MEAN ARTERIAL PRESSURE/NOREPINEPHRINE EQUIVALENT DOSE INDEX AS AN EARLY MEASURE FOR MORTALITY RISK IN PATIENTS WITH SHOCK ON VASOPRESSORS.

ABSTRACT: Purpose: We aimed to investigate the association between the early mean arterial pressure (MAP)/norepinephrine equivalent dose (NEQ) index and mortality risk in patients with shock on vasopressors and further identify the breakpoint value of the MAP/NEQ index for high mortality risk. Methods: Based on the Medical Information Mart for Intensive Care IV database, we conducted a retrospective cohort study involving 19,539 eligible intensive care unit records assigned to three groups (first tertile, second tertile, and third tertile) by different MAP/NEQ indexes within 24 h of intensive care unit admission. The study outcomes were 7-, 14-, 21-, and 28-day mortality. A Cox model was used to examine the risk of mortality following different MAP/NEQ indexes. The receiving operating characteristic curve was used to evaluate the predictive ability of the MAP/NEQ index. The restricted cubic spline was applied to fit the flexible correlation between the MAP/NEQ index and risk of mortality, and segmented regression was further used to identify the breakpoint value of the MAP/NEQ index for high mortality risk. Results: Multivariate Cox analysis showed that a high MAP/NEQ index was independently associated with decreased mortality risks. The areas under the receiving operating characteristic curve of the MAP/NEQ index for different mortality outcomes were nearly 0.7. The MAP/NEQ index showed an L-shaped association with mortality outcomes or mortality risks. Exploration of the breakpoint value of the MAP/NEQ index suggested that a MAP/NEQ index less than 183 might be associated with a significantly increased mortality risk. Conclusions: An early low MAP/NEQ index was indicative of poor prognosis in patients with shock on vasopressors.

Single-nucleus transcriptomic mapping uncovers targets for traumatic brain injury.

The subventricular zone (SVZ) is a neurogenic niche that contributes to homeostasis and repair after brain injury. However, the effects of mild traumatic brain injury (mTBI) on the divergence of the regulatory DNA landscape within the SVZ and its link to functional alterations remain unexplored. In this study, we mapped the transcriptome atlas of murine SVZ and its responses to mTBI at the single-cell level. We observed cell-specific gene expression changes following mTBI and unveiled diverse cell-to-cell interaction networks that influence a wide array of cellular processes. Moreover, we report novel neurogenesis lineage trajectories and related key transcription factors, which we validate through loss-of-function experiments. Specifically, we validate the role of Tcf7l1, a cell cycle gene regulator, in promoting neural stem cell differentiation toward the neuronal lineage after mTBI, providing a potential target for regenerative medicine. Overall, our study profiles an SVZ transcriptome reference map, which underlies the differential cellular behavior in response to mTBI. The identified key genes and pathways that may ameliorate brain damage or facilitate neural repair serve as a comprehensive resource for drug discovery in the context of mTBI.

Platelet count predicts mortality in patients with sepsis: A retrospective observational study.

Platelet count is a key component of sepsis severity score. However, the predictive value of the platelet count at admission for mortality in sepsis remains unclear. We designed a retrospective observational study of patients with sepsis admitted to our hospital from January 2017 to September 2021 to explore the predictive value of platelet count at admission for mortality. A total of 290 patients with sepsis were included in this study. Multivariate logistic regression analysis was used to evaluate the risk factors for mortality and construct a predictive model with statistically significant factors. Compared with survivors, nonsurvivors tended to be much older and had significantly higher acute physiology and chronic health evaluation II and sequential organ failure assessment scores (P < .001). The platelet count was significantly lower in the nonsurvivor group than in the survivor group (P < .001). Multivariate logistic regression analysis indicated that age (P = .003), platelet count (P < .001) and lactate level (P = .018) were independent risk factors for mortality in patients with sepsis. Finally, the area under the receiver operating characteristic curve of platelet count predicting mortality in sepsis was 0.763 (95% confidence interval, 0.709-0.817, P < .001), with a sensitivity of 55.6% and a specificity of 91.8%. In our study, platelet count at admission as a single biomarker showed good predictability for mortality in patients with sepsis.

