cardiac dysfunction resulting from sepsis may cause significant morbidity and mortality, and ferroptosis plays a role in this pathology. dexmedetomidine (dex), a α2-adrenergic receptor (α2-ar) agonist exerts cardioprotective effects against septic heart dysfunction, but the exact mechanism is unknown. In the present study, sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6 mice. Dex and yohimbine hydrochloride (YoH), an α2-AR inhibitor, were administered before inducing CLP. Then, 24 h after CLP, serum and heart tissue were collected to detect changes of troponin-I (TN-I), interleukin 6 (IL-6), superoxide dismutase (SOD), malonaldehyde (Mda) and glutathione (GSH) levels, and iron release. Ferroptosis-targeting proteins, apoptosis and inflammatory factors were assessed by western blotting or ELISA. It was found that, 24 h after CLP, TN-I, a biomarker of myocardial injury, was significantly increased compared with the control group. Furthermore, the levels of Mda, 8-hydroxy-2'-deoxyguanosine and the inflammatory factors IL-6 and monocyte chemoattractant protein-1 were also significantly increased. It was demonstrated that treatment with Dex reverted or attenuated these changes (CLP + Dex vs. CLP; P<0.05), but these protective effects of Dex were reversed by YOH. Moreover, CLP significantly decreased the protein expression levels of glutathione peroxidase 4 (GPX4), SOD and GSH. However, clP increased expression levels of heme oxygenase-1 (Ho-1), transferrin receptor, cleaved caspase 3, inducible nitric oxide synthase and gasdermin D, and iron concentrations. It was found that Dex reversed these changes, but YOH abrogated the protective effects of dex (clP + dex + YoH vs. clP + dex; P<0.05). Therefore, the present results suggested that the attenuation of sepsis-induced Ho-1 overexpression and iron concentration, and the reduction of ferroptosis via enhancing GPX4, may be the major mechanisms via which Dex alleviates sepsis-induced myocardial cellular injury.

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Introduction: Studies have shown nonlinear relationships between systolic blood pressure (SBP) and outcomes, with increased risk observed at both low and high blood pressure levels. However, the relationships between cumulative times at different SBP levels and outcomes in critically ill patients remain unclear. We hypothesized that an appropriate SBP level is associated with a decrease in adverse outcomes after intensive care unit (ICU) admission. Methods: This study was a retrospective analysis of data from the Medical Information Mart for Intensive Care (MIMIC) III database, which includes more than 1,000,000 SBP records from 12,820 patients. Associations of cumulative times at four SBP ranges (<100 mm Hg, 100-120 mm Hg, 120-140 mm Hg, and 140 mm Hg) with mortality (12-, 3-, 1-month mortality and in-hospital mortality) were evaluated. Restricted cubic splines and multivariable Cox regression models were employed to assess associations between mortality and cumulative times at SBP levels (4 levels: <2, 2-12, 12-36, and 36 h) over 72 h of ICU admission. Additionally, 120 mm Hg to 140 mm Hg was subdivided into <12 h (Group L) and 12 h (Group M) subsets and subjected to propensity-score matching and subgroup analyses. Results: At 120 mm Hg to 140 mm Hg, level-4 SBP was associated with lower adjusted risks of mortality at 12 months (OR, 0.71; CI, 0.61-0.81), 3 months (OR, 0.72; CI, 0.61-0.85), and 1 month (OR, 0.61; CI, 0.48-0.79) and in the hospital (OR, 0.71; CI, 0.58-0.88) than level-1 SBP. The cumulative times at the other 3 SBP ranges (<100 mm Hg, 100-120 mm Hg, and 140 mm Hg) were not independent risk predictors of prognosis. Furthermore, Group M had lower 12-month mortality than Group L, which remained in the propensity-score matched and subgroup analyses. Conclusions: SBP at 120 mm Hg to 140 mm Hg was associated with decreased adverse outcomes. Randomized trials are required to determine whether the outcomes in critically ill patients improve with early maintenance of a SBP level at 120 mm Hg to 140 mm Hg.

