Background: This study aimed to explore whether the snuffbox resistive index (SBRI) measured by ultrasound can serve as an indicator of vasoplegia in patients with sepsis. Methods: Patients admitted to the intensive care unit with sepsis were enrolled, and their systemic vascular resistance index (SVRI) was measured using a pulse contour cardiac output monitor. The SBRI and peripheral perfusion index (PI) were measured immediately after measuring the SVRI. The Pearson correlation coefficient (r) was used to test both the correlation between patients’ SBRI and SVRI, and the correlation between SBRI and PI. Results: Of the 76 patients with sepsis, 53 (70%) were male. A total of 166 sets of measurements were obtained. The mean (±standard deviation [SD]) cardiac index was 3.01 (±0.98) L/min/m², the mean (±SD) SVRI was 2367 (±914) dyn·s·m²/cm 5 , and the mean (±SD) SBRI measured by ultrasound was 0.9 (±0.14). The SBRI was not correlated with the SVRI (r = 0.003, P = 0.956) but was moderately negatively correlated with the PI (r = −0.516, P < 0.001). Conclusions: SBRI was not correlated with the SVRI but was moderately negatively correlated with the PI. Caution should be made when the SBRI is used to evaluate systemic vascular status.

Carbon monoxide (CO) poisoning causes 50,000 to 100,000 emergency department visits and ~1,500 deaths in the United States annually. Current treatments are limited to supplemental and/or hyperbaric oxygen to accelerate CO elimination. Even with oxygen therapy, nearly half of CO poisoning survivors suffer long-term cardiac and neurocognitive deficits related to slow CO clearance, highlighting a need for point of care antidotal therapies. Given the natural interaction between CO and ferrous heme, we hypothesized that the hemoprotein RcoM, a transcriptional regulator of microbial CO metabolism, would make an ideal platform for CO-selective scavenging from endogenous hemoproteins. We engineered an RcoM truncate (RcoM-HBD-CCC) that exhibits high CO affinity ( K a,CO = 2.8 × 10 10 M −1 ), remarkable selectivity for CO over oxygen ( K a,O2 = 1.4 × 10 5 M −1 ; K a,CO / K a,O2 = 1.9 × 10 5 ), thermal stability (T m = 72 °C), and slow autoxidation rate ( k ox = 1.1 h −1 ). In a murine model of acute CO poisoning, infused RcoM-HBD-CCC accelerated CO clearance from hemoglobin in red blood cells (RBCs) and was rapidly excreted in urine. Moreover, infused RcoM-HBD-CCC elicited minimal hypertension in mice compared to infused globins (hemoglobin, myoglobin, and neuroglobin), attributed to a comparatively limited reactivity toward nitric oxide (NO) via dioxygenation [ k NOD (RcoM) = 6 to 8 × 10 6 M −1 s −1 vs k NOD (Hb) = 6 to 8 × 10 7 M −1 s −1 ]. These data suggest that RcoM-HBD-CCC is a safe, selective, and efficacious CO scavenger. By limiting hypertension through minimal NO scavenging, RcoM-HBD-CCC improves end-organ adverse effects compared with other hemoprotein-based therapeutics.

