2023. These patients were divided into two groups based on the prognostic outcome: a survival group consisting of 34 patients and a death group consisting of 22 patients. The determination of vasopressor inflection time and procalcitonin (PCT) inflection time of each patient was undertaken with the initiation of vasopressor therapy serving as the reference point. The vasopressor inflection point was defined as the time when the dosage of vasopressors commenced decreasing, while the PCT inflection point denoted the time when PCT levels began to decline. The incidence of patients reaching the vasopressor and PCT inflection points on the 2nd, 3rd, and 4th days following the initiation of vasopressor therapy was tabulated for both groups. The comparison of inflection points between the two groups at each time point was conducted using Fisher's exact test. Furthermore, logistic regression analysis was employed for univariate prognostic assessment. The diagnostic performance of vasopressor and PCT inflection point was assessed using the four-table method. The discrepancy and consistency between the two methods were evaluated through paired chi-squared test and Kappa consistency test. Results: The vasopressor inflection point demonstrates promising utility in the assessment of short-term prognosis among patients with septic shock, exhibiting sensitivities of 76.4%, 88.2%, and 100%, specificities of 90.9%, 90.9%, and 86.4%, positive predictive values of 92.9%, 93.8%, and 91.9%, and negative predictive values of 71.4% on the 2nd, 3rd, and 4th day, respectively. Correspondingly, the Youden indices were calculated as 0.673, 0.791, and 0.864 on these respective days. Notably, all metrics at comparable intervals surpassed those of the PCT inflection point. Conclusion : The vasopressor inflection point presents as a robust prognostic tool for the short-term outcomes in patients with septic shock and exhibits superiority over PCT in prognostic assessment.

Anti-inflammatory effect of proanthocyanidins from blueberry through NF-κß/NLRP3 signaling pathway in vivo and in vitro.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) is an uncontrolled systemic inflammatory response. Proanthocyanidins (PC) is a general term of polyphenol compounds widely existed in blueberry fruits and can treat inflammation-related diseases. This study aimed to explore the regulatory effect of PC on lipopolysaccharide (LPS)-induced systemic inflammation and its potential mechanism, providing effective strategies for the further development of PC. METHODS: Here, RAW264.7 macrophages were stimulated with LPS to establish an inflammation model in vitro, while endotoxin shock mouse models were constructed by LPS in vivo. The function of PC was investigated by MTT, ELISA kits, H&E staining, immunohistochemistry, and Western blot analysis. RESULTS: Functionally, PC could demonstrate the potential to mitigate mortality in mice with endotoxin shock, as well as attenuated the levels of inflammatory cytokines (IL-6, TNF-α) and biochemical indicators (AST, ALT, CRE and BUN). Moreover, it had a significant protective effect on lung and kidney tissues damage. Mechanistically, PC exerted anti-inflammatory effects by inhibiting the activation of the NF-κB/NLRP3 signaling pathway. CONCLUSION: PC might have the potential ability of anti-inflammatory effects via modulation of the NF-κB/NLRP3 signaling pathway.

Bruton's tyrosine kinase inhibition limits endotoxic shock by suppressing IL-6 production by marginal zone B cells in mice.

Sepsis is a systemic inflammatory response to a severe, life-threatening infection with organ dysfunction. Although there is no effective treatment for this fatal illness, a deeper understanding of the pathophysiological basis of sepsis and its underlying mechanisms could lead to the development of new treatment approaches. Here, we demonstrate that the selective Bruton's tyrosine kinase (Btk) inhibitor acalabrutinib augments survival rates in a lipopolysaccharide (LPS)-induced septic model. Our in vitro and in vivo findings both indicate that acalabrutinib reduces IL-6 production specifically in marginal zone B (MZ B) cells rather than in macrophages. Furthermore, Btk-deficient MZ B cells exhibited suppressed LPS-induced IL-6 production in vitro. Nuclear factor-kappa B (NF-κB) signaling, which is the downstream signaling cascade of Toll-like receptor 4 (TLR4), was also severely attenuated in Btk-deficient MZ B cells. These findings suggest that Btk blockade may prevent sepsis by inhibiting IL-6 production in MZ B cells. In addition, although Btk inhibition may adversely affect B cell maturation and humoral immunity, antibody responses were not impaired when acalabrutinib was administered for a short period after immunization with T-cell-independent (TI) and T-cell-dependent (TD) antigens. In contrast, long-term administration of acalabrutinib slightly impaired humoral immunity. Therefore, these findings suggest that Btk inhibitors may be a potential option for alleviating endotoxic shock without compromising humoral immunity and emphasize the importance of maintaining a delicate balance between immunomodulation and inflammation suppression.

