Abstract Background There is conflicting evidence on association between quick sequential organ failure assessment (qSOFA) and sepsis mortality in ICU patients. The primary aim of this study was to determine the association between qSOFA and 28-day mortality in ICU patients admitted for sepsis. Association of qSOFA with early (3-day), medium (28-day), late (90-day) mortality was assessed in low and lower middle income (LLMIC), upper middle income (UMIC) and high income (HIC) countries/regions. Methods This was a secondary analysis of the MOSAICS II study, an international prospective observational study on sepsis epidemiology in Asian ICUs. Associations between qSOFA at ICU admission and mortality were separately assessed in LLMIC, UMIC and HIC countries/regions. Modified Poisson regression was used to determine the adjusted relative risk (RR) of qSOFA score on mortality at 28 days with adjustments for confounders identified in the MOSAICS II study. Results Among the MOSAICS II study cohort of 4980 patients, 4826 patients from 343 ICUs and 22 countries were included in this secondary analysis. Higher qSOFA was associated with increasing 28-day mortality, but this was only observed in LLMIC ( p < 0.001) and UMIC ( p < 0.001) and not HIC ( p = 0.220) countries/regions. Similarly, higher 90-day mortality was associated with increased qSOFA in LLMIC ( p < 0.001) and UMIC ( p < 0.001) only. In contrast, higher 3-day mortality with increasing qSOFA score was observed across all income countries/regions ( p < 0.001). Multivariate analysis showed that qSOFA remained associated with 28-day mortality (adjusted RR 1.09 (1.00–1.18), p = 0.038) even after adjustments for covariates including APACHE II, SOFA, income country/region and administration of antibiotics within 3 h. Conclusions qSOFA was independently associated with 28-day mortality in ICU patients admitted for sepsis. In LLMIC and UMIC countries/regions, qSOFA was associated with early to late mortality but only early mortality in HIC countries/regions. Graphical Abstract
To determine the allele frequencies and genotype distribution of interleukin (IL)-1 alpha, IL-1 beta and IL-1 receptor antagonist (IL-1ra) gene polymorphism in septic patients.A prospective, consecutive entry study was made among 60 patients with the diagnosis of sepsis who were admitted consecutively into the general intensive care unit (ICU), Peking Union Medical College Hospital between 1997 and 1999. APACHE II scoring and MODS scoring were made within 24 hours after admission. The genomic DNA of peripheral blood nucleated cells was extracted. The polymorphic regions within intron 6 of IL-1 alpha gene containing variable numbers of a tandem repeat (VNTR) of 46 bp, and intron 2 of IL-1ra gene containing VNTR of 86 bp were amplified by means of polymerase chain reaction (PCR). Alleles A1-4 and RN1-4 were identified according to the size of amplified DNA product. The region containing the AvaI polymorphic site at position -511 of IL-1 beta gene was amplified by PCR, and subsequently digested with AvaI restriction enzyme.The frequencies of allele IL-1ra RN2 and genotype RN2/2 in the 60 septic patients were significantly higher than those in normal controls (0.34 vs 0.23, P < 0.01, and 0.12 vs 0.05, P < 0.05, respectively). The allele frequencies or genotype distribution of IL-1 alpha VNTR gene polymorphism and IL-1 beta AvaI polymorphism did not differ between the septic patients and normal controls. In addition, genotypes A2/2, B2/2 and RN2/2 were associated with a significantly higher mortality (80%, 81% and 71%, respectively) in septic patients. Patients with any 2 of the three alleles, i.e. A2, B2 and RN2, suffered from a much more severe sepsis (as measured by APACHE II and MODS scores) and higher mortality rate ( 55-65%), while septic patients with genotypes A1/1, B1/1 or RN1/1 showed a much lower mortality (0-13%).Allele IL-1RN2 polymorphism, but not IL-1A or IL-1B gene polymorphism, is associated with susceptibility to sepsis. Alleles A2, B2 and RN2 might be important high-risk genetic markers for sepsis.