Introduction: Hemorrhagic shock remains a leading cause of preventable death in warfare or acute trauma. Thus, the ongoing research for a successful artificial oxygen carrier as an alternative to blood. Our protein, the Bacterial Regulator of Carbon Monoxide Metabolism (RcoM), helps bridge this gap through its easily sourced nature, reproducibility, and effectiveness in delivering oxygen to the tissues. RCom is an engineered variant that lacks a DNA binding domain and contains cysteine mutations for improved stability (RcoM HBD-CCC), this optimized it's ligand binding ability, autoxidation rate, thermostability and nitric reduction rate. Hypothesis: We hypothesize that resuscitation with RcoM would improve mean arterial pressure (MAP) in hemorrhagic shock more than crystalloid resuscitation. Methods: A murine model of traumatic hemorrhagic shock was anesthetized with 1.5% isofluorane and received a laparotomy with a 2 cm abdominal incision to induce soft-tissue trauma. Left femoral artery and vein were cannulated for blood pressure monitoring and intravenous infusion respectively. Hemorrhage was induced by a 30-minute controlled pressure bleeding (25 to 40 mmHg) then shock was maintained for 30 minutes followed by resuscitation infusion for 30 minutes by either 2 mM lactated Ringer (LR) solution, human hemoglobin (HHb), or RcoM with a volume equal to the shed blood volume. Baseline MAP, post-resuscitation MAP, and MAP change were compared across the three groups using a one-way ANOVA. Results: There was no difference in the ratio of shed blood volume to the total blood volume (26.8 ± 3.4% for LR, 26.0 ±2.6% for HHb and 27.6 ± 1.3% for Rcom, p = 0.7295). There was no difference for the baseline MAP between LR (83.5 ± 5.7 mmHg), HHb (87.4 ± 3.0 mmHg) and Rcom (82.3 ± 1.9 mmHg; p = 0.2931). Post-resuscitation MAP was significantly higher for RcoM (67.0 ± 6.3 mmHg) and HHb (60.4 ± 16.0 mmHg) compared to LR (25.9 ± 21.4 mmHg, p = 0.0029). There was no difference between Rcom and HHb in the post-resuscitation MAP (p = 0.8573). Similarly, the MAP change was significantly lower for Rcom (-15.3 ± 6.8 mmHg) and HHb (-27.0 ± 13.5 mmHg) compared to LR (-57.5 ± 18.7 mmHg, p = 0.0011) but no difference between the HHb and Rcom groups (p = 0.5462). Conclusion: This study demonstrates that resuscitation with RcoM supports the blood pressure in a murine traumatic hemorrhagic shock model, suggesting its potential application as a non-globin artificial oxygen carrier for hemorrhagic shock.

Background: Bedside ultrasound is widely utilized for critically ill patients, yet there is no standardized approach for teaching lung ultrasound to medical staff, particularly respiratory therapists (RTs), in the United States. Thus, we aimed to evaluate the efficacy of a lung ultrasound training program designed for RTs. Methods: With approval from the ethics committee, we recruited RTs with over 3 months of experience at Rush University Medical Center to participate in our lung ultrasound training program. The program comprised of a 1-h didactic lecture followed by hands-on practice on a healthy volunteer. A refresher training session was provided 6-9 months later for those who remained interested in lung ultrasound and were still employed at Rush University Medical Center. Pre- and post-training assessments were conducted to evaluate the effectiveness of the training and identify areas requiring further knowledge development. Results: Between October 2022 and April 2023, 23 RTs completed the initial training, and 7 attended both the initial and the refresher training sessions. Following the initial session, total scores significantly improved (post-training 11.0 [9.0-14.0] versus pre-training 1.0 [0-2.0], P < .001), with the subgroup focusing on "identification of patterns" achieving the highest percentage of correct answers. Among the 7 RTs who attended the refresher training, total scores significantly decreased over 6-9 months (12.9 ± 2.3 vs 4.4 ± 1.8, P = .001). However, scores significantly rebounded after the refresher training (post-training 11.3 ± 3.1 vs pre-training 4.4 ± 1.8, P = .008), with no significant difference in post-training total scores between the initial and the refresher sessions. Conclusions: Both the initial and refresher training sessions of our lung ultrasound training programs effectively improved participants' knowledge. The observed decline in knowledge retention over 6-9 months highlights the necessity for periodic refresher courses and ongoing use of lung ultrasound in clinical practice to maintain skills. Incorporating a visual format may be beneficial for acquiring and retaining knowledge.

