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.

In sepsis or septic shock, prolonged vs. intermittent infusion of ß-lactam antibiotics reduces mortality at 90 d.

SOURCE CITATION: Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs intermittent infusions of ß-lactam antibiotics in adults with sepsis or septic shock: a systematic review and meta-analysis. JAMA. 12 June 2024. [Epub ahead of print.] 38864162.

Iloprost and Organ Dysfunction in Adults With Septic Shock and Endotheliopathy: A Randomized Clinical Trial.

Importance: Soluble thrombomodulin is a marker of endotheliopathy, and iloprost may improve endothelial function. In patients with septic shock, high plasma levels of soluble thrombomodulin (>10 ng/mL) have been associated with worse organ dysfunction and mortality. Objective: To assess the effects of treatment with iloprost vs placebo on the severity of organ failure in patients with septic shock and plasma levels of soluble thrombomodulin higher than 10 ng/mL. Design, Setting, and Participants: This investigator-initiated, adaptive, parallel group, stratified, double-blind randomized clinical trial was conducted between November 1, 2019, and July 5, 2022, at 6 hospitals in Denmark. The trial had a maximum sample size of 380, with an interim analysis for futility only at 200 patients with 90 days of follow-up. In total, 279 adults in the intensive care unit (ICU) with septic shock and endotheliopathy were included. Interventions: Patients were randomized 1:1 to masked intravenous infusion of iloprost, 1 ng/kg/min (n = 142), or placebo (n = 137) for 72 hours. Main Outcomes and Measures: The primary outcome was mean daily Sequential Organ Failure Assessment (SOFA) score in the ICU adjusted for trial site and baseline SOFA score for the per-protocol population. SOFA scores for each of the 5 organ systems ranged from 0 to 4, with higher scores indicating more severe dysfunction (maximum score, 20). The secondary outcomes included serious adverse reactions and serious adverse events at 7 days and mortality at 90 days. Results: Of 279 randomized patients, data from 278 were analyzed (median [IQR] age, 69 [58-77] years; 171 (62%) male), 142 in the iloprost group and 136 in the placebo group. The trial was stopped for futility at the planned interim analysis. The mean [IQR] daily SOFA score was 10.6 (6.4-14.8) in the iloprost group and 10.5 (5.9-15.5) in the placebo group (adjusted mean difference, 0.2 [95% CI, -0.8 to 1.2]; P = .70). Mortality at 90 days in the iloprost group was 57% (81 of 142) vs 51% (70 of 136) in the placebo group (adjusted relative risk, 1.12 [95% CI, 0.91-1.40]; P = .33). Serious adverse events occurred in 26 of 142 patients (18%) for the iloprost group vs 20 of 136 patients (15%) for the placebo group (adjusted relative risk, 1.25 [95% CI, 0.73-2.15]; P = .52). Only 1 serious adverse reaction was observed. Conclusions and Relevance: In this randomized clinical trial of adults in the ICU with septic shock and severe endotheliopathy, infusion of iloprost, 1 ng/kg/min, for 72 hours did not reduce mean daily SOFA scores compared with placebo. In a clinical context, administration of iloprost will be unlikely to improve outcome in these patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04123444.

Antibiotic dose optimisation in the critically ill: targets, evidence and future strategies.

PURPOSE OF REVIEW: To highlight the recent evidence for antibiotic pharmacokinetics and pharmacodynamics (PK/PD) in enhancing patient outcomes in sepsis and septic shock. We also summarise the limitations of available data and describe future directions for research to support translation of antibiotic dose optimisation to the clinical setting. RECENT FINDINGS: Sepsis and septic shock are associated with poor outcomes and require antibiotic dose optimisation, mostly due to significantly altered pharmacokinetics. Many studies, including some randomised controlled trials have been conducted to measure the clinical outcome effects of antibiotic dose optimisation interventions including use of therapeutic drug monitoring. Current data support antibiotic dose optimisation for the critically ill. Further investigation is required to evolve more timely and robust precision antibiotic dose optimisation approaches, and to clearly quantify whether any clinical and health-economic benefits support expanded use of this treatment intervention. SUMMARY: Antibiotic dose optimisation appears to improve outcomes in critically ill patients with sepsis and septic shock, however further research is required to quantify the level of benefit and develop a stronger knowledge of the role of new technologies to facilitate optimised dosing.