High-dose vitamin C improves norepinephrine level in patients with septic shock: A single-center, prospective, randomized controlled trial.

BACKGROUND: The effects of vitamin C supplementation on patients with septic shock remain controversial. We aimed to evaluate the effects of different vitamin C dosages on norepinephrine (NE) synthesis in adult patients with septic shock. METHODS: A total of 58 patients with septic shock admitted to our intensive care unit (ICU) between July 2021 and December 2022 were included. Patients were randomly divided into 3 groups: high-dose vitamin C (150 mg/kg/d, group A), low-dose vitamin C (50 mg/kg/d, group B), and placebo (group C). NE synthesis-related indicators (dopamine-ß-hydroxylase [DßH], tyrosine hydroxylase [TH], tetrahydrobiopterin [BH4], and dopamine [DA]), plasma NE, and vitamin C levels were measured every 24 hours and analyzed. All-cause mortality within 28 days and other clinical outcomes (including Acute Physiology and Chronic Health Evaluation [APACHE], Sequential Organ Failure Assessment [SOFA], and Multiple-Organ Dysfunction Syndrome [MODS] scores) were compared. RESULTS: Changes in TH, BH4, and DßH levels at 96 hours in groups A and B were greater than those in group C. These differences became more pronounced over the course of the intravenous vitamin C administration. Significant differences between groups A and C were detected at 96-hours TH, 72-hours BH4, 96-hours BH4, 96-hours DA, and DßH levels every 24 hours. The 96-hours TH, 96-hours BH4, and 48-hours DßH in group B were significantly higher than those in group C. The NE levels every 24 hours in groups A and B were higher than those in group C, group A and group C had a statistically significant difference. The 96-hours exogenous NE dosage in groups A and B was significantly lower than that in group C. No significant reductions in APACHE, SOFA, or MODS scores were observed in the vitamin C group, including the duration of ICU stay and mechanical ventilation. The 28-days mortality was lower in groups A and B than in group C (0%, 10%, and 16.67%, P = .187), but the difference was not significant. CONCLUSION: For patients with septic shock, treatment with vitamin C significantly increased TH, BH4, and DßH levels and reduced the exogenous NE dosage, but did not significantly improve clinical outcomes.

VASOPRESSOR REDUCTION EFFECT OF POLYMYXIN B HEMOPERFUSION IN PATIENTS WITH PERITONITIS-INDUCED SEPTIC SHOCK: A PROPENSITY SCORE-MATCHED ANALYSIS.

ABSTRACT: Background : This study aimed to evaluate the effect of polymyxin B hemoperfusion (PMX-HP) in patients with peritonitis-induced septic shock who still required high-dose vasopressors after surgical source control. Methods : This retrospective study included adult patients admitted to the surgical intensive care unit (ICU) at Seoul National University Hospital between July 2014 and February 2021 who underwent major abdominal surgery to control the source of sepsis. Patients were divided into two groups based on whether PMX-HP was applied after surgery or not. The primary and secondary endpoints were the vasopressor reduction effect, and in-ICU mortality, respectively. Propensity score matching was performed to compare the vasopressor reduction effect. Results : A total of 338 patients met the inclusion criteria, of which 23 patients underwent PMX-HP postoperatively, whereas 315 patients did not during the study period. Serum norepinephrine concentration decreased over time regardless of whether PMX-HP was applied. However, it decreased more rapidly in the PMX-HP(+) group than in the PMX-HP(-) group. There were no significant differences in demographics including age, sex, body mass index, and most underlying comorbidities between the two groups. Risk factors for in-ICU mortality were identified by comparing patient characteristics and perioperative factors between the two groups using multivariate analysis. Conclusion : For patients with peritonitis-induced septic shock, PMX-HP rapidly reduces the requirement of vasopressors immediately after surgery but does not reduce in-ICU mortality. This effect could potentially accelerate recovery from shock, reduce sequelae from vasopressors, and ultimately improve quality of life after discharge.