Background: Hemorrhagic shock remains a leading cause of preventable death. No artificial oxygen carrier based on hemoglobin or hemoproteins has been approved in the US as an alternative to donated blood. A major challenge for the hemoprotein oxygen carrier is the vasoconstrictive effects due to the nitric oxide (NO) scavenging. We have engineered a modified Regulator of Carbon Monoxide Metabolism (RcoM) heme-containing protein which shows no vasoconstrictive effects. We aim to validate the oxygen binding, NO dioxygenation rate, stability, and resuscitative effects of RcoM. Hypothesis: We hypothesize that RcoM is well tolerated and can behave as an artificial oxygen carrier due to ideal oxygen binding rate, low autoxidation rate, slow NO dioxygenation rate, and high thermal/chemical stability. Approach: We assessed biochemical features using UV-visible spectroscopy methods to determine the transitions between RcoM oxidation state and ligand binding and dissociation. We performed measures of oxygen binding and autoxidation. We carried out competition experiments in which equimolar amounts of RcoM and Hb were exposed to NO to measure NO deoxygenation rate. To assess oxygen carrier capabilities of Rcom, we used a murine model of traumatic, hemorrhagic shock utilizing anesthetized mice with a 2cm abdominal incision and left femoral artery and vein catheterization. Hemorrhage was induced by a 30-minute controlled bleeding to a target blood pressure of 25 to 40 mmHg, shock was maintained for 30 minutes, then infusion by lactated Ringer (LR) solution, 2mM stroma-free Hb, or 2mM RcoM at volume equal to removed blood and monitored for 30 minutes. Mean arterial pressure post resuscitation were compared to assess the tolerance and hemodynamics effects. Results: RcoM displays appropriate oxygen binding capacity and has an NO deoxygenation rate ten-fold lower than Hb. In the murine hemorrhagic model, there was no difference for the baseline MAP or in blood removed during the bleeding phase. Post-resuscitation MAP was significantly higher for RcoM (67.0 ± 6.3 mmHg) and Hb (60.4 ± 16.0 mmHg) compared to LR (25.9 ± 21.4 mmHg, p = 0.0029). There was no difference between Rcom and Hb in the post-resuscitation MAP ( p = 0.8573). Conclusion: This study demonstrates that resuscitation with RcoM supports the blood pressure in a murine traumatic hemorrhagic shock model, suggesting its potential application as a non-globin artificial oxygen carrier for hemorrhagic shock.

Nitric oxide (NO) regulates vascular function through the activation of soluble guanylate cyclase in vascular smooth muscle and platelets. NO signaling is mediated by paracrine diffusion from endothelial cells to smooth muscle. Many questions relate to how intracellular, paracrine, and endocrine diffusion is possible in hemoglobin/myoglobin-rich environments. This diffusion is constrained by fast reactions of NO with both oxygenated and deoxygenated ferric hemoproteins and by radical-radical reactions with superoxide and hydrogen peroxide. Extensive data now supports the hypothesis that red blood cells support NO-dependent signaling through nitrite reductase reaction pathways of nitrite with deoxygenated hemoglobin and the red blood cell expressed "endothelial" NOS. Diffusion of NO outside of a red blood cell should be limited by scavenging reactions of NO with hemoglobin and multiple scavenging reactions in endothelium and smooth muscle with reactive oxygen species, however, this signaling is observed in preclinical and clinical studies. We propose a potential solution to this paradox based on a recent discovery of a rapid reaction pathway between NO, oxidized heme, and reduced thiols. The reaction of NO with ferric heme in the presence of reduced thiols rapidly generates an NO-ferroheme complex and a thiol radical, with electron transfer from the thiol to the NO-ferric heme complex. This reaction is first-order in NO and produces an NO-ferroheme complex. The NO-ferroheme is stable in red cell membrane and bound to albumin, and promotes potent vasodilation in vivo. Furthermore, this species is not scavenged by hemoglobin or myoglobin. We propose a novel signaling paradigm whereby NO-ferroheme can form via nitrite reduction or red cell eNOS and can transfer a stable NO-ferroheme between membrane, albumin, and smooth muscle, where the NO-ferroheme can activate soluble guanylate cyclase. This new signaling molecule offers a potential explanation for NO signaling in a heme- and reactive oxygen species-rich cellular environment.