Machine learning algorithms for prediction of ventilator associated pneumonia in traumatic brain injury patients from the MIMIC-III database.

BACKGROUND: Ventilator associated pneumonia (VAP) is a common complication and associated with poor prognosis of traumatic brain injury (TBI) patients. OBJECTIVES: This study was conducted to explore the predictive performance of different machine-learning algorithms for VAP in TBI patients. METHODS: TBI patients receiving mechanical ventilation more than 48 hours from the Medical Information Mart for Intensive Care-III (MIMIC-III) database were eligible for the study. The VAP was confirmed based on the ICD-9 code. Included patients were separated to the training cohort and the validation cohort with a ratio of 7:3. Predictive models based on different machine learning algorithms were developed using 5-fold cross validation in the training cohort and then verified in the validation cohort by evaluating the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, accuracy and F score. RESULTS: 786 TBI patients from the MIMIC-III were finally included with the VAP incidence of 44.0%. The random forest performed the best on predicting VAP in the training cohort with a AUC of 1.000. The XGBoost and AdaBoost were ranked the second and the third with a AUC of 0.915 and 0.789 in the training cohort. While the AdaBoost performed the best on predicting VAP in the validation cohort with a AUC of 0.706. The XGBoost and random forest were ranked the second and the third with the AUC of 0.685 and 0.683 in the validation cohort. Generally, the random forest and XGBoost were likely to be over-fitting while the AdaBoost was relatively stable in predicting the VAP. CONCLUSIONS: The AdaBoost performed well and stably on predicting the VAP in TBI patients. Developing programs using AdaBoost in portable electronic devices may effectively assist physicians in assessing the risk of VAP in TBI.

The effects of early mobilization in mechanically ventilated adult ICU patients: systematic review and meta-analysis.

Background: The effects of early mobilization (EM) on intensive care unit (ICU) patients remain unclear. A meta-analysis of randomized controlled trials was performed to evaluate its effect in mechanically ventilated adult ICU patients. Methods: We searched randomized controlled trials (RCTs) published in Medline, Embase, and CENTRAL databases (from inception to November 2022). According to the difference in timing and type, the intervention group was defined as a systematic EM group, and comparator groups were divided into the late mobilization group and the standard EM group. The primary outcome was mortality. The secondary outcomes were ICU length of stay, duration of mechanical ventilation (MV), and adverse events. EM had no impact on 180-day mortality and hospital mortality between intervention groups and comparator groups (RR 1.09, 95% CI 0.89-1.33, p = 0.39). Systemic EM reduced the ICU length of stay (LOS) (MD -2.18, 95% CI -4.22--0.13, p = 0.04) and the duration of MV (MD -2.27, 95% CI -3.99--0.56, p = 0.009), but it may increase the incidence of adverse events in patients compared with the standard EM group (RR 1.99, 95% CI 1.25-3.16, p = 0.004). Conclusion: Systematic EM has no significant effect on short- or long-term mortality in mechanically ventilated adult ICU patients, but systematic EM could reduce the ICU LOS and duration of MV.

Therapeutic assessment of crystalloid fluid resuscitation in experimental military injury.

BACKGROUND: A significant part of blast injury is accompanied by hemorrhagic shock (BS), while research on its fluid resuscitation strategies have not been reported. Although blood products are usually recommended in most resuscitation cases, they are less available in certain conditions. To this end, here, we focused on a widely used and more accessible fluid type- crystalloid fluid, in BS treatment. METHODS: We conducted studies in rats comparing the therapeutic effects of 3 different crystalloid solutions at different time points after BS, and explored the underlying mechanisms. Generally, the survival rates gradually dropped along with the time when fluid resuscitation was given. RESULTS: Among different types of solution, the hypertonic saline (HS) group showed the highest survival rates. The lactated Ringer's solution (LR) only displayed lifesaving effect at 0.5h resuscitation time point. Moreover, it is worth noting that the survival rates of the normal saline (NS) group at all the time points were lower than the non-treatment control. Mechanism study in rats indicated that the therapeutic differences may be caused by varied degrees of pulmonary edema and inflammatory responses under different crystalloid fluid resuscitation. CONCLUSIONS: In conclusion, we assessed the effects and investigated the mechanisms of different crystalloid fluid resuscitation strategies for BS for the first time, which potentially contributes to the establishment of guidance for crystalloid fluid resuscitation of BS patients.