Objective To observe the association between exposure to midazolam within 24 hours prior to delirium assessment and the risk of delirium. Methods We performed a systematic cohort study with two sets of cohorts to estimate the relative risks of outcomes among patients administered midazolam within 24 hours prior to delirium assessment. Propensity score matching was performed to generate a balanced 1:1 matched cohort and identify potential prognostic factors. The outcomes included the odds of delirium, mortality, length of intensive care unit stay, length of hospitalization, and odds of being discharged home. Results A total of 78,364 patients were included in this study, of whom 22,159 (28.28%) had positive records. Propensity matching successfully balanced covariates for 9348 patients (4674 per group). Compared with no administration of midazolam, midazolam administration was associated with a significantly higher risk of delirium, higher mortality, and a longer intensive care unit stay. Patients treated with midazolam were relatively less likely to be discharged home. There was no significant difference in hospitalization duration. Conclusions Midazolam may be an independent risk factor for delirium in critically ill patients.

Background: Sedatives are commonly used in patients with or at risk for acute respiratory distress syndrome (ARDS) during mechanical ventilation. To systematically compare the outcomes of sedation with midazolam, propofol, and dexmedetomidine in patients with or at risk for ARDS.Methods: We developed a dataset of real-world data to enable the comparison of the effectiveness and safety of sedatives and the associated outcomes from the MIMIC-III database and the eICU Collaborative Research database. We performed a systematic study with six cohorts to estimate the relative risks of outcomes among patients administered different sedatives. Propensity score matching was performed to generate a balanced 1:1 matched cohort and to identify potential prognostic factors. The outcomes included hospital mortality, duration of mechanical ventilation, length of intensive care unit stay, length of hospitalization, and likelihood of being discharged home.Results: We performed 60 calibrated analyses among all groups and outcomes with 17,410 eligible patients. Sedation with dexmedetomidine was associated with a lower in-hospital mortality rate than sedation with midazolam and propofol or sedation without dexmedetomidine (p &lt; 0.001). When compared with no sedation, the use of midazolam, propofol or dexmedetomidine was associated with a longer ICU stay and longer hospitalization duration (p &lt; 0.01). Patients treated with midazolam were relatively less likely to be discharged home (p &lt; 0.05).Conclusion: Patients treated with dexmedetomidine had a reduced risk of mortality. These data suggest that dexmedetomidine may be the preferred sedative in patients with or at risk for ARDS.

BackgroundPain is common in men undergoing rigid cystoscopy. Even with the application of a lubricant containing 2 % lidocaine, about 76 % of men suffer from mild to severe pain when undergoing rigid cystoscopy. The most painful part of the procedure for men is when the cystoscope passes through the membranous urethra. Song et al. (Neurourol Urodyn 29:592–5, 2010) did autopsies on males and found that the dorsal nerve of the penis (DNP), the terminal branch of the pudendal nerve, innervates the membranous urethra in 53.3 % of specimens. In addition, the urethral mucosa has branches of innervated DNP. Dorsal penile nerve block (DPNB) is usually used for circumcision in children, and it has been shown to provide effective analgesia for penile surgeries. In this study, we hypothesized that DPNB could reduce the overall pain level in men during rigid cystoscopy.Methods/designThe trial is a prospective, randomized, double-blind, placebo-controlled, single-center trial to evaluate the effectiveness and safety of DPNB in analgesia for men undergoing rigid cystoscopy. Participants will be enrolled and randomly allocated into one of three groups according to the different analgesia regimens: 1) tetracaine gel group (DPNB with saline), 2) DPNB group (DPNB with ropivacaine plus plain lubricant), 3) combination group (DPNB with ropivacaine plus tetracaine gel). The primary outcome of this study is the visual analog scale (VAS, 0–10) for pain at cystoscopic inspection of the external sphincter. VAS scores evaluated at other time points serve as secondary outcomes. Vital signs are secondary outcomes that address the discomfort and pain during the procedure. Furthermore, the incidence of adverse events as secondary outcomes will also be recorded for evaluation of the safety of DPNB in rigid cystoscopy. Clinical assessments will be evaluated prior to DPNB, at administration of the lubricant gel, at cystoscopic inspection of the penile and bulbar urethra, external sphincter, prostate, and bladder, as well as at withdrawal of the cystoscope.DiscussionThis research will determine the effectiveness and safety of DPNB in men undergoing rigid cystoscopy. The results of this trial may have important implications for exploring the role of DPNB in analgesia for cystoscopy in men.Trial registrationClinicalTrials.gov identifier NCT02502487 (6 Jul 2015).