Abstract Background Elevated central venous pressure (CVP) is deemed as a sign of right ventricular (RV) dysfunction. We aimed to characterize the echocardiographic features of RV in septic patients with elevated CVP, and quantify associations between RV function parameters and 30-day mortality. Methods We retrospectively reviewed a cohort of septic patients with CVP ≥ 8 mmHg in a tertiary hospital intensive care unit. General characteristics and echocardiographic parameters including tricuspid annular plane systolic excursion (TAPSE), pulmonary vascular resistance (PVR) as well as prognostic data were collected. Associations between RV function parameters and 30-day mortality were assessed using Cox regression models. Results Echocardiography was performed in 244 septic patients with CVP ≥ 8 mmHg. Echocardiographic findings revealed that various types of abnormal RV function can occur individually or collectively. Prevalence of RV systolic dysfunction was 46%, prevalence of RV enlargement was 34%, and prevalence of PVR increase was 14%. In addition, we collected haemodynamic consequences and found that prevalence of systemic venous congestion was 16%, prevalence of RV-pulmonary artery decoupling was 34%, and prevalence of low cardiac index (CI) was 23%. The 30-day mortality of the enrolled population was 24.2%. In a Cox regression analysis, TAPSE (HR:0.542, 95% CI:0.302–0.972, p = 0.040) and PVR (HR:1.384, 95% CI:1.007–1.903, p = 0.045) were independently associated with 30-day mortality. Conclusions Echocardiographic findings demonstrated a high prevalence of RV-related abnormalities (RV enlargement, RV systolic dysfunction and PVR increase) in septic patients with elevated CVP. Among those echocardiographic parameters, TAPSE and PVR were independently associated with 30-day mortality in these patients.

Introduction: Hemorrhage is a leading cause of death in trauma patients. Interventions dedicated to hemostatic resuscitation have demonstrated benefit in decreasing mortality due to hemorrhagic injury. There remain significant limitations to donor-based blood transfusions. We have identified a heme-binding protein, the Bacterial Regulator of carbon monoxide metabolism (RcoM), with suitable properties to be a robust artificial oxygen carrier. We have engineered a variant that lacks a DNA binding domain and contains cysteine mutations for improved stability (RcoM HBD-CCC). Hypothesis: We hypothesize that engineered RcoM HBD-CCC can be used as an ideal artificial oxygen carrier due to the optimization of 4 factors: ligand binding, nitrite reduction rate, autoxidation rate, and thermal denaturation. Methods: Spectrophotometric methods were used to characterize RcoM HBD-CCC in terms of its biochemical properties for optimal oxygen transport and release. Specifically, ligand binding was tested by determination of the P50 (oxygen pressure for 50% saturation of the molecule) value indicating the affinity of RcoM HBD-CCC towards oxygen. Nitrite reduction assays were carried out to test the rate at which nitric oxide (NO) forms to counteract potential NO scavenging. The autoxidation rate determines how long a protein stays in the reduced state, where it is able to bind to oxygen. Thermal denaturation (T m ) identifies the resistance of a protein to higher temperatures. Results: We determined that RcoM HBD-CCC’s P50 value was 4.2 mmHg which is within the ideal range for oxygen binding affinity given that optimal values for oxygen carriers to mimic hemoglobin oxygen dissociation are between 1 to 26 mmHg. Nitrite reductase rate was 5.6M -1 s -1 which is well above the rate for Hb (K = 0.12 M -1 s -1 ). RcoM HBD-CCC has a low autoxidation rate at 0.016 min -1 . RcoM HBD-CCC has a T m of 71°C which is well above all ambient environmental temperatures. Conclusion: We have designed and synthesized a variant of RcoM that we have demonstrated in in vitro spectrophotometric assays to have ideal biochemical properties for an artificial oxygen carrier. We next plan to test the efficacy of RcoM HBD-CCC in animal models of hemorrhage and assess safety in animal exposure models.