Xenon attenuated neonatal lipopolysaccharide exposure induced neuronal necroptosis and subsequently improved cognition in juvenile rats.

Background: Neonatal sepsis is known to cause neurodevelopment impairment and has been reported to increase risks for neurological/psychiatric disorders. In this study, we investigated the effect of xenon, a well-known potent neuroprotective gas, on neonatal sepsis-induced neurodevelopment impairment in rats together with underlying mechanism by focusing on receptor-interacting protein kinase (RIP) mediated neuronal necroptosis. Methods: 3-day-old Sprague-Dawley rat pups were exposed to either 70% xenon or N2 balanced with O2 for 6 h, during which lipopolysaccharide (LPS) was injected intraperitoneally for 3 times (500 µg/kg for the 1st and 250 µg/kg for the second and third dose; n = 6-10/group). In another cohort of 3-day-old rat pups, intracerebroventricular injection of necrostatin-1 (4 µg in 4 µl saline, a RIP-1-targeted inhibitor of necroptosis) was performed 20 min after the third dose of LPS. The learning ability and memory were assessed 25 days after LPS injection. Then, their hippocampus was collected for neuronal necroptosis with RIP and MIKL assessments using western blot and in situ immunostaining. Systemic and neuro-inflammation was also assessed. Results: LPS insult resulted in elevation of pro-inflammatory cytokine TNF-𝝰 and IL-6, caused neuronal necroptosis and damaged synaptic integrity at the brain developing stage, which finally led to the long-term cognitive impairment. Xenon inhibited necroptosis associated mediator RIP-1, RIP-3, and MLKL activation, protected neurons and attenuated cognitive dysfunction induced by LPS. Like xenon, the similar pattern changes induced by a RIP-1 inhibitor Necrostatin-1 were also found. Conclusion: This study indicates that necroptosis is involved in neonatal sepsis-induced neurofunctional impairments and xenon may be a novel therapeutic strategy to prevent/treat cognitive impairment in neonatal septic patients.

Sedation Effects Produced by a Ciprofol Initial Infusion or Bolus Dose Followed by Continuous Maintenance Infusion in Healthy Subjects: A Phase 1 Trial.

INTRODUCTION: The effects of continuous infusions of ciprofol on its pharmacodynamic and pharmacokinetic properties and safety profiles in healthy Chinese subjects were evaluated. METHODS: In this open-label, randomized, two-way cross-over study, subjects received initial doses of continuous ciprofol/propofol as an infusion for 30 min in part 1 (n = 8) and a bolus dose in part 2 (n = 8) followed by maintenance infusions for a total of 4 h in part 1 and 12 h in part 2. Each subject participated in both parts with a washout time of at least 40 h. RESULTS: The safety and tolerability parameters of ciprofol were similar to those of propofol, and all treatment-emergent adverse events were mild. The incidences of injection pain and respiratory depression in subjects given ciprofol were lower than those receiving propofol. The pharmacokinetic parameters Cmax, tmax, t1/2, λz and MRT for ciprofol and propofol were similar, while CL, Vd and Vss were statistically significantly different. Pharmacodynamic parameters including the Richmond Agitation Sedation Scale and bispectral index profiles of ciprofol were similar to those of propofol. CONCLUSION: Ciprofol has potential for clinical application for continuous intravenous infusion to maintain sedation for 12 h with the same safety, tolerability and efficacy as propofol.

CRP Albumin ratio is positively associated with poor outcome in patients with traumatic brain injury.