[Lomentospora prolificans Fungemia in a Patient With T-Cell Large Granular Leukemia: A Rare Pathogen in Türkiye]. / T-hücreli Büyük Granüler Lösemili Bir Hastada Lomentospora prolificans Fungemisi: Türkiye'de Nadir Bir Etken.

Scedosporium/Lomentospora is an opportunistic fungal pathogen found worldwide. While Scedosporium apiospermum and Scedosporium boydii are commonly observed globally, Lomentospora prolificans, which mainly affects immunosuppressed individuals, is rarely encountered and is more prevalent in arid climates, particularly in Australia and Spain. L.prolificans is a fungus commonly found in environmental sources such as contaminated water and soil. This species is known as an opportunistic pathogen that can cause deep-seated fungal infections, especially in immunosuppressed individuals. In this case report, a fatal case of L.prolificans fungemia in a patient with T-cell large granular leukemia during profound neutropenia was presented. The patient admitted to the hospital with prolonged fever, neutropenia, and shortness of breath. Antibiotherapy was administered to the patient for febrile neutropenia, but the fever persisted and his clinical status rapidly deteriorated. L.prolificans was isolated from the blood culture, and considering its antifungal resistance, combination therapy of voriconazole and terbinafine was initiated. However, the patient died of septic shock and multiple organ failure. In conclusion, although L.prolificans infections are rare, they can be life-threatening, especially in immunosuppressed individuals. Diagnosis and treatment of such infections may be difficult, therefore rapid diagnostic methods and appropriate treatment protocols should be developed. Consideration of infections caused by rare fungal pathogens in patients with risk factors may be critical for patient care. The literature review revealed that the first case of L.prolificans fungemia from Türkiye was reported in 2023. This case presentation represents the second reported case. However, in our case, L.prolificans fungemia occurred in 2018, it can be considered that L.prolificans may have been an invasive fungal pathogen of significant concern in Türkiye much earlier than previously documented.

Effects of different doses of remimazolam on hemodynamics during general anesthesia in patients with septic shock.

OBJECTIVE: The stability of hemodynamics plays a vital role in the process of anesthesia induction for patients with septic shock. As a new-type benzodiazepine, remimazolam has numerous advantages, including rapid induction, rapid recovery, stable hemodynamics, and mild respiratory depression. Nevertheless, reports about the effects of remimazolam on hemodynamics in patients with septic shock are still limited. The study aimed to evaluate the effects that different doses of remimazolam have on hemodynamics in inducing general anesthesia in patients with septic shock. PATIENTS AND METHODS: Admitted to the intensive care unit of our hospital from January 2023 to June 2023, 75 patients with septic shock caused by acute appendicitis-induced sepsis were selected as observation subjects. They were randomly assigned to receive low-dose [0.2 mg/(kg·h)], medium-dose [0.3 mg/(kg·h)], and high-dose [0.4 mg/(kg·h)] remimazolam by using a random number table, with 25 patients in each group. Their intraoperative conditions were recorded, including operation duration, intraoperative hemorrhage volume, intraoperative transfusion volume, and decannulation time. Hemodynamic parameters, including mean arterial pressure (MAP), heart rate (HR), cardiac index (CI), and stoke volume index (SVI) were collected at seven-time points (T0: before induction; T1: before intubation; T2: after intubation; T3: the start of operation; T4: 15 min after operation; T5: 30 min after operation; T6: the end of operation). We also compared hepatic and renal function indexes, including blood urea nitrogen (BUN), serum creatinine (sCr), procalcitonin (PCT), white blood cells (WBC), tumor necrosis factor-α2 (TNF-α2), and Interleukin-6 (IL-6), of the three groups of patients before operation and 1, 3, 5, 7 days after operation. In addition, the incidence of adverse reactions in the three groups was recorded and compared. RESULTS: During remimazolam induction, the number of patients with intraoperative need for rescue remimazolam in the medium-dose and high-dose groups was significantly lower than in the low-dose group (p < 0.05). In terms of hemodynamic indexes, MAP in the high-dose group at T2 was lower than that at T0 (p < 0.05), and MAP at T2 was significantly lower in the high-dose group than that in the medium-dose group (p < 0.05). Furthermore, MAP at T4 in the medium-dose and high-dose groups declined compared with the low-dose group (p < 0.05). There were no significant differences in HR, CI, and SVI at different time points among the three groups (p > 0.05), but levels of HR and SVI decreased and CI increased after anesthesia compared with those before operation. Additionally, in comparison with the levels before operation, levels of sCR, BUN, PCT, WBC, TNF-α, and IL-6 were higher on postoperative days 1, 3 (p < 0.05) and lower on postoperative day 7 (p < 0.05). After the operation, both levels of BUN and sCR in the medium-dose and high-dose groups were lower than those in the low-dose group (p < 0.05). CONCLUSIONS: Remimazolam is safe and effective for inducing general anesthesia in patients with septic shock. Low, medium, and high doses of remimazolam can maintain a stable hemodynamic state, and the recovery of hepatic and renal function is certain to depend on the dose.