A photochemically induced dynamic nuclear polarization (photo-CIDNP) study of yeast and horse muscle phosphoglycerate kinase with flavin dyes was undertaken to identify the histidine, tryptophan, and tyrosine resonances in the aromatic region of the simplified 1H NMR spectra of these enzymes and to investigate the effect of substrates on the resonances observable by CIDNP. Identification of the CIDNP-enhanced resonances with respect to the type of amino acid residue has been achieved since only tyrosine yields emission peaks and the dye 8-aminoriboflavin enhances tryptophan but not histidine. By use of the known amino acid sequences and structures derived from X-ray crystallographic studies of the enzymes from the two species, assignment of the specific residues in the protein sequences giving rise to the CIDNP spectra was partially achieved. In addition, flavin dye accessibility was used to probe any changes in enzyme structure induced by substrate binding. The nine resonance peaks observed in the CIDNP spectrum of yeast phosphoglycerate kinase have been assigned tentatively to five residues: histidines-53 and -151, tryptophan-310, and tyrosines-48 and -195. The accessibility of a tyrosine to photoexcited flavin is reduced in the presence of MgATP. Since the tyrosine residues are located some distance from the MgATP binding site of the catalytic center, it is proposed either that this change is due to a distant conformational change or that a second metal-ATP site inferred from other studies lies close to one of the tyrosines. Horse muscle phosphoglycerate kinase exhibits seven resonances by CIDNP NMR.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitric oxide (NO) is an endogenously produced physiological signaling molecule that regulates blood flow and platelet activation. However, both the intracellular and intravascular diffusion of NO is severely limited by scavenging reactions with hemoglobin, myoglobin, and other hemoproteins, raising unanswered questions as to how free NO can signal in hemoprotein-rich environments, like blood and cardiomyocytes. We explored the hypothesis that NO could be stabilized as a ferrous heme-nitrosyl complex (Fe 2+ -NO, NO-ferroheme) either in solution within membranes or bound to albumin. Unexpectedly, we observed a rapid reaction of NO with free ferric heme (Fe 3+ ) and a reduced thiol under physiological conditions to yield NO-ferroheme and a thiyl radical. This thiol-catalyzed reductive nitrosylation reaction occurs readily when the hemin is solubilized in lipophilic environments, such as red blood cell membranes, or bound to serum albumin. NO-ferroheme albumin is stable, even in the presence of excess oxyhemoglobin, and potently inhibits platelet activation. NO-ferroheme-albumin administered intravenously to mice dose-dependently vasodilates at low- to mid-nanomolar concentrations. In conclusion, we report the fastest rate of reductive nitrosylation observed to date to generate a NO-ferroheme molecule that resists oxidative inactivation, is soluble in cell membranes, and is transported intravascularly by albumin to promote potent vasodilation.

Objective To explore the relationship between the post-operative peak value of central venous pressure (CVPp) and the incidence of acute kidney injury (AKI) in patients who had undergone cardiopulmonary bypass surgery (CBS). Methods Clinical data were retrospectively collected from 1 May 2016 to 1 May 2018 from all patients undergoing CBS in the Department of Intensive Care Medicine, Peking Union Medical College Hospital. The CVP values immediately after transfer to ICU (CVP 0h) and at 6 h(CVP 6h), and CVPp within 48 h(CVPp 48h) of transfer to ICU, the incidence of AKI after 48 h of transfer to ICU and in-hospital mortality were recorded. The receiver operating characteristic (ROC) curve was used to evaluate the clinical value of CVP-related indicators in predicting AKI after CBS and determine the optimal threshold. The risk factors for AKI and in-hospital mortality after CBS were analysed using single factor and multifactorial Logistic regression. Results A total of 485 patients after CBS who met the inclusion and exclusion criteria were enrolled, with an incidence of AKI after 48 h of transfer to ICU of 25.2% (122/485) and an in-hospital mortality rate of 2.5% (12/485). The ROC curve analysis showed that the area under the curve (AUC) for CVPp 48h to predict AKI after CBS was 0.634 (95% CI: 0.577-0.692, P < 0.001), with an optimal threshold value of 14 mm Hg, sensitivity of 49.6% and specificity of 63.5%. Multifactorial logistic regression analysis showed that hypertension(OR=2.505, 95% CI: 1.581-3.969, P < 0.001), pulmonary hyperten-sion(OR=2.552, 95% CI: 1.573-4.412, P < 0.001), prolonged aortic block time(OR=1.009, 95% CI: 1.004-1.014, P=0.001), and CVPp 48h≥14 mm Hg(OR=1.613, 95% CI: 1.030-2.526, P=0.037) were independent risk factors for AKI after CBS; CVPp 48h≥14 mm Hg was an independent risk factor for in-hospital death(OR=8.044, 95% CI: 1.579-40.979, P=0.012). Conclusions CVPp 48h is associated with AKI in patients who have undergone CBS. The monitoring and management of CVP might be a way to improve the prognosis of these patients.