Efficacy and safety of dynamic arterial elastance for weaning vasopressor support in septic shock patients: a randomised controlled trial protocol.

INTRODUCTION: The dynamic arterial elastance (EaDyn), calculated as pulse pressure variation divided by stroke volume variation, has been studied as a predictor of vasopressor weaning. However, its potential as a haemodynamic tool for tapering off vasopressors in patients with sepsis remains unexplored. Therefore, our study aimed to assess whether using EaDyn for weaning vasopressor support could reduce the duration of vasopressor support in patients with sepsis. METHODS AND ANALYSIS: This pragmatic single-centre controlled clinical trial will take place at Fundación Santa Fe de Bogotá, Colombia. Adult patients diagnosed with septic shock according to the sepsis-3 criteria and a Sequential Organ Failure Assessment score ≥4 will be included. A total of 114 patients (57 per group) will undergo conventional critical care monitoring, and the weaning of vasopressor support will be initiated based on the EaDyn or mean arterial pressure (MAP), depending on the assigned group. EaDyn will be estimated based on the measurements obtained from a PiCCO device connected to a PulsioFlex Monitoring Platform (PULSION Medical Systems SE, Feldkirchen, Germany). Our primary outcome is the difference in vasopressor support duration between the EaDyn and MAP groups.Participants and statisticians performing the statistical analysis will be blinded to the group allocation. Dependent and independent variables will be analysed through univariate and multivariate statistical tests. Since we will perform three repeated measurements for analysis, we will implement a Bonferroni post hoc correction. Additionally, Cox regression and Kaplan-Meier analyses will be conducted to address objectives related to time. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee at Fundación Santa Fe de Bogotá (CCEI-16026-2024). Written informed consent will be obtained from all participants. The results will be disseminated through publication in peer-reviewed journals and presentations at national and international events. TRIAL REGISTRATION NUMBER: NCT06118775.

Beta-Blockers as an Immunologic and Autonomic Manipulator in Critically Ill Patients: A Review of the Recent Literature.

The autonomic nervous system plays a key role in maintaining body hemostasis through both the sympathetic and parasympathetic nervous systems. Sympathetic overstimulation as a reflex to multiple pathologies, such as septic shock, brain injury, cardiogenic shock, and cardiac arrest, could be harmful and lead to autonomic and immunologic dysfunction. The continuous stimulation of the beta receptors on immune cells has an inhibitory effect on these cells and may lead to immunologic dysfunction through enhancing the production of anti-inflammatory cytokines, such as interleukin-10 (IL-10), and inhibiting the production of pro-inflammatory factors, such as interleukin-1B IL-1B and tissue necrotizing factor-alpha (TNF-alpha). Sympathetic overstimulation-induced autonomic dysfunction may also happen due to adrenergic receptor insensitivity or downregulation. Administering anti-adrenergic medication, such as beta-blockers, is a promising treatment to compensate against the undesired effects of adrenergic surge. Despite many misconceptions about beta-blockers, beta-blockers have shown a promising effect in decreasing mortality in patients with critical illness. In this review, we summarize the recently published articles that have discussed using beta-blockers as a promising treatment to decrease mortality in critically ill patients, such as patients with septic shock, traumatic brain injury, cardiogenic shock, acute decompensated heart failure, and electrical storm. We also discuss the potential pathophysiology of beta-blockers in various types of critical illness. More clinical trials are encouraged to evaluate the safety and effectiveness of beta-blockers in improving mortality among critically ill patients.

Antibiotics Removal during Continuous Renal Replacement Therapy in Septic Shock Patients: Mixed Modality Versus "Expanded Haemodialysis".