Dr. Wiedermann commented on our systematic review and meta-regression for the sources of heterogeneity in trials reporting HES 130/0.4 or 0.42 associated excess mortality in septic patients[1] that the pooled analysis of mortality, which showed neither benefit nor harm, might be influenced by trials of low-quality. Statistically, we agree with this conclusion if two of the recruited trials judged as the intermediate risk of bias are precluded. Sensitivity tests in a meta-analysis are important. But an issue need for further discussing is that whether the results from a sensitivity analysis should be considered as the confirmatory or just exploratory. The fundamental thought of meta-analysis is to synthesis all the evidence current available. The article search strategy and the study inclusion/exclusion criteria had both been prespecified without any knowledge of the pooled analysis of mortality. The overall results should be taken as primary analysis because all the studies were fulfilled the prespecified principle. Over-interpretation of any subgroup analysis may have raised potential risk even if only focus on the trials with low risk of bias, the reasons were followed below. (1) Quality of the reporting of a study does not equal to the quality of the study itself. A well conduct study may have a very low-quality on reporting.[2] In addition, the process for risk of bias assessment is a sort of subjective even two independent reviewers assessing separately. It is hard to demonstrate any solid result from sensitivity analysis unless the consensus on the risk of bias assessment focus on study conducting could be achieved. (2) The multiplicity issue is not very common mentioned in the meta-analysis. However, the false-positive rate does significantly increased accompany with the raised number of tests. Currently, the meta-analysis includes 11 trials in total.[1] If we assume 6 of them are a low risk of bias, but the question is they are not easy to identify. Theoretically, there will be 462 possible combinations (randomly choose 6 trials from 11) under this scenario. The corresponding type I error rate (at least to observe one false-positive subgroup result) would be almost 100% (=1-0.95^462). By this reason, it should use a more restricted significant level for each subgroup result. Further, the test for subgroup difference between trials with low versus high risk of bias is a kind of interaction test. It also has to face the multiplicity issue. More importantly, the uncertainty of chosen the threshold for the significant level for interaction test is still controversial. Thus, the significant results of subgroup should be interpreted with cautions.[3] There are many reasons for the heterogeneity of mortality as primary outcome under the same intervention in randomized controlled trials (RCTs).[4] Most importantly, bias associated with execution factors such as intervention or its subsequent effects may cause questionable results in RCTs.[5] The efficiency of fluid therapy as a subsequent effect was found incomparable between HES and control group in some of the recruited RCTs in this meta-regression. Interestedly, all of 3 out of 11 RCTs, which were calculated with more positive fluid balance in HES group (a colloid with more efficiency on plasma volume expansion than crystalloids in general) than in control group, similarly reported a high risk of HES on excess mortality in septic patients and with significance in Perner's trial.[6] Our analysis further suggested daily delta fluid balance being likely associated with mortality in septic patients receiving HES 130/130/0.4* (P = 0.079). Whereas, we failed to determine a dose-effect relationship of HES 130/0.4 or 0.42 with mortality (P = 0.298). These results indicated that fluid balance was an important factor confounding the results of these RCTs. This was the main finding of this meta-regression. In conclusion, information from bedside (such as incomparable subsequent effects in fluid therapy) should be considered with priority over statistics in interpreting the results of available RCTs in evaluating the impact of any clinical intervention on mortality in critically ill patients.
Endothelial nitric oxide synthase (eNOS) -786T→C and 894G→T polymorphisms have been associated with eNOS dysfunction, which might further compromise microcirculatory blood flow during sepsis and increase the risk of organ injury. The purpose of this study is to investigate the association of those two eNOS gene polymorphisms with the severity of organ dysfunction and outcome in patients with severe sepsis.A cohort of patients with severe sepsis was studied and genotyped for eNOS -786T→C and 894G→T polymorphisms. Acute Physical and Chronic Health Evaluation score, the Sequential Organ Failure Assessment score, with or without shock, and the outcomes were compared in patients with different genotypes.One hundred seventeen patients fulfilled with inclusion criteria were enrolled from nine intensive care units of academic hospital in Beijing. In comparison with the GG genotype, patients with the GT genotype (894G→T) had a trend toward an increase in the frequency of shock (87% vs. 68.1%, p=0.071) and significantly fewer days to shock onset (p<0.05). Those patients also had significantly higher Acute Physical and Chronic Health Evaluation II scores (p<0.05), Sequential Organ Failure Assessment scores (p<0.001), and mortality at both 7 days and 28 days (p<0.001). Multivariate analyses identified the GT genotype (894G→T) as an independent risk factor for outcome in patients with severe sepsis. However, we found that the eNOS -786T→C polymorphism was not associated with severity of disease or mortality of patients with sepsis.Carriage of the GT genotype at 894 of eNOS gene was associated with the occurrence of shock and impaired organ function.