I.v. administration of a high-affinity carbon monoxide-binding (CO-binding) molecule, recombinant neuroglobin, can improve survival in CO poisoning mouse models. The current study aims to discover how biochemical variables of the scavenger determine the CO removal from the RBCs by evaluating 3 readily available hemoproteins, 2,3-diphosphoglycerate stripped human hemoglobin (StHb); N-ethylmaleimide modified hemoglobin (NEMHb); and equine myoglobin (Mb). These molecules efficiently sequester CO from hemoglobin in erythrocytes in vitro. A kinetic model was developed to predict the CO binding efficacy for hemoproteins, based on their measured in vitro oxygen and CO binding affinities, suggesting that the therapeutic efficacy of hemoproteins for CO poisoning relates to a high M value, which is the binding affinity for CO relative to oxygen (KA,CO/KA,O2). In a lethal CO poisoning mouse model, StHb, NEMHb, and Mb improved survival by 100%, 100%, and 60%, respectively, compared with saline controls and were well tolerated in 48-hour toxicology assessments. In conclusion, both StHb and NEMHb have high CO binding affinities and M values, and they scavenge CO efficiently in vitro and in vivo, highlighting their therapeutic potential for point-of-care antidotal therapy of CO poisoning.

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Introduction Right ventricle (RV) dilation in combination with elevated central venous pressure (CVP), which is a state of RV congestion, is seen as a sign of RV failure (RVF). On the other hand, RV systolic function is usually assessed by tricuspid annular plane systolic excursion (TAPSE) and fractional area change (FAC). This study aimed to investigate the prevalence and prognostic value of RVF and RV systolic dysfunction (RVSD) in septic patients. Methods Mechanically ventilated sepsis and septic shock patients were included. We collected haemodynamic and echocardiographic parameters as well as prognostic information including mechanical ventilation duration, length of ICU stay and 30-day mortality. RVF was defined as a right and left ventricular end-diastolic area ratio ≥ 0.6 in combination with CVP ≥ 8 mmHg. RVSD was defined as TAPSE < 16 mm or FAC < 35%. Results A total of 215 patients were enrolled in this study, and the patients were divided into 4 groups: patients with normal RV function (normal, n = 101), patients with RVF but without RVSD (RVF only, n = 38), patients with RVSD but without RVF (RVSD only, n = 44), and patients with combined RVF–RVSD (RVF/RVSD, n = 32). The RVF/RVSD group and RVSD only group had a lower cardiac index than the RVF only group and normal groups ( p < 0.05). At 30 days after ICU admission, 50.0% of patients had died in the RVF/RVSD group, which was much higher than the mortality in the RVF only group (13.2%) and normal group (13.9%) ( p < 0.05). In a Cox regression analysis, the presence of RVF/RVSD was independently associated with 30-day mortality (HR 3.004, 95% CI:1.370–6.587, p = 0.006). In contrast, neither the presence of RVF only nor the presence of RVSD only was associated with 30-day mortality (HR 0.951, 95% CI:0.305–2.960, p = 0.931; HR 1.912, 95% CI:0.853–4.287, p = 0.116, respectively). Conclusion The presence of combined RVF–RVSD was associated with 30-day mortality in mechanically ventilated septic patients. Additional studies are needed to confirm and expand this finding.

Background This study aimed to determine whether a focused 2-day cardiac ultrasound training course could enable physicians to obtain and interpret focused cardiac ultrasound (FCU) images from critically ill patients. Methods We retrospectively reviewed the FCU images submitted by the physicians who attended a 2-day FCU training courses. Three experienced trainers reviewed the images separately. They determined whether the images were assessable and scored the images on an 8-point scale. They also decided whether the physicians provided correct responses for visual estimations of the left ventricular ejection fraction (LVEF) and right ventricle (RV) dilatation and septal motion. Results Among the 327 physicians, 291 obtained images that were considered assessable (89%). The scores for parasternal short-axis view were lower than those obtained for other transthoracic echocardiographic views, p < 0.001. More physicians provided incorrect appraisals of LVEF than of RV dilatation and septal motion (19.9% vs. 3.1%, p < 0.001). The percentages of incorrect answers by LVEF category were as follows: 34.8% on images of LVEF < 30, 24.7% on images of LVEF 30–54, and 16.4% on images of LVEF ≥55%, p < 0.001. A logistic regression analysis showed that patients with abnormal LVEF were associated with physicians’ incorrect assessment of LVEF, with an odds ratio of 1.923 (95% confidence interval (CI):1.071–3.456, p = 0.029). Conclusions A large proportion of physicians could obtain and interpret FCU images from critically ill patients after a 2-day training course. However, they still scored low on the parasternal short-axis view and were more likely to make an incorrect assessment of LVEF in patients with abnormal left ventricular systolic function.