BACKGROUND AND OBJECTIVE: Renal replacement therapy (RRT) plays a critical role in antimicrobial removal, particularly for low-molecular-weight drugs with low plasma protein binding, low distribution volume and hydrophilicity. Medium cut-off (MCO) membranes represent a new generation in dialysis technology, enhancing diffusive modality efficacy and increasing the cut-off from 30 to 45 kDa, crucial for middle molecule removal. This monocentric randomized crossover pilot study aimed to evaluate the impact of continuous haemodialysis with MCO membrane (MCO-CVVHD) on the removal of piperacillin, tazobactam and meropenem compared with continuous veno-venous hemodiafiltration with standard high-flux membrane (HFM-CVVHDF). METHODS: Twenty patients were randomized to undergo MCO-CVVHD followed by HFM-CVVHDF or vice versa. Extraction ratio (ER), effluent clearance (Cleff) and treatment efficiency were assessed at various intervals. Antibiotic nadir plasma levels were measured for both treatment days. RESULTS: HFM-CVVHDF showed greater ER compared with MCO-CVVHD for meropenem (ß = - 8.90 (95% CI - 12.9 to - 4.87), p < 0.001) and tazobactam (ß = - 8.29 (95% CI - 13.5 to - 3.08), p = 0.002) and Cleff for each antibiotic (meropenem ß = - 10,206 (95% CI - 14,787 to - 5787), p = 0.001); tazobactam (ß = - 4551 (95% CI - 7781 to - 1322), p = 0.012); piperacillin (ß = - 3913 (95% CI - 6388 to - 1437), p = 0.002), even if the carryover effect influenced the Cleff for meropenem and tazobactam. No difference was observed in nadir plasma concentrations or efficiency for any antibiotic. Piperacillin (ß = - 38.1 (95% CI - 47.9 to - 28.3), p < 0.001) and tazobactam (ß = - 4.45 (95% CI - 6.17 to - 2.72), p < 0.001) showed lower nadir plasma concentrations the second day compared with the first day, regardless the filter type. CONCLUSION: MCO demonstrated comparable in vivo removal of piperacillin, tazobactam and meropenem to HFM.

Prolonged Antibiotic Infusions Reduce Mortality in Adults with Sepsis and Septic Shock.

According to this study.

Discovery of Potent, Specific, and Orally Available NLRP3 Inflammasome Inhibitors Based on Pyridazine Scaffolds for the Treatment of Septic Shock and Peritonitis.

The NLRP3 inflammasome is a multiprotein complex that is a component of the innate immune system, involved in the production of pro-inflammatory cytokines. Its abnormal activation is associated with many inflammatory diseases. In this study, we designed and synthesized a series of NLRP3 inflammasome inhibitors based on pyridazine scaffolds. Among them, P33 exhibited significant inhibitory effects against nigericin-induced IL-1ß release in THP-1 cells, BMDMs, and PBMCs, with IC50 values of 2.7, 15.3, and 2.9 nM, respectively. Mechanism studies indicated that P33 directly binds to NLRP3 protein (KD = 17.5 nM), inhibiting NLRP3 inflammasome activation and pyroptosis by suppressing ASC oligomerization during NLRP3 assembly. Additionally, P33 displayed excellent pharmacokinetic properties, with an oral bioavailability of 62%. In vivo efficacy studies revealed that P33 significantly ameliorated LPS-induced septic shock and MSU crystal-induced peritonitis in mice. These results indicate that P33 has great potential for further development as a candidate for treating NLRP3 inflammasome-mediated diseases.

High adsorption capacity of hemoperfusion on imipenem in critically ill patients with septic shock: a case report.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by an excessive host response to infection, manifested by elevated levels of inflammatory cytokines. At present, the use of hemoperfusion to remove inflammatory cytokines from the bloodstream has been expanding. Meanwhile, the pharmacokinetics and pharmacodynamics characteristics of antibiotics in critically ill patients may be impacted by hemoperfusion. CASE PRESENTATION: The patient was a 69-year-old male with poorly controlled type 2 diabetes. When admitted to the ICU, Multiple Organ Dysfunction Syndrome (MODS) appeared within 48 h, and he was suspected of septic shock due to acute granulocytopenia and significantly increased procalcitonin. Broad-spectrum antibiotics imipenem was administered according to Sepsis 3.0 bundle and hemoperfusion lasting 4 h with a neutron-macroporous resin device (HA-380, Jafron, China) five times was conducted to lower the extremely high value of serum inflammatory factors. Blood samples were collected to measure imipenem plasma concentration to investigate the effect of hemoperfusion quantitatively. This study showed that 4 h of hemoperfusion had a good adsorption ability on inflammatory factors and could remove about 75.2% of imipenem. CONCLUSIONS: This case demonstrated the high adsorption capacity of hemoperfusion on imipenem in critically ill patients. It implies a timely imipenem supplement is required, especially before hemoperfusion.