OBJECTIVES: The C-reactive protein/albumin ratio (CAR), a novel inflammation-based index, has been proved useful in predicting outcome of various diseases. We designed this study to explore the prognostic value of CAR in patients with traumatic brain injury (TBI). PATIENTS AND METHODS: We retrospectively included 151 patients diagnosed with TBI and collected related clinical and laboratory data. Univariate and multivariate logistic regression were conducted to find independent risk factors of mortality. Then, we incorporated CAR into prognostic model and drew receiver operating characteristic (ROC) curve of models. Finally, we compared the predictive value of different models by evaluating the area under the receiver operating characteristic curves (AUC). RESULTS: In this study, a total of 54 patients had poor survival outcome with mortality rate of 35.8 %. Results of multivariate analysis showed that GCS score in admission (OR 0.700, 95 %Cl 0.570-0.860, p=0.001), acute kidney injury (AKI) (OR 3.952, 95Cl 1.631-9.577, p=0.002) and CAR (OR 1.202, 95Cl 1.039-1.390, p=0.013) were independently associated with in-hospital mortality. The AUC value of predictive model composed of the above three factors was higher than GCS or CAR alone. CONCLUSION: CAR is an independent risk factor of mortality in patients with TBI. Incorporating CAR into predictive model could increase the value in predicting outcome of TBI patients.

Neuromuscular blockers in the acute respiratory distress syndrome: A meta-analysis.

BACKGROUND: The effects of neuromuscular blocking agents (NMBAs) on adult patients with acute respiratory distress syndrome (ARDS) remain unclear. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate its effect on mortality. METHODS: We searched the Cochrane (Central) database, Medline, Embase, the Chinese Biomedical Literature Database (SinoMed), WanFang data and ClinicalTrials from inception to June 2019, with language restriction to English and Chinese. We included published RCTs and eligible clinical trials from ClinicalTrials.gov that compared NMBAs with placebo or usual treatment in adults with ARDS. We pooled data using random-effects models. The primary outcome was mortality. The secondary outcomes were the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FIO2), total positive end expiratory pressure (PEEP), plateau pressure (Pplat), days free of ventilator at day 28, barotrauma and ICU-acquired weakness. RESULTS: We included 6 RCTs (n = 1557). Compared with placebo or usual treatment, NMBAs were associated with lower 21 to 28-day mortality (RR 0.72, 95% CI 0.53-0.97, I2 = 59%). NMBAs significantly improved oxygenation (Pao2:Fio2 ratios) at 48 hours (MD 27.26 mm Hg, 95% CI 1.67, 52.84, I2 = 92%) and reduced the incidence of barotrauma (RR 0.55, 95% CI 0.35, 0.85, I2 = 0). However, NMBAs had no effect on oxygenation (Pao2:Fio2 ratios) (MD 18.41 mm Hg, 95% CI -0.33, 37.14, I2 = 72%) at 24 hours. We also found NMBAs did not affect total PEEP, plateau pressure, days free of ventilation at day 28 and ICU-acquired weakness. CONCLUSIONS: In patients with moderate-to-severe ARDS, the administration of NMBAs could reduce 21 to 28-day mortality and barotrauma, and improve oxygenation at 48 hours, but have no significant effects on 90-day/ICU mortality, days free of ventilation at day 28 and the risk of ICU-acquired weakness. Further large-scale, high-quality RCTs are needed to confirm our findings. Registration: PROSPERO (ID: CRD 42019139656).

The Effects of Safflower Yellow on Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Randomized, Controlled Clinical Trial.

OBJECTIVES: To evaluate the efficacy of safflower yellow in the acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: In a prospective, randomized, controlled trial, 127 patients who met the inclusion criteria were enrolled and were randomly divided into two groups. The control group included 64 patients treated according to the global strategy for diagnosis, management, and prevention of COPD (www.goldcopd.org, updated 2011). The intervention group included 63 patients who received intravenous infusions of safflower yellow (100 mg of safflower yellow dissolved in 250 ml 0.9% saline) once daily for 14 consecutive days in addition to standard diagnosis and treatment. The difference in the average length of the hospital stay between the two groups of patients was determined. The follow-up period was 28 days; the differences in symptoms, clinical indicators, and 28-day mortality in the two groups were compared. Statistical analysis was conducted using SPSS 22.0 software to determine whether there were statistically significant differences (P <0.05) between groups. RESULTS: There were no statistically significant differences between the intervention group and the control group in changes in secondary indicators. There were no statistically significant differences in the 28-day mortality or in the survival curves of the two groups (P=0.496 and P=0.075, respectively). Safflower yellow treatment of AECOPD may relieve the patient's clinical symptoms, such as dyspnoea, shorten the average length of hospital stay (P=0.006, respectively), and decrease the duration of mechanical ventilation. CONCLUSION: Safflower yellow in the treatment of AECOPD has a degree of clinical value. This trial is registered under the identifier ChiCTR-IPR-17014176.