OBJECTIVE The authors aimed to explore whether tricuspid annular plane systolic excursion (TAPSE) and right ventricular outflow fractional shortening (RVOT-FS) were associated with long-term prognosis in mechanically ventilated septic patients. DESIGN A prospective observational study. SETTING A tertiary hospital intensive care unit (ICU). PARTICIPANTS One hundred eighty-one septic patients who were on mechanical ventilation. INTERVENTIONS Echocardiography was performed within 24 hours of ICU admission. MEASUREMENTS AND MAIN RESULTS Several echocardiographic parameters, including TAPSE and RVOT-FS, as well as prognostic information, were collected. A Cox regression survival analysis showed that TAPSE was independently associated with one-year all-cause mortality (hazard ratio [HR] 0.407, 95% confidence interval [CI]: 0.200-0.827, p = 0.013), but ROVT-FS was not (HR 0.997, 95% CI: 0.970-1.025, p = 0.828). ROC analysis showed that the optimal cutoff value for TAPSE and RVOT-FS to determine one-year mortality was TAPSE <18 mm and RVOT-FS <40%. The one-year mortality in patients with low TAPSE (n = 88) and in patients with both low TAPSE and low RVOT-FS (n = 60) was 45.5% and 48.3%, respectively; p = 0.724. In a multivariate analysis, RVOT-FS did not add significant prognostic information to that provided by TAPSE <18 mm (p = 0.197). CONCLUSIONS TAPSE was an independent predictor of one-year all-cause mortality in mechanically ventilated septic patients. RVOT-FS was not associated with one-year mortality and added no prognostic value to TAPSE in these patients.

OBJECTIVE:Acute fatty liver of pregnancy(AFLP) is a rare but very urgent obstetric disease in clinical. It is a common cause of liver failure in pregnancy and often needs to be admitted to the department of critical care medicine because of the rapid development of acute hepatic dysfunction and severe acute renal dysfunction. The etiology and pathogenesis of this disorder is not very clear although there have been many studies on it before. Meanwhile, the relatively high mortality requires a better recognition in order to better guide clinical decision making. Our previous multicentre retrospective study on AFLP demonstrated that total bilirubin and serum creatinine were independent risk factors for perinatal maternal mortality. And we aim to further assess maternal outcomes and risk factors in AFLP patients treated without plasma exchange or renal replacement therapy based on previous data we collected. METHODS:Retrospective cohort study of 133 hospitalized patients with AFLP was collected from four Chinese tertiary hospitals during the period between January 2009 and April 2014. One hundred thirty three patients were divided into two subgroups containing patients treated without plasma exchange (PE) or renal replacement therapy (CRT) and patients treated with PE or/and CRT. Logistic regression was used to analyze independent risk factors for maternal mortality of AFLP treated without PE or CRT. RESULTS:The maternal mortality rate was 12.0% in subgroup of patients treated without PE or CRT. And in subgroup of patients treated with PE or/and CRT, the maternal mortality rate was 26.8%. Independent risk factors for maternal mortality of AFLP treated without PE or CRT were direct bilirubin (OR = 1.012; 95% CI, 1.002-1.022) and serum creatinine (OR = 1.022; 95% CI, 1.007-1.036). CONCLUSION:Although less liver and kidney damage in AFLP treated without PE or CRT, direct bilirubin and serum creatinine remained to be independent risk factors for maternal mortality. Thus, the level of bilirubin and serum creatinine might not be necessary for AFLP to decide whether to give plasma exchange or dialysis treatment.