Blockade of sympathetic ganglia improves vascular dysfunction in septic shock.

Sepsis/septic shock activates the sympathetic nervous system (SNS) to deal with the infection stress. However, an imbalanced or maladaptive response due to excessive or uncontrolled activation characterizes autonomic dysfunction. Our hypothesis was that reducing this excessive activation of the autonomic nervous system would impact positively in sepsis. Using ganglionic blockers as a pharmacological approach, the main aim of the present report was to assess the role of ganglionic transmission in the vascular dysfunction associated with sepsis.Sepsis was induced in rats by cecal ligation and puncture (CLP). One hour after CLP surgery, rats were treated subcutaneously with hexamethonium (15 mg/kg; ganglionic blocker), pentolinium (5 mg/kg; a blocker with a higher selectivity for sympathetic ganglia compared to hexamethonium), or vehicle (PBS). Basal blood pressure and the response to adrenergic agonists were evaluated at 6 and 24 h after CLP surgery. Reactivity to vasoconstrictors, nitric oxide (NO) synthase 2 (NOS-2) expression, IL-1 and TNF plasma levels, and density of α1 adrenergic receptors were evaluated in the aorta 24 h after CLP.Septic shock resulted in hypotension and hyporesponsiveness to norepinephrine and phenylephrine, increased plasma cytokine levels and NOS-2 expression in the aorta, and decreased α1 receptor density in the same vessel. Pentolinium but not hexamethonium recovered responsiveness and α1 adrenergic receptor density in the aorta. Both blockers normalized the in vivo response to vasoconstrictors, and reduced plasma IL-1 and NOx levels and NOS-2 expression in the aorta.Blockade of ganglionic sympathetic transmission reduced the vascular dysfunction in experimental sepsis. This beneficial effect seems to be, at least in part, due to the preservation of α1 adrenergic receptor density and to reduced NOS-2 expression and may lead to adjuvant ways to treat human sepsis.

EFFECT OF STRATIFIED DOSE OF NOREPINEPHRINE ON CELLULAR IMMUNE RESPONSE IN PATIENTS WITH SEPTIC SHOCK AND THE CONSTRUCTION OF A PROGNOSTIC RISK MODEL.

ABSTRACT: Objective: To explore the effect of a stratified dose of norepinephrine (NE) on cellular immune response in patients with septic shock, and to construct a prognostic model of septic shock. Methods: A total of 160 patients with septic shock (B group) and 58 patients with sepsis (A group) were given standard cluster therapy. Patients with septic shock were divided into four groups (B1-B4 groups: 0.01-0.2, 0.2-0.5, 0.5-1.0, and >1 µg/kg/min) according to the quartile method of the early (72 h) time-weighted average dose of NE and clinical application. The cellular immune indexes at 24 h (T0) and 4-7 days (T1) after admission were collected. The difference method was used to explore the effect of NE stratified dose on cellular immune effect in patients with septic shock. A multivariate COX proportional risk regression model was used to analyze the independent prognostic risk factors, and a prognostic risk model was constructed. Results: The differences of ΔIL-1ß, ΔIL-6, ΔIL-10, absolute value difference of T lymphocyte (ΔCD3+/CD45+#) and Th helper T cell (ΔCD3+ CD4+/CD45+#), CD64 infection index difference, ΔmHLA-DR, regulatory T lymphocyte ratio difference (ΔTregs%) between group A, B1, B2, B3, and B4 were statistically significant ( P < 0.05). There was a nonlinear relation between the stratified dose of NE and ΔIL-6, ΔIL-10, ΔCD3+/CD45+#, ΔmHLA-DR%. The threshold periods of NE-induced proinflammatory and anti-inflammatory immune changes were 0.3-0.5 µg/kg/min. Multivariate COX model regression analysis showed that age, nutritional patterns, weighted average dose of norepinephrine, IL-6, absolute value of T lymphocytes, and mHLA-DR were independent risk factors affecting the prognosis of patients with septic shock ( P < 0.05). The prognostic risk model was constructed (AUC value = 0.813, 95% CI: 0.752-0.901). Conclusion: NE has a certain inhibitory effect on cellular immune function in patients with septic shock. A prognostic risk model was constructed with stronger prediction efficiency for the prognosis of patients with septic shock.

