Long-term cardiovascular complications following sepsis: is senescence the missing link?

Among the long-term consequences of sepsis (also termed “post-sepsis syndrome”) the increased risk of unexplained cardiovascular complications, such as myocardial infarction, acute heart failure or stroke, is one of the emerging specific health concerns. The vascular accelerated ageing also named premature senescence is a potential mechanism contributing to atherothrombosis, consequently leading to cardiovascular events. Indeed, vascular senescence-associated major adverse cardiovascular events (MACE) are a potential feature in sepsis survivors and of the elderly at cardiovascular risk. In these patients, accelerated vascular senescence could be one of the potential facilitating mechanisms. This review will focus on premature senescence in sepsis regardless of age. It will highlight and refine the potential relationships between sepsis and accelerated vascular senescence. In particular, key cellular mechanisms contributing to cardiovascular events in post-sepsis syndrome will be highlighted, and potential therapeutic strategies to reduce the cardiovascular risk will be further discussed.

Designing Support Structures Post Sepsis in Children: Perspectives of the Queensland Paediatric Sepsis Program

Introduction: Paediatric post sepsis syndrome is poorly defined and causes physical, neurocognitive, psychosocial morbidity, and family dysfunction. Families of sepsis survivors report unmet needs during care. Worldwide, the provision of post sepsis care is in its infancy with limited evidence to design clinical support pathways.Perspective: The Queensland Paediatric Sepsis Program (QPSP) developed a family support structure (FSS) to improve care during all stages of childhood sepsis. It was designed in partnership with consumers guided by information from consumers and it is partly delivered by consumers. Key areas include online, multimodal education for families and the ability to connect with other families affected by sepsis. The FSS is delivered by a multidisciplinary team (MDT) acting with clinicians local to the child. Families can join the FSS registry at any stage of their sepsis journey which connects them to our MDT team and opens opportunities to participate in future research and other initiatives. Improving public awareness is a critical outcome for our consumers and they have co-designed media and digital campaigns.Discussion: The ideal FSS for post sepsis syndrome management is a clinical pathway designed in partnership with consumers of interventions proven to improve outcomes from sepsis that meets their requirements. The QPSP FSS is novel as it is co-designed with, and partly delivered by, consumers with interventions aimed to improve the entire spectrum of morbidities suffered by survivors and their families, not just physical sequelae. Evaluation is embedded in the program and outcomes will guide evolution of the FSS.

Therapeutic Effect of α-MSH in Primary Cultured Orbital Fibroblasts Obtained from Patients with Thyroid Eye Disease

Inflammation, hyaluronan production, and adipogenesis are the main pathological events leading to thyroid eye disease (TED). α-Melanocytemelanocyte-stimulating hormone (α-MSH) is a well-known tridecapeptidetreatment for several inflammatory disorders including sepsis syndrome, acute respiratory distress syndrome, rheumatoid arthritis, and encephalitis. Here, we investigated the effect of α-MSH treatment on TED. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Lactate Dehydrogenase (LDH) assays were performed to analyze the effect of α-MSH on cell viability and it’s toxicity. Using primary cultures of orbital fibroblasts from TED patients and non-TED as control, we examined the effects of α-MSH on proinflammatory cytokine production induced by interleukin (IL)-1β, further analyzed by real-time reverse transcription-polymerase chain reaction (qPCR) and western blotting. Immunofluorescence staining assay and qPCR were performed to examine proopiomelanocortin (POMC) expression, the upstream neuropeptide of α-MSH in TED patients and non-TED control. Treatment with non-cytotoxic concentrations of α-MSH resulted in the dose-dependent inhibition of mRNA and protein levels (p < 0.05) for IL-1β-induced inflammatory cytokines: IL-6, IL-8, MCP-1, ICAM-1, and COX-2. The expression of POMC mRNA and protein were significantly higher in TED patients compared to non-TED control (p < 0.05). Our data show significant inhibitory effects of α-MSH on inflammation, POMC production in orbital fibroblasts. At present, this is the first in vitro preclinical evidence of α-MSH therapeutic effect on TED. These findings indicate that POMC and α-MSH may play a role in the immune regulation of TED and can be a potential therapeutic target.