Background Sepsis, a dysregulated host response to infection with results in organ dysfunction, has been a major challenge to the development of effective therapeutics. Sepsis-associated acute kidney injury (S-AKI) results in a 3–5-fold increase in the risk of hospital mortality compared to sepsis alone. The development of therapies to reverse S-AKI could therefore significantly affect sepsis outcomes. However, the translation of therapies from preclinical studies into humans requires model systems that recapitulate clinical scenarios and the development of renal fibrosis indicative of the transition from acute to chronic kidney disease. Results Here we characterized a murine model of S-AKI induced by abdominal sepsis developing into a chronic phenotype. We applied a small molecule histone deacetylase-8 inhibitor, UPHD186, and found that early treatment, beginning at 48 h post-sepsis, worsened renal outcome accompanied by decreasing mononuclear cell infiltration in the kidney, skewing cells into a pro-inflammatory phenotype, and increased pro-fibrotic gene expression, while delayed treatment, beginning at 96 h post-sepsis, after the acute inflammation in the kidney had subsided, resulted in improved survival and kidney histology presumably through promoting proliferation and inhibiting fibrosis. Conclusions These findings not only present a clinically relevant S-AKI model, but also introduce a timing dimension into S-AKI therapeutic interventions that delayed treatment with UPHD186 may enhance renal histologic repair. Our results provide novel insights into successful repair of kidney injury and sepsis therapy.

Abstract Background To explore the association between the ratio of tricuspid annular plane systolic excursion (TAPSE) and pulmonary arterial systolic pressure (PASP), and long- and short-term outcomes in mechanically ventilated septic shock patients. Methods Septic shock patients admitted to the intensive care unit (ICU) were screened for enrollment. Echocardiographic parameters including TAPSE and tricuspid regurgitation velocity, haemodynamic and respiratory parameters, and prognostic data were obtained. Results One hundred eighteen subjects were enrolled in this study, among whom 75 survived and 43 died at the one-year follow-up. ROC curve analysis revealed that the TAPSE/PASP ratio was able to assess one-year all-cause mortality with an area under the curve of 0.817 (95% CI: 0.739–0.896, p < 0.001) and the optimal cutoff value was 0.50 mm/mmHg. Kaplan-Meier survival analysis showed that one-year all-cause mortality was significantly higher in patients with TAPSE/PASP ≤0.5 mm/mmHg than in patients with TAPSE/PASP > 0.5 mm/mmHg (log-rank 32.934, p < 0.001). According to the Cox regression survival analyses, the TAPSE/PASP ratio was independently associated with one-year all-cause mortality (HR 0.007, 95% CI:0.000–0.162, p = 0.002) and ICU mortality (HR 0.027, 95% CI:0.001–0.530, p = 0.017). According to the multivariable analysis, the TAPSE/PASP ratio was an independent variable associated with mechanical ventilation (MV) duration (standard coefficient − 0.240, p = 0.010). Conclusion The TAPSE/PASP ratio demonstrated prognostic value for one-year all-cause mortality, ICU mortality and MV duration in mechanically ventilated septic shock patients.

Carbon monoxide (CO) remains the most common cause of human poisoning. The consequences of CO poisoning include cardiac dysfunction, brain injury, and death. CO causes toxicity by binding to hemoglobin and by inhibiting mitochondrial cytochrome c oxidase (CcO), thereby decreasing oxygen delivery and inhibiting oxidative phosphorylation. We have recently developed a CO antidote based on human neuroglobin (Ngb-H64Q-CCC). This molecule enhances clearance of CO from red blood cells in vitro and in vivo. Herein, we tested whether Ngb-H64Q-CCC can also scavenge CO from CcO and attenuate CO-induced inhibition of mitochondrial respiration. Heart tissue from mice exposed to 3% CO exhibited a 42 ? 19% reduction in tissue respiration rate and a 33 ? 38% reduction in CcO activity compared with unexposed mice. Intravenous infusion of Ngb-H64Q-CCC restored respiration rates to that of control mice correlating with higher electron transport chain CcO activity in Ngb-H64Q-CCC?treated compared with PBS-treated, CO-poisoned mice. Further, using a Clark-type oxygen electrode, we measured isolated rat liver mitochondrial respiration in the presence and absence of saturating solutions of CO (160 ?m) and nitric oxide (100 ?m). Both CO and NO inhibited respiration, and treatment with Ngb-H64Q-CCC (100 and 50 ?m, respectively) significantly reversed this inhibition. These results suggest that Ngb-H64Q-CCC mitigates CO toxicity by scavenging CO from carboxyhemoglobin, improving systemic oxygen delivery and reversing the inhibitory effects of CO on mitochondria. We conclude that Ngb-H64Q-CCC or other CO scavengers demonstrate potential as antidotes that reverse the clinical and molecular effects of CO poisoning.