Functional Outcomes and Morbidity in Pediatric Sepsis Survivors: A Tanzanian Experience

Pediatric sepsis remains a significant cause of childhood morbidity and mortality, disproportionately affecting resource-limited settings. As more patients survive, it is paramount that we improve our understanding of post-sepsis morbidity and its impact on functional outcomes. The functional status scale (FSS) is a pediatric validated outcome measure quantifying functional impairment, previously demonstrating decreased function following critical illnesses, including sepsis, in resource-rich settings. However, functional outcomes utilizing the FSS in pediatric sepsis survivors have never been studied in resource-limited settings or in non-critically ill septic children. In a Tanzanian cohort of pediatric sepsis patients, we aimed to evaluate morbidity associated with an acute septic episode using the FSS modified for resource-limited settings. This was a prospective cohort study at an urban referral hospital in Tanzania, including children with sepsis aged 28 days to 14 years old over a 12-month period. The FSS was adapted to the site's available resources. Functional status scale scores were obtained by interviewing guardians both at the time of presentation to determine the child's baseline and at 28-day follow-up. The primary outcome was “decline in functional status,” as defined by a change in FSS score of at least 3. In this cohort, 4.3% of the 1,359 surviving children completing 28-day follow-up had a “decline in functional status.” Conversely, 13.8% of guardians reported that their child was not yet back to their pre-illness state. Three-quarters of children reported as not fully recovered were not identified via the FSS as having a decline in functional status. In our cohort of pediatric sepsis patients, we identified a low rate of decline in functional status when using the FSS adapted for resource-limited settings. A higher proportion of children were subjectively identified as not being recovered to baseline. This suggests that the FSS has limitations in this population, despite being adapted for resource-limited settings. Next steps include developing and validating a further revised FSS to better capture patients identified as not recovered but missed by the current FSS.

The prognostic utility of protein C as a biomarker for adult sepsis: a systematic review and meta-analysis

Background Sepsis, the dysregulated host response to infection, triggers abnormal pro-coagulant and pro-inflammatory host responses. Limitations in early disease intervention highlight the need for effective diagnostic and prognostic biomarkers. Protein C’s role as an anticoagulant and anti-inflammatory molecule makes it an appealing target for sepsis biomarker studies. This meta-analysis aims to assess the diagnostic and prognostic value of protein C (PC) as a biomarker for adult sepsis. Methods We searched MEDLINE, PubMed, EMBASE, CINAHL and Cochrane Library from database inception to September 12, 2021. We included prospective observational studies of (1) adult patients (> 17) with sepsis or suspicion of sepsis that; (2) measured PC levels with 24 h of study admission with; and (3) the goal of examining PC as a diagnostic or prognostic biomarker. Two authors screened articles and conducted risk of bias (RoB) assessment, using the Quality in Prognosis Studies (QUIPS) and the Quality Assessment in Diagnostic Studies-2 (QUADAS-2) tools. If sufficient data were available, meta-analysis was conducted to estimate the standardized mean difference (SMD) between patient populations. Results Twelve studies were included, and 8 were synthesized for meta-analysis. Pooled analysis demonstrated moderate certainty of evidence that PC levels were less reduced in sepsis survivors compared to non-survivors (6 studies, 741 patients, SMD = 0.52, 95% CI 0.24–0.81, p = 0.0003, I2 = 55%), and low certainty of evidence that PC levels were less reduced in septic patients without disseminated intravascular coagulation (DIC) compared to those with DIC (3 studies, 644 patients, SMD = 0.97, 95% CI 0.62–1.32, p < 0.00001, I2 = 67%). PC could not be evaluated as a diagnostic tool due to heterogeneous control populations between studies. Conclusion and relevance Our review demonstrates that PC levels were significantly higher in sepsis survivors compared to non-survivors and patients with sepsis but not disseminated intravascular coagulation (DIC). Our evaluation is limited by high RoB in included studies and poor reporting of the sensitivity and specificity of PC as a sepsis biomarker. Future studies are needed to determine the sensitivity and specificity of PC to identify its clinical significance as a biomarker for early sepsis recognition. Trial Registration PROSPERO registration number: CRD42021229786. The study protocol was published in BMJ Open.