Additional benefit of induced pluripotent stem cell-derived mesenchymal stem cell therapy on sepsis syndrome-associated acute kidney injury in rat treated with antibiotic

Background This study tested whether human induced-pluripotent stem-cell-derived mesenchymal-stem-cells (iPS-MSCs) would offer an additional benefit to the rodent with acute kidney injury (AKI) (ischemia for 1 h followed by reperfusion for 120 h) associated sepsis syndrome (SS) (by cecal-ligation-puncture immediately after AKI-induction) undergoing ciprofloxacin therapy. Results Male-adult SD rats (n = 80) were categorized into group 1 (sham-operated-control, n = 10), group 2 (AKI + SS, n = 24), group 3 (AKI + SS + ciprofloxacin/3 mg/kg, orally for 120 h, n = 12), group 4 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 3 h after AKI, n = 12), group 5 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 18 h after AKI, n = 12), group 6 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 3 h after AKI induction + ciprofloxacin, n = 10] and euthanized by 120 h. The result showed that the mortality was significantly higher in group 2 than in other groups (all p < 0.01). The creatinine level was highest in group 2, lowest in group 1, significantly lower in group 6 than in groups 3, 4 and 5, (all p < 0.0001), but it showed no difference among the latter 3 groups. Flow cytometric analysis showed that the circulatory inflammatory cells (Ly6G/CD11b/c), early (AN-V+/PI−)/late (AN-V+/PI+) apoptosis, and circulatory/splenic immune cells (CD3+/CD4+, CD3+/CD8a+) were highest in group 2, lowest in group 1, significantly lower in group 6 than in groups 3/4/5 and significantly lower in group 4 than in groups 3/5 (all p < 0.0001), but they showed no difference between groups 3/5. Protein expressions of oxidative-stress (NOX-1/NOX2/oxidized protein), apoptotic (cleaved-caspase3/cleaved-PARP/mitochondrial-Bax), fibrotic (TGF-ß/Smad3), inflammatory (MMP-9/IL-6/TNF-α) and autophagic (Atg5/Beclin) biomarkers in kidney exhibited an identical pattern of circulatory inflammatory cells (all p < 0.0001). Conclusion Combined iPS-MSCs-ciprofloxacin therapy was superior to either one alone for protecting AKI complicated by SS.

Kinetics of Immunoglobulins in Septic Shock Patients Treated With an IgM- and IgA-Enriched Intravenous Preparation: An Observational Study

Objective: To assess the variations of the blood levels of immunoglobulins (Ig) in septic shock patients treated with an Ig preparation enriched in IgM and IgA (eIg).Design: The blood levels of Ig in survivors (S) and non-survivors (NS) of a group of septic shock patients were measured before the initial administration (D0) and 1 (D1), 4 (D4), and 7 (D7) days thereafter. The SAPS II score, the capillary permeability, the primary site of infection, the antibiotic appropriateness, and the outcome at 28 days were also assessed.Results: In the interval D0–D7, the IgM increased significantly only in the S while remained stable in NS; the IgA significantly increased in both groups; the IgG did not vary significantly in both groups. At D4, the capillary permeability significantly decreased in S but not in NS.Conclusions: The kinetics of the different classes of Ig after eIg were different between S and NS. This could be related either to (a) different capillary permeability in the two groups or to (b) higher Ig consumption in NS. Further studies to confirm the benefits of eIg in the treatment of sepsis syndrome and to define the specific target population and the correct eIg dose are warranted.

Why Septic Patients Remain Sick After Hospital Discharge?