CM1, a Chrysin Derivative, Protects from Endotoxin-Induced Lethal Shock by Regulating the Excessive Activation of Inflammatory Responses.

Sepsis, a leading cause of death worldwide, is a harmful inflammatory condition that is primarily caused by an endotoxin released by Gram-negative bacteria. Effective targeted therapeutic strategies for sepsis are lacking. In this study, using an in vitro and in vivo mouse model, we demonstrated that CM1, a derivative of the natural polyphenol chrysin, exerts an anti-inflammatory effect by inducing the expression of the ubiquitin-editing protein TNFAIP3 and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Interestingly, CM1 attenuated the Toll-like receptor 4 (TLR4)-induced production of inflammatory cytokines by inhibiting the extracellular-signal-regulated kinase (ERK)/MAPK and nuclear factor kappa B (NF-κB) signalling pathways. In addition, CM1 induced the expression of TNFAIP3 and SIRT1 on TLR4-stimulated primary macrophages; however, the anti-inflammatory effect of CM1 was abolished by the siRNA-mediated silencing of TNFAPI3 or by the genetic or pharmacologic inhibition of SIRT1. Importantly, intravenous administration of CM1 resulted in decreased susceptibility to endotoxin-induced sepsis, thereby attenuating the production of pro-inflammatory cytokines and neutrophil infiltration into the lung compared to control mice. Collectively, these findings demonstrate that CM1 has therapeutic potential for diverse inflammatory diseases, including sepsis.

Albumin versus saline infusion for sepsis-related peripheral tissue hypoperfusion: a proof-of-concept prospective study.

BACKGROUND: Albumin has potential endothelial protective effects through antioxidant and anti-inflammatory properties. However, the effect of albumin on peripheral tissue perfusion in human sepsis remains poorly known. METHODS: Bi-centric prospective study included patients with sepsis with or without shock and prolonged CRT > 3 s despite initial resuscitation. Clinicians in charge of the patients were free to infuse either saline 500 mL or human serum albumin 20% 100 mL over 15 min. Global hemodynamic parameters as well as peripheral tissue perfusion were analyzed after 1 (H1) and 4 h (H4). The primary endpoint was CRT normalization (< 3 s) at H1. RESULTS: 62 patients were screened, and 50 patients (13 sepsis and 37 septic shock) were included, 21 in the saline group and 29 in the albumin group. SOFA score was 8 [5-11], and SAPS II was 53 [45-70]. Median age was 68 [60-76] years with a higher proportion of men (74%). The primary sources of infection were respiratory (54%) and abdominal (24%). At baseline, comorbidities, clinical and biological characteristics were similar between groups. At H1, CRT normalization (< 3 s) was more frequent in patients receiving albumin as compared to patients treated by saline (63 vs 29%, P = 0.02). The decrease in fingertip CRT was more important in the albumin group when compared to saline group (- 1.0 [- 0.3; - 1.5] vs - 0.2 [- 0.1; - 1.1] seconds, P = 0.04) as well as decrease in mottling score. At H4, beneficial effects of albumin on peripheral tissue perfusion were maintained and urinary output trended to be higher in the albumin group (1.1 [0.5-1.8] vs 0.7 [0.5-0.9] ml/kg/h, P = 0.08). Finally, arterial lactate level did not significantly change between H0 and H4 in the saline group but significantly decreased in the albumin group (P = 0.03). CONCLUSION: In patients with resuscitated sepsis, albumin infusion might lead to greater improvement of tissue hypoperfusion compared to saline. CLINICALTRIALS: gov Identifier: NCT05094856.