Cognitive impairments induced by severe acute pancreatitis are attenuated by berberine treatment in rats.

Cognitive impairments induced by severe acute pancreatitis (SAP) are severe complications, for which there are a lack of effective pharmacological treatment strategies. Berberine is an isoquinoline alkaloid extracted from the Chinese herb, Coptis rhizome, which exhibits numerous biological effects on gastrointestinal disorders. However, the effects of berberine on SAP­induced cognitive impairments remain unknown. The present study aimed to investigate the effects of berberine on cognitive impairments associated with SAP. Wistar rats were randomly divided into Sham, Sham + berberine, SAP and SAP + berberine groups. Rats were intraperitoneally injected with L­arginine (3 g/kg) to induce SAP. Subsequently, selected rats were intragastrically administered berberine (100 mg/kg) once daily for 6 consecutive days. Disease severities of rats were investigated 48 h post­induction of SAP via determination of serum amylase levels and hematoxylin and eosin staining. Survival rates, performance of behavioral tests (automated rotarod and fear conditioning tests), blood brain barrier (BBB) permeability, and the expression levels of tumor necrosis factor (TNF)­α and interleukin (IL)­1ß in hippocampal tissues were also determined. Proteins associated with apoptosis and necroptosis in the hippocampal tissues of SAP rats, including caspase­3, receptor­interacting protein kinase (RIP)1 and RIP3, were detected via western blotting. The results revealed that treatment with L­arginine induced SAP, which subsequently resulted in increased BBB permeability, mortality rates and cognitive deficits in rats. The expression levels of TNF­α, IL­1ß, caspase­3, RIP1 and RIP3 were significantly increased in the hippocampal tissues of SAP rats, thus suggesting that neuroinflammation, apoptosis and necroptosis may be involved in neurodegeneration associated with the development of SAP. Notably, administration of berberine protected the integrity of the BBB, decreased levels of brain inflammation and mortality rates, and attenuated increased levels of proteins associated with apoptosis and necroptosis and cognitive deficits associated with SAP in rats. The results of the present study demonstrated that daily treatment with berberine may attenuate cognitive deficits and reduce associated mortality via exhibition of anti­neuroinflammatory effects and attenuation of neuronal apoptosis and necroptosis in the hippocampal tissues of SAP rats.

Mismatch between GLUTs and glucose levels causes neuronal damage during glucose fluctuations.

Abnormal glucose levels damage the central nervous system, especially in case of rapid fluctuations. Even a single episode of glucose reperfusion can result in overt impairment of neurons. Oxidative stress plays an important role in this process, sharing properties with the pathophysiologic changes of glucose neurotoxicity. Glucose transporters (GLUTs) located in the brain are involved in direct glucose uptake by neurons. Instead of being insulin-sensitive, these transporters are regulated by glucose levels in the extracellular fluid, increasing their expression while glucose levels fall, to absorb more glucose. Therefore, we hypothesized that mismatch between altered GLUTs and sudden glucose level changes is responsible for neuronal damage during glucose fluctuations. Modulating hypoglycemia by increasing blood glucose slowly may improve the neurological outcomes of hypoglycemia.

Perineural versus intravenous dexamethasone as an adjuvant in regional anesthesia: a systematic review and meta-analysis.