BackgroundOver the last few decades intensive studies have been carried out on the molecular targets mediating general anesthesia as well as the effects of general anesthetics. The γ-aminobutyric acid type A receptor (GABAAR) has been indicated as the primary target of general anaesthetics such as propofol, etomidate and isoflurane, and sedating drugs including benzodiazepines and barbiturates. The GABAAR is also involved in drug tolerance and dependence. However, the involvement of other ion channels is possible.MethodsUsing reverse transcription and quantitative PCR techniques, we systematically investigated changes in the mRNA levels of ion channel genes in response to exposure to midazolam, pentobarbital and ketamine in a freshwater model animal, Daphnia pulex. To retrieve the sequences of Daphnia ion channel genes, Blast searches were performed based on known human or Drosophila ion channel genes. Retrieved sequences were clustered with the maximum-likelihood method. To quantify changes in gene expression after the drug treatments for 4 hours, total RNA was extracted and reverse transcribed into cDNA and then amplified using quantitative PCR.ResultsA total of 108 ion channel transcripts were examined, and 19, 11 and 11 of them are affected by midazolam (100 μM), pentobarbital (200 μM) and ketamine (100 μM), respectively, covering a wide variety of ion channel types. There is some degree of overlap with midazolam- and pentobarbital-induced changes in the mRNA expression profiles, but ketamine causes distinct changes in gene expression pattern.In addition, flumazenil (10 μM) eliminates the effect of midazolam on the mRNA expression of the GABAA receptor subunit Rdl, suggesting a direct interaction between midazolam and GABAA receptors.ConclusionsRecent research using high throughput technology suggests that changes in mRNA expression correlate with delayed protein expression. Therefore, the mRNA profile changes in our study may reflect the molecular targets not only in drug actions, but also in chronic drug addiction. Our data also suggest the possibility that hypnotic/anesthetic drugs are capable of altering the functions of the nervous system, as well as those non-nerve tissues with abundant ion channel expressions.

Introduction Opioids are potent painkillers but can have severe adverse effects in the intensive care unit (ICU). The aim of this study was to compare the outcomes of fentanyl and morphine use among patients at risk for and with acute respiratory distress syndrome (ARDS). Methods We developed a dataset of real-world data to enable the comparison of the effectiveness and safety of opioids and the associated outcomes from the Multiparameter Intelligent Monitoring in Intensive Care (MIMIC)-III database and the eICU Collaborative Research Database. Patients who were admitted to the ICU with a diagnosis of or at risk for ARDS and received mechanical ventilation for at least 12 h were included. Patients were enrolled sequentially into one of six groups in three cohorts: treated with fentanyl or not; treated with morphine or not; and treated with fentanyl or morphine. Propensity score matching and multivariable analyses were performed. Results Fentanyl was associated with higher in-hospital mortality in the propensity score-matched model but not in the linear regression model. The use of morphine was associated with a higher in-hospital mortality in both models. Both fentanyl and morphine were associated with longer duration of mechanical ventilation, ICU stay, and hospitalization and a decreased likelihood of being discharged home in both models. Notably, compared with morphine, fentanyl was associated with a lower mortality and an increased likelihood of being discharged home. Conclusions Both fentanyl and morphine were independent risk factors for worse outcomes in patients with or at risk for ARDS. Compared with morphine, fentanyl may be preferred in these patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40268-021-00338-3.