Efficacy and side-effect profile of tedizolid in the treatment of streptococcal toxic shock syndrome due to clindamycin-resistant Streptococcus pyogenes: A case report.

Oxazolidinones, such as tedizolid and linezolid, are bacteriostatic antibiotics that inhibit protein synthesis. Based on the findings from animal studies and their mechanism of action, these antibiotics are considered for managing toxic shock caused by clindamycin-resistant Group A Streptococcus (GAS; Streptococcus pyogenes). However, clinical reports on their usage in such cases are limited. Herein, we report a case of a 67-year-old woman with chronic myeloid leukemia who presented with fever, facial swelling, and myalgia. She was diagnosed with cellulitis and empirically treated with meropenem. Blood culture later revealed GAS, and she was diagnosed with streptococcal toxic shock syndrome. The antibiotic regimen was adjusted based on sensitivity results, with clindamycin initially replaced by linezolid and later switched to tedizolid owing to concerns about potential bone marrow suppression. Her condition improved, and she was discharged 15 days after admission. Therefore, tedizolid may be a safer option for managing toxic shock syndrome in patients with comorbidities that include thrombocytopenia.

Serious Bacterial Infections Associated with Eculizumab: A Pharmacovigilance Study.

Objective Molecular-targeted agents, including eculizumab and rituximab, are considered treatment options for refractory myasthenia gravis (MG), but bacterial infections can occur as serious adverse events when using these agents. The present study elucidated the relative risks of bacterial infections associated with eculizumab and rituximab using a pharmacovigilance database. Methods We analyzed eculizumab- and rituximab-associated adverse events reported between 2007 and 2021 in the US Food and Drug Administration Adverse Event Reporting System (FAERS) and herein report a refractory MG patient who developed streptococcal toxic shock syndrome during eculizumab treatment. Patients We evaluated a 74-year-old Japanese woman with refractory MG who developed severe bacteremia after receiving eculizumab. Results A total of 44,215 and 108,485 adverse events were reported with eculizumab and rituximab, respectively, from among 13,742,321 individual case safety reports in the FAERS database after data cleaning. We found a strong association between eculizumab and Neisseria infections. In contrast, we found only one case of meningococcal meningitis treated with rituximab. Both eculizumab and rituximab were weakly associated with streptococcal infections. Two cases of streptococcal toxic shock syndrome were associated with rituximab. Conclusion Careful monitoring of serious bacterial infections associated with eculizumab treatment is warranted.

PD-L1 Blockade Improves Survival in Sepsis by Reversing Monocyte Dysfunction and Immune Disorder.

Monocyte dysfunction is critical to sepsis-induced immunosuppression. Programmed death ligand-1 (PD-L1) has shown a close relationship with inflammatory disorder among animal models and patients. We aimed to investigate the potential beneficial immunologic mechanisms of anti-PD-L1 on monocyte dysfunction of mice with sepsis. Firstly, we assessed the potential association between PD-L1 expression on monocyte subsets and sepsis severity as well as 28-day mortality. In this study, 52 septic patients, 28 septic shock patients, and 40 healthy controls were enrolled and their peripheral whole blood was examined by flow cytometry. Then, cecal ligation and puncture (CLP) were performed for establishing the mouse sepsis model. Subsequently, effects of anti-PD-L1 antibody on monocyte subset, major histocompatibility complex II (MHC II) expression, cytokine production, and survival were investigated. PD-L1 expression on the classical monocytes (CD14 + + CD16 -) was significantly upregulated among septic shock patients and the 28-day death group than non-septic shock group and 28-day survival group (P < 0.05). Compared to septic mice, anti-PD-L1-treated mice had significantly elevated percentages of major histocompatibility complex (MHC) II on peripheral Ly6chi monocyte at 24 h after CLP. Our results showed that the anti-PD-L1 antibody markedly decreased the level of serum inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-10 in sepsis mice at 24 h, 48 h, and 72 h, respectively (P < 0.05). The survival rate of CLP mice was significantly improved by anti-PD-L1 antibody treatment. Classical monocytes with high expression of PD-L1 were thought to be connected with sepsis progression. The PD-L1 blockade protects from sepsis, at least partially by inhibiting the reversal of monocyte dysfunction.

Methylene Blue Reduces Mortality in Critically Ill and Perioperative Patients: A Meta-Analysis of Randomized Trials.