Association of second antibiotic dose delays on mortality in patients with septic shock.

OBJECTIVE: Determine whether a delay in the administration of the second dose of antibiotics is associated with an increased risk of mortality for patients admitted with septic shock. DESIGN: Retrospective, observational evaluation. SETTING: Regional multicenter evaluation including four institutions in western Pennsylvania. PATIENTS: A total of 905 patients were included in this study who met the criteria for septic shock. Patients that did not receive a second dose of antibiotics, were transferred from an outside facility, or expected death within six hours of hospital admission were excluded. INTERVENTIONS: The frequency of second antibiotic dose administration delay was determined. A delay was defined as a delay greater than or equal to 25% of the antibiotic dosing interval. MEASUREMENTS AND MAIN RESULTS: A delay in second antibiotic dose administration was found in 181 (20%) of patients. Patients with a delay in the administration of second dose antibiotics had a higher mortality rate (35%) than patients without a delay (26%) (p =0.018). Patients with and without a delay in the administration of second-dose antibiotics had similar median 28-day vasopressor free days (median = 26.0, IQR = 2.0). Differences in the distribution of the 28-day vasopressor free days between groups resulted in the achievement of statistical significance (Mann-Whitney U = 57,294.5, z = -2.690, p = 0.006). There was no difference in 28-day ventilator-free days between groups. A delay in the administration of second dose antibiotics led to a longer in-hospital length of stay (9 days vs. 7 days; p = 0.022) and a longer ICU length of stay than patients without a delay (5 days vs. 3 days; p = 0.007). CONCLUSIONS: Delays in second antibiotic dose administration in septic shock patients were present but lower than previous studies. These delays were associated with increased mortality, increased ICU and hospital length of stay.

The impact of norepinephrine dose reporting heterogeneity on mortality prediction in septic shock patients.

BACKGROUND: Norepinephrine (NE) is a cornerstone drug in the management of septic shock, with its dose being used clinically as a marker of disease severity and as mortality predictor. However, variations in NE dose reporting either as salt formulations or base molecule may lead to misinterpretation of mortality risks and hinder the process of care. METHODS: We conducted a retrospective analysis of the MIMIC-IV database to assess the impact of NE dose reporting heterogeneity on mortality prediction in a cohort of septic shock patients. NE doses were converted from the base molecule to equivalent salt doses, and their ability to predict 28-day mortality at common severity dose cut-offs was compared. RESULTS: 4086 eligible patients with septic shock were identified, with a median age of 68 [57-78] years, an admission SOFA score of 7 [6-10], and lactate at diagnosis of 3.2 [2.4-5.1] mmol/L. Median peak NE dose at day 1 was 0.24 [0.12-0.42] µg/kg/min, with a 28-day mortality of 39.3%. The NE dose showed significant heterogeneity in mortality prediction depending on which formulation was reported, with doses reported as bitartrate and tartrate presenting 65 (95% CI 79-43)% and 67 (95% CI 80-47)% lower ORs than base molecule, respectively. This divergence in prediction widened at increasing NE doses. When using a 1 µg/kg/min threshold, predicted mortality was 54 (95% CI 52-56)% and 83 (95% CI 80-87)% for tartrate formulation and base molecule, respectively. CONCLUSIONS: Heterogeneous reporting of NE doses significantly affects mortality prediction in septic shock. Standardizing NE dose reporting as base molecule could enhance risk stratification and improve processes of care. These findings underscore the importance of consistent NE dose reporting practices in critical care settings.

[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.