Sepsis is well known to cause a high patient death rate (up to 50%) during the intensive care unit (ICU) stay. In addition, sepsis survival patients also exhibit a very high death rate after hospital discharge compared to patients with any other disease. The addressed question is then: why septic patients remain ill after hospital discharge? The cellular and molecular mechanisms involved in the high rate of septic patient deaths are still unknown. We described herein the studies that investigated the percentage of septic patients that died after hospital discharge ranging from 90 days up to 5 years. We also reported the symptoms of septic patients after hospital discharge and the development of the recently called post-sepsis syndrome (PSS). The most common symptoms of the PSS are cognitive disabilities, physical functioning decline, difficulties in performing routine daily activities, and poor life quality. The PSS also associates with quite often reinfection and re-hospitalization. This condition is the cause of the high rate of death mentioned above. We reported the proportion of patients dying after hospital discharge up to 5 years of followed up and the PSS symptoms associated. The authors also discuss the possible cellular and metabolic reprogramming mechanisms related with the low survival of septic patients and the occurrence of PSS.

Clinical utility of procalcitonin in severe odontogenic maxillofacial infection

Background Most of the maxillofacial infections are bacterial infections, and there is a possibility that systemic infections occur by maxillofacial infections. The aim of this study was to investigate the diagnostic value of procalcitonin in patients with odontogenic bacterial infections of the maxillofacial region. Methods We enrolled sixty patients, who were admitted with odontogenic maxillofacial infection from September 2018 to March 2020. White blood cell counts, C-reactive protein, and procalcitonin concentrations were evaluated. Sixty patients were classified into two groups, sepsis and non-sepsis groups, based on systemic inflammatory response syndrome. A Student t test was performed to statistically analyze the difference in inflammatory markers between sepsis and non-sepsis groups. Results The mean procalcitonin values on admission were 7.24 ng/mL (range, 0.09–37.15 ng/mL) and 0.40 ng/mL (range, 0.02–4.94 ng/mL) in the sepsis group and non-sepsis group, respectively. The procalcitonin values between the two groups showed a significant difference (P < 0.05). The area under the curve of procalcitonin was 0.927 (P < 0.001), and the cutoff value of procalcitonin that maximizes the area under the curve was calculated to be 0.87 ng/mL. Conclusions According to our study, routine laboratory tests have insufficient accuracy in diagnosing sepsis syndrome. Therefore, it is strongly recommended to perform the procalcitonin test in patients with maxillofacial infection in addition to the conventional laboratory tests to diagnose the systemic inflammatory condition of the patients.

Evaluation of linezolid pharmacokinetics in critically-ill obese patients with severe skin and soft tissue infections

Background: Linezolid standard dosing is fixed at 600 mg q12h for adults. Literature suggests critically-ill, obese patients require higher doses. The study aim is two-fold: (i) to describe linezolid PK and (ii) to evaluate if PK/PD target attainment is achieved with standard dosing in critically-ill, obese patients with severe SSTIs. Methods: Adult patients with a body mass index (BMI) ≥ 30 kg/m2 and receiving IV linezolid from August 2018 to April 2019 were eligible for consent in this prospective study. Severe SSTIs were defined as necrotizing fasciitis, myonecrosis, or SSTI with sepsis syndrome. Four blood samples were collected at steady state at 1, 3, 5 hours post-infusion and as a trough. Target attainment was defined as achieving AUC0-24h/MIC ≥ 100 hr*mg/L. Monte Carlo simulations were used to determine probability of target attainment (PTA). Results: Eleven patients were included in the study. The median BMI was 45.7 kg/m2 and median total body weight (TBW) was 136.0 kg. Seven patients received standard linezolid doses and four received 600 mg q8h. A one-compartment model described linezolid PK. Based on AUC0-24h/MIC targets, for non-cirrhotic patients at 140 kg, PTA with standard linezolid doses was 100%, 98.8%, 34.1%, and 0% for MICs 0.5, 1, 2, and 4 mg/L, respectively. Conclusion: Target attainment ≥ 90% is not achieved with standard linezolid doses for non-cirrhotic patients ≥ 140 kg with MICs ≥ 2 mg/L. This study adds to accumulating evidence that standard linezolid doses may not be adequate for all patients.