Abstract Background Regulatory functions of nitric oxide (NO • ) that bypass the second messenger cGMP are incompletely understood. Here, cGMP-independent effects of NO • on gene expression were globally examined in U937 cells, a human monoblastoid line that constitutively lacks soluble guanylate cyclase. Differentiated U937 cells (>80% in G0/G1) were exposed to S-nitrosoglutathione, a NO • donor, or glutathione alone (control) for 6 h without or with dibutyryl-cAMP (Bt 2 cAMP), and then harvested to extract total RNA for microarray analysis. Bt 2 cAMP was used to block signaling attributable to NO • -induced decreases in cAMP. Results NO • regulated 110 transcripts that annotated disproportionately to the cell cycle and cell proliferation (47/110, 43%) and more frequently than expected contained AU-rich, post-transcriptional regulatory elements (ARE). Bt 2 cAMP regulated 106 genes; cell cycle gene enrichment did not reach significance. Like NO • , Bt 2 cAMP was associated with ARE-containing transcripts. A comparison of NO • and Bt 2 cAMP effects showed that NO • regulation of cell cycle genes was independent of its ability to interfere with cAMP signaling. Cell cycle genes induced by NO • annotated to G1/S (7/8) and included E2F1 and p21/Waf1/Cip1; 6 of these 7 were E2F target genes involved in G1/S transition. Repressed genes were G2/M associated (24/27); 8 of 27 were known targets of p21. E2F1 mRNA and protein were increased by NO • , as was E2F1 binding to E2F promoter elements. NO • activated p38 MAPK, stabilizing p21 mRNA (an ARE-containing transcript) and increasing p21 protein; this increased protein binding to CDE/CHR promoter sites of p21 target genes, repressing key G2/M phase genes, and increasing the proportion of cells in G2/M. Conclusion NO • coordinates a highly integrated program of cell cycle arrest that regulates a large number of genes, but does not require signaling through cGMP. In humans, antiproliferative effects of NO • may rely substantially on cGMP-independent mechanisms. Stress kinase signaling and alterations in mRNA stability appear to be major pathways by which NO • regulates the transcriptome.
Suboptimal sedation practices continue to be frequent, although the updated guidelines for management of pain, agitation, and delirium in mechanically ventilated (MV) patients have been published for several years. Causes of low adherence to the recommended minimal sedation protocol are multifactorial. However, the barriers to translation of these protocols into standard care for MV patients have yet to be analyzed. In our view, it is necessary to develop fresh insights into the interaction between the patients' responses to nociceptive stimuli and individualized regulation of patients' tolerance when using analgesics and sedatives. By better understanding this interaction, development of novel tools to assess patient pain tolerance and to define and predict oversedation or delirium may promote better sedation practices in the future.
Introduction Postoperative delirium (POD) is prevalent in patients after major surgery and is associated with adverse outcomes. Several studies have reported that dexmedetomidine, a highly selective α2-adrenergic receptor agonist, can decrease the incidence of POD. However, neurosurgical patients are usually excluded from previous studies. The present study was designed to investigate the impact of prophylactic use of low-dose dexmedetomidine on the incidence of POD in patients after intracranial operation. Methods and analysis This is a multicentre, randomised, double-blinded and placebo-controlled trial. Seven hundred intensive care unit admitted patients after elective intracranial operation for brain tumours under general anaesthesia are randomly assigned to the dexmedetomidine group or the placebo group with a 1:1 ratio. For patients in the dexmedetomidine group, a continuous infusion of dexmedetomidine will be started at a rate of 0.1 μg/kg/hour immediately after enrolment on the day of operation and continued until 08:00 on postoperative day 1. For patients in the placebo group, normal saline will be administered at the same rate as in the dexmedetomidine group. The patients will be followed up for 28 days after enrolment. The primary endpoint is the incidence of POD, which is assessed two times per day using the Confusion Assessment Method for the intensive care unit (ICU), during the first 5 postoperative days. The secondary endpoints include the incidence of dexmedetomidine-related adverse events and non-delirium complications, the length of stay in the ICU and hospital and all-cause 28-day mortality after the operation. Ethics and dissemination The study protocol was approved by the Institutional Review Board of Beijing Tiantan Hospital Affiliated to Capital Medical University (No KY2019-091-02) and registered at ClinicalTrials.gov. The results of the trial will be presented at national and international conferences relevant to subject fields and submitted to international peer-reviewed journals. Trial registration number Trial registration number: NCT04399343 ; Pre-results.