BACKGROUND: Dexamethasone is a common adjuvant for local anesthetics in regional anesthesia, but the optimal route of administration is controversial. Therefore, we did a systematic review and meta-analysis of randomized controlled trials to assess the effect of perineural versus intravenous dexamethasone on local anesthetic regional nerve-blockade outcomes. MATERIALS AND METHODS: Medline (through PubMed), Embase, Cochrane, Web of Science, and Biosis Previews databases were systematically searched (published from inception of each database to January 1, 2017) to identify randomized controlled trials. The data of the selected trials were statistically analyzed to find any significant differences between the two modalities. The primary outcome was the duration of analgesia. Secondary outcomes included duration of motor block, postoperative nausea and vomiting, and postoperative analgesic dose at 24 hours. We conducted a planned subgroup analysis to compare the effects between adding epinephrine or not. RESULTS: Ten randomized controlled trials met the inclusion criteria of our analysis, with a total of 749 patients. Without the addition of epinephrine, the effects of perineural and intravenous dexamethasone were equivalent concerning the duration of analgesia (mean difference 0.03 hours, 95% CI -0.17 to 0.24). However, with the addition of epinephrine, the analgesic duration of perineural dexamethasone versus intravenous dexamethasone was prolonged (mean difference 3.96 hours, 95% CI 2.66-5.27). Likewise, the impact of epinephrine was the same on the duration of motor block. The two routes of administration did not show any significant differences in the incidence of postoperative nausea and vomiting, nor on postoperative analgesic consumption at 24 hours. CONCLUSION: Our results show that perineural dexamethasone can prolong the effects of analgesic duration when compared to the intravenous route, only when epinephrine is coadministered. Without epinephrine, the two modalities show equivalent effect as adjuvants on regional anesthesia.

Therapeutic hypothermia increases the risk of cardiac arrhythmia for perinatal hypoxic ischaemic encephalopathy: A meta-analysis.

OBJECTIVE: To determine whether therapeutic hypothermia after hypoxic ischaemic encephalopathy (HIE) in neonates increases the risk of cardiac arrhythmia during intervention. DESIGN: A meta-analysis was conducted using a fixed-effect model. Risk ratios, risk differences, and 95% confidence intervals, were measured. DATA SOURCES: Studies identified from the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Google Scholar, previous reviews, and abstracts from onset to August, 2016. REVIEW METHODS: Reports that compared therapeutic hypothermia with normal care for neonates with HIE and that included data on safety or cardiac arrhythmia, which is of interest to patients and clinicians, were selected. RESULTS: We found seven trials, encompassing 1322 infants that included information on safety or cardiac arrhythmia during intervention. Therapeutic hypothermia considerably increased the combined rate of cardiac arrhythmia in the seven trials (risk ratio 2.42, 95% confidence interval 1.23 to 4.76. p = 0.01; risk difference 0.02, 95% CI 0.01 to 0.04) during intervention. CONCLUSIONS: In infants with hypoxic ischaemic encephalopathy, therapeutic hypothermia is associated with a consistent increase in cardiac arrhythmia during intervention.

Effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure: a meta-analysis of randomized controlled trials.

BACKGROUND: Conflicting recommendations exist on whether high-flow nasal cannula (HFNC) oxygen therapy should be administered to adult patients in critical care with acute hypoxemic respiratory failure. We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate its effect on intubation rates. METHODS: We searched electronic databases from inception to April 2016. We included RCTs that compared HFNC oxygen therapy with usual care (conventional oxygen therapy or noninvasive ventilation) in adults with acute hypoxemic respiratory failure. Because of the different methodologies and variation in clinical outcomes, we conducted 2 subgroup analyses according to oxygen therapy used and disease severity. We pooled data using random-effects models. The primary outcome was the proportion of patients who required endotracheal intubation. RESULTS: We included 6 RCTs (n = 1892). Compared with conventional oxygen therapy, HFNC oxygen therapy was associated with a lower intubation rate (risk ratio [RR] 0.60, 95% confidence interval [CI] 0.38 to 0.94; I2 = 49%). We found no significant difference in the rate between HFNC oxygen therapy and noninvasive ventilation (RR 0.86, 95% CI 0.68 to 1.09; I2 = 2%). In the subgroup analysis by disease severity, no significant differences were found in the intubation rate between HFNC oxygen therapy and either conventional oxygen therapy or noninvasive ventilation (interaction p = 0.3 and 0.4, respectively). INTERPRETATION: The intubation rate with HFNC oxygen therapy was lower than the rate with conventional oxygen therapy and similar to the rate with noninvasive ventilation among patients with acute hypoxemic respiratory failure. Larger, high-quality RCTs are needed to confirm these findings.