The role of neutrophil gelatinase-associated lipocalin and iron homeostasis in object recognition impairment in aged sepsis-survivor rats

Older adult patients with sepsis frequently experience cognitive impairment. The roles of brain neutrophil gelatinase-associated lipocalin (NGAL) and iron in older sepsis patients remain unknown. We investigated the effects of lipopolysaccharide-induced sepsis on novel object recognition test, NGAL levels, an inflammatory mediator tumor necrosis factor-α (TNFα) levels, and iron ion levels in the hippocampus and cortex of young and aged rats. The effect of an iron chelator deferoxamine pretreatment on aged sepsis rats was also examined. Young sepsis-survivor rats did not show impaired novel object recognition, TNFα responses, or a Fe2+/Fe3+ imbalance. They showed hippocampal and cortical NGAL level elevations. Aged sepsis-survivor rats displayed a decreased object discrimination index, elevation of NGAL levels and Fe2+/Fe3+ ratio, and no TNFα responses. Pretreatment with deferoxamine prevented the reduction in the object recognition of aged sepsis-survivor rats. The elevation in hippocampal and cortical NGAL levels caused by lipopolysaccharide was not influenced by deferoxamine pretreatment. The lipopolysaccharide-induced Fe2+/Fe3+ ratio elevation was blocked by deferoxamine pretreatment. In conclusion, our findings suggest that iron homeostasis in the cortex and hippocampus contributes to the maintenance of object recognition ability in older sepsis survivors.

Comparison of fatigue, cognitive dysfunction and psychological disorders in post-COVID patients and patients after sepsis: is there a specific constellation?

Background Sequelae of COVID-19 can be severe and longlasting. We compared frequencies of fatigue, depression and cognitive dysfunction in survivors of SARS-CoV-2-infection and sepsis. Methods We performed a prospective cohort study of 355 symptomatic post-COVID patients who visited our out-patient clinic for post-COVID-19 care. We compared them with 272 symptomatic patients from the Mid-German Sepsis Cohort, which investigates the long-term courses of sepsis survivors. Possible predictors for frequent clinical findings (fatigue, signs of depression, cognitive dysfunction) in post-COVID were investigated with multivariable logistic regression. Results Median age of the post-COVID patients was 51 years (range 17–86), 60.0% were female, and 31.8% required hospitalization during acute COVID-19. In the post-COVID patients (median follow-up time: 163 days) and the post-sepsis patients (180 days), fatigue was found in 93.2% and 67.8%, signs of depression were found in 81.3% and 10.9%, and cognitive dysfunction was found in 23.5% and 21.3%, respectively. In post-COVID, we did not observe an association between fatigue or depression and the severity of acute COVID-19. In contrast, cognitive dysfunction was associated with hospitalization (out-patient versus in-patient) and more frequent in post-COVID patients treated on an ICU compared to the MSC patients. Conclusion In post-COVID patients, fatigue and signs of depression are more common than in sepsis survivors, independent from the acute SARS-CoV-2-infection. In contrast, cognitive dysfunction is associated with hospitalization. Despite the differences in frequencies, owing to the similarity of post-COVID and post-sepsis sequelae, this knowledge may help in implementing follow-up approaches after SARS-CoV-2 infection.

Artificial Intelligence for Risk Prediction of Rehospitalization with Acute Kidney Injury in Sepsis Survivors

Sepsis survivors have a higher risk of long-term complications. Acute kidney injury (AKI) may still be common among sepsis survivors after discharge from sepsis. Therefore, our study utilized an artificial-intelligence-based machine learning approach to predict future risks of rehospitalization with AKI between 1 January 2008 and 31 December 2018. We included a total of 23,761 patients aged ≥ 20 years who were admitted due to sepsis and survived to discharge. We adopted a machine learning method by using models based on logistic regression, random forest, extra tree classifier, gradient boosting decision tree (GBDT), extreme gradient boosting, and light gradient boosting machine (LGBM). The LGBM model exhibited the highest area under the receiver operating characteristic curves (AUCs) of 0.816 to predict rehospitalization with AKI in sepsis survivors and followed by the GBDT model with AUCs of 0.813. The top five most important features in the LGBM model were C-reactive protein, white blood cell counts, use of inotropes, blood urea nitrogen and use of diuretics. We established machine learning models for the prediction of the risk of rehospitalization with AKI in sepsis survivors, and the machine learning model may set the stage for the broader use of clinical features in healthcare.

Effects of Renin‐Angiotensin–Aldosterone System Inhibitors on Long‐Term Major Adverse Cardiovascular Events in Sepsis Survivors

Background Sepsis is known to increase morbidity and duration of hospital stay and is a common cause of mortality worldwide. Renin‐angiotensin‐aldosterone system inhibitors (RAASis) are commonly used to treat hypertension but are usually discontinued during hospitalization for sepsis because of concerns about renal hypoperfusion. The aim of our study was to investigate whether RAASis should be continued after discharge in sepsis survivors and to identify the effects on the clinical outcomes. Methods and Results A total of 9188 sepsis survivors aged 20 years and older who were discharged from January 1, 2012 to December 31, 2019 were included in our analyses. We further divided sepsis survivors into RAASi users and nonusers. These groups were matched by propensity scores before the outcomes of interest, including all‐cause mortality and major adverse cardiac events (MACE), were examined. After propensity score matching, 3106 RAASi users and 3106 RAASi nonusers were included in our analyses. Compared with RAASi nonusers, RAASi users had lower risks of all‐cause mortality (hazard ratio [HR], 0.68; 95% CI, 0.62–0.75), MACEs (HR, 0.87; 95% CI, 0.81–0.94), ischemic stroke (HR, 0.85; 95% CI, 0.76–0.96), myocardial infarction (HR, 0.74; 95% CI, 0.61–0.90), and hospitalization for heart failure (HR, 0.84; 95% CI, 0.77–0.92). Subgroup analyses stratified by admission to the ICU and the use of inotropes showed similar results. Conclusions In our study, we found that RAASi users had reduced risks of all‐cause mortality and MACEs. These findings suggested a beneficial effect of RAASi use by sepsis survivors after discharge.