The study aimed to explore factors associated with deep sedation practice in intensive care units (ICUs).A post hoc analysis was conducted for a cross-sectional survey on sedation practices in mechanically ventilated (MV) patients, combined with a questionnaire for physicians regarding their preferences for light sedation (P-pls Score) in 92 Chinese ICUs.There were 457 and 127 eligible MV patients in the light and deep sedation groups respectively. A multivariable logistic regression analysis demonstrated that the control mode of mechanical ventilation, plasma lactate level, and the Sequential Organ Failure Assessment (SOFA) score were independent risk factors for deep sedation practice (p <0.01). Notably, the adjusted odds ratio (95% CI) of the average P-pls score in the ICU ≤ 2 for deep sedation practice was 1.861 (1.163, 2.978, p = 0.01). In addition, the areas under curves of receiver operating characteristics (AUC-ROC) of the model to predict the probability of deep sedation practice were 0.753 (0.699, 0.806) and 0.772 (0.64, 0.905) in the training set and the validation set, respectively. The 28-day mortality was increased in patients with exposure to deep sedation practice but not significantly.Both factors related to stressful stimuli and the ICU physicians' perception of patient tolerability in mechanical ventilation were likely associated with deep sedation practice in MV patients.
Background: The role of sodium bicarbonate therapy (SBT) remains controversial. This study aimed to investigate whether hemodynamic status before SBT contributed to the heterogeneous outcomes associated with SBT in acute critically ill patients. Methods: We obtained data from patients with metabolic acidosis from the Medical Information Mart for Intensive Care (MIMIC)-III database. Propensity score matching (PSM) was applied to match the SBT group with the control group. Logistic regression and Cox regression were used to analyze a composite of newly “developed or exacerbated organ dysfunction” (d/eOD) within 7 days of ICU admission and 28-day mortality associated with SBT for metabolic acidosis. Results: A total of 1,765 patients with metabolic acidosis were enrolled, and 332 pairs obtained by PSM were applied to the final analyses in the study. An increased incidence of newly d/eOD was observed in the SB group compared with the control group (54.8 vs. 44.6%, p < 0.01). Multivariable logistic regression indicated that the adjusted OR of SBT for this composite outcome was no longer significant [OR (95% CI): 1.39 (0.9, 1.85); p = 0.164]. This effect of SBT did not change with the quintiles stratified by pH. Interestingly, SBT was associated with an increased risk of the composite of newly d/eOD in the subgroup of patients with worsening hemodynamics before SBT [adjusted OR (95% CI): 3.6 (1.84, 7.22), p < 0.001]. Moreover, the risk potential for this composite of outcomes was significantly increased in patients characterized by both worsening [adjusted OR (95% CI): 2.91 (1.54, 5.47), p < 0.001] and unchanged hemodynamics [adjusted OR (95% CI): 1.94 (1.01, 3.72), p = 0.046] compared to patients with improved hemodynamics before SBT. Our study failed to demonstrate an association between SBT and 28-day mortality in acute critically ill patients with metabolic acidosis. Conclusions: Our findings did not demonstrate an association between SBT and outcomes in critically ill patients with metabolic acidosis. However, patients with either worsening or unchanged hemodynamic status in initial resuscitation had a significantly higher risk potential of newly d/eOD subsequent to SBT.
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