Vasodilatory hypotension is common in critically ill and perioperative patients, and is associated with adverse outcomes. As a nitric oxide production inhibitor, methylene blue (MB) exerts its vasoconstrictor property and is an adjuvant for catecholamine-refractory vasodilatory shock. However, the effects of MB on clinically relevant outcomes remain unclear. Therefore, the authors performed a meta-analysis of randomized trials on MB in critically ill and perioperative patients. The authors searched through databases for randomized trials on MB in critically ill and perioperative patients, which yielded 11 studies consisting of 556 patients. The primary outcome was mortality at the longest follow-up. Secondary outcomes included hemodynamic parameters and organ dysfunction (PROSPERO: CRD42023409243). Nine out of the 11 included randomized trials reported mortality, which was significantly lower in the MB group (risk ratio, 0.60 [95% CI 0.43-0.84] p = 0.003), with findings confirmed in septic shock and cardiac surgery subgroups. The authors found reduced lengths of stay in the intensive care unit (mean difference [MD], -0.9 days [95% CI -1.06 to -0.77] p < 0.001) and in the hospital (MD, -2.2 days [95% CI, -2.68 to -1.70] p < 0.001) in the MB group. MB was associated with increased mean arterial pressure (MD, 8.4 mmHg [95% CI 5.01-11.75] p < 0.001) and systemic vascular resistance (MD, 94.5 dyn/s/cm5 [95% CI 17.73-171.15] p = 0.02), with no difference in cardiac output (standardized MD, 0.16 [95% CI, -0.25 to 0.57] p = 0.45). This meta-analysis showed that MB reverses vasodilation in critically ill and perioperative patients and might improve survival. Further adequately powered randomized trials are needed to confirm these findings.

Ameliorative effect of anisodamine (654-1/654-2) against myocardial dysfunction induced by septic shock via the NF-κB/NLRP-3 or the PI3K-AKT/NF-κB pathway.

BACKGROUND: Septic shock, an extremely dangerous condition that causes impairment of organ function, always largely contributes to mortality in intensive care units. The impact of septic shock-induced organ damage on morbidity and mortality is substantially influenced by myocardial dysfunction. However, it remains unclear whether and in what manner anisodamine (654-1/654-2) ameliorates myocardial dysfunction caused by septic shock. PURPOSE: This study is the pioneering investigation and validation about the protective efficacy of anisodamine (654-1/654-2) against LPS-induced myocardial dysfunction in septic shock rats. It also aims to explore the differences in the underlying molecular mechanisms of both drugs. METHODS: A septic shock model was established in SD rats by after tail vein administration of LPS. 64 rats were distributed into eight groups, such as LPS group, control group, LPS+654-1 group (1.25, 2.5, and 5 mg/kg), and LPS+654-2 group (1.25, 2.5, and 5 mg/kg). The hemodynamics, echocardiography, immunohistochemical analysis, TEM, TUNEL assay, and H&E staining were utilized to assess the septic shock model and myocardial function. Lactic acid, inflammatory markers (IL-1ß, IL-6, and TNF-α), endothelial injure markers (SDC-1, HS and TM) and myocardial injury markers (CK, c-TNT and NT-pro BNP) were assessed using ELISA or biochemical kits. Additionally, the mechanisms of 654-1/654-2 were analyzed using RNA-seq and bioinformatics, and validated using western blotting and RT-PCR. RESULTS: Administration of 654-1/654-2 significantly restored hemodynamics and improved myocardial and endothelial glycocalyx injury in septic shock rats. Furthermore, 654-1/654-2 dose-dependently reduced plasma levels of lactic acid, inflammatory cytokines, and markers of endothelial and myocardial injury. Analyses using RNA-seq, WB and RT-PCR techniques indicated that 654-1/654-2 could mitigate myocardial and endothelial injury by inhibiting the NF-κB and NLRP-3 pathways, and activating the PI3K-AKT pathway. CONCLUSIONS: These findings demonstrated that 654-1/654-2 could alleviate myocardial damage in septic shock rats. Specifically, 654-1 inhibited the NF-κB/NLRP-3 pathway, whereas 654-2 promoted the PI3K-AKT pathway and inhibited the NF-κB pathway, effectively mitigating the inflammatory response and cell apoptosis.