Platelet-lymphocyte ratio and sepsis outcome in children

Background Sepsis is the most common cause of death in infants and children worldwide. Identification of patients with a high risk of death and accurately anticipating outcomes in the early phase is very important in order to provide adequate intervention to the patient. Predictors and scoring systems have been used to determine the prognosis of sepsis n children. The platelet-lymphocyte ratio (PLR), a newly-used marker for inflammation, has received recent attention, as it can act as an indicator in a variety of diseases, including sepsis. Objective o investigate the relationship between PLR and clinical outcomes in pediatric patients with sepsis. Methods This study was conducted using an analytic, observational method with a prospective cohort approach in children with sepsis in the Pediatric Intensive Care Unit (PICU) of Prof. Dr. R. D. Kandou Central General Hospital, Manado, North Sulawesi, from February to August 2020. We analyzed patients’ platelet-lymphocyteratio (PLR), mortality rate, and length of stay using SPSS software. The PLR were recorded once within the first 24 hours of PICU admission. Results Of 96 PICU patients, 87 patients were eligible for this study. In total, 50 patients (57.47%) died. Mean PLR was 77.53 among sepsis survivors and 157.2 among non-survivors (rpb=0.566, P<0.0001) indicating a strong relationship between PLR and mortality. We also found a strong positive linear relationship between PLR and PICU length of stay. Conclusion Platelet-lymphocyte ratio is a predictor of sepsis outcomes that can be easily and inexpensively checked. Thus, it can be used in regions with limited health facilities.

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.

Long-Term Abnormalities of Lipid Profile After a Single Episode of Sepsis

Background: Acute disturbances of the lipid profile are commonplace during acute sepsis episode. However, their long-term persistence has not to be investigated despite pivotal role of dyslipidemia in several comorbidities excessively noted in sepsis survivors (stroke, cardiomyopathy).Methods: A total of 9,861 individuals hospitalized for a singular episode of sepsis between 2009 and 2019 were identified from electronic medical records. Lab measurements of total cholesterol (Tchol), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c), very low-density lipoprotein (VLDL), triglycerides (TG), lipoprotein(a) [Lp (a)], apolipoprotein B (ApoB), and C-reactive protein (CRP). The data were examined as baseline values before sepsis, during hospitalization, and &lt;3 months, 3–6 months, 6–12 months, 1–2 years, and more than 2 years from initial sepsis.Results: Significant reductions in HDL-c (HDLbaseline = 44.06 vs. HDLsepsis = 28.2; U = −37.79, p &lt; 0.0001, Cohen's d = 0.22) and LDL-c serum levels were observed during and up to three months post sepsis, with females much less affected. In contrast, male subjects had derangement in HDL present for up to two years after a singular septic episode. Total cholesterol levels were slightly yet significantly elevated for up to two years after sepsis. TG were elevated up to one year [TGbaseline = 128.26 vs. TGsepsis = 170.27, t(8255) = −21.33, p &lt; 0.0001, Cohen's d = 0.49] and normalized. Lp(a) was elevated up to two years after initial episode [Lp(a)baseline = 24.6 ± 16.06; Lp(a)sepsis−2year = 8.25 ± 5.17; Lp(a)morethan2years = 61.4 ± 40.1; ANOVA F(2, 24) = 7.39; p = 0.0032]. Response to statin therapy was blunted in sepsis survivors for several years after sepsis resolution. Significant drop-out in prescription of statins and niacin after sepsis was observed. Serum high sensitivity C-reactive protein was elevated for up to five years after sepsis resolution (H [6;1685] = 502.2; p &lt; 0.0001).Discussion: Lipid abnormalities persisted long after the initial septic insult suggesting potential role in accelerating atherosclerosis and other abnormalities. In addition, sepsis seems to blunt statin effectiveness. Additionally, a significant and unexplained drop in statin use was seen in post-septic period.Conclusions: Our study suggests that persistent derangements of lipid profile components for up to two years after sepsis may be associated with altered risk of atherosclerosis-related events among sepsis survivors.