Insights into COVID-19-associated critical illness: a narrative review.

Background and Objective: Since the outbreak of the 2019 novel coronavirus disease (COVID-19), acute respiratory distress syndrome (ARDS) and sepsis resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have surged in intensive care units around the world. The heterogeneity of ARDS and sepsis has long been observed, and multiple subphenotypes and endotypes correlated with different outcomes and treatment response have been identified in the search for treatable traits. Despite their similarity to typical ARDS and sepsis, COVID-19-associated ARDS and sepsis harbor distinct features, raising the question as to whether they could be considered as subphenotypes or endotypes of the historical syndromes and, accordingly, benefit from specific therapeutic strategies. This review aimed to summarize and discuss the current knowledge of COVID-19-associated critical illness and the intrinsic subphenotypes or endotypes. Methods: Literature on the pathogenesis of COVID-19 and the subphenotyping of COVID-19-associated critical illness was derived from the PubMed database and reviewed. Key Content and Findings: Accumulating evidence, varying from clinical observation to basic research, has contributed to revealing the fundamental pathophysiological features of severe COVID-19 and has advanced our knowledge of the disease. COVID-19-associated ARDS and sepsis exhibit some distinctive features compared to the classic syndromes, including remarkable vascular abnormality and coagulopathy, and distinct respiratory mechanics and immune response. Some conventional subphenotypes derived from classic ARDS and sepsis have been validated in COVID-19, while novel subphenotypes and endotypes have also been identified in patients with this disease, who experience variable clinical outcomes and treatment responses. Conclusions: Subphenotyping of COVID-19-associated ARDS and sepsis can provide new insights into the development and management of these illnesses.

Contrast-Enhanced Ultrasonography Value for Early Prediction of Delayed Graft Function in Renal Transplantation Patients.

OBJECTIVES: Delayed graft function (DGF) is a common early complication after kidney transplantation. The aim of the present study was to evaluate the value of contrast-enhanced ultrasonography (CEUS) in the early prediction of DGF after kidney transplantation. METHODS: A total of 89 renal transplant recipients were retrospectively enrolled and divided into DGF group or normal graft function (NGF) group according to the allograft function. Conventional Doppler ultrasound and CEUS examination data on the first postoperative day were collected and analyzed. RESULTS: The resistive indices of segmental and interlobar artery in the DGF group were significantly higher than those in the NGF group (0.71 ± 0.17 versus 0.63 ± 0.08, P = .006; 0.70 ± 0.16 versus 0.62 ± 0.08, P = .004, respectively). The patients experiencing DGF had significantly lower PI-c (14.7 dB ± 6.1 dB versus 18.5 dB ± 3.3 dB, P = .001) and smaller AUC-c (779.8 ± 375.8 dB·seconds versus 991.0 ± 211.7 dB·seconds, P = .003), as well as significantly lower PI-m (12.6 dB ± 5.9 dB versus 15.9 dB ± 3.9 dB, P = .006), shorter MTT-m (30.7 ± 9.4 seconds versus 36.3 ± 7.1 seconds, P = .01), and smaller AUC-m (P = .007). Multivariate analysis demonstrated that PI-c, AUC-c, and MTT-m were independent risk factors for DGF. The area under the receiver operating characteristic curve values of the combined predicted value (PI-c + MTT-m, PI-c + AUC-c + MTT-m) of DGF incidence were bigger than that of PI-c, AUC-c, or MTT-m. CONCLUSIONS: CEUS parameters of the cortex and medulla have a good value for an early prediction of DGF after renal transplantation.

Feasibility and discriminatory value of tissue motion annular displacement in sepsis-induced cardiomyopathy: a single-center retrospective observational study.

BACKGROUND: There is no formal diagnostic criterion for sepsis-induced cardiomyopathy (SICM), but left ventricular ejection fraction (LVEF) < 50% was the most commonly used standard. Tissue motion annular displacement (TMAD) is a novel speckle tracking indicator to quickly assess LV longitudinal systolic function. This study aimed to evaluate the feasibility and discriminatory value of TMAD for predicting SICM, as well as prognostic value of TMAD for mortality. METHODS: We conducted a single-center retrospective observational study in patients with sepsis or septic shock who underwent echocardiography examination within the first 24 h after admission. Basic clinical information and conventional echocardiographic data, including mitral annular plane systolic excursion (MAPSE), were collected. Based on speckle tracking echocardiography (STE), global longitudinal strain (GLS) and TMAD were, respectively, performed offline. The parameters acquisition rate, inter- and intra-observer reliability, time consumed for measurement were assessed for the feasibility analysis. Areas under the receiver operating characteristic curves (AUROC) values were calculated to assess the discriminatory value of TMAD/GLS/MAPSE for predicting SICM, defined as LVEF < 50%. Kaplan-Meier survival curve analysis was performed according to the cutoff values in predicting SICM. Cox proportional hazards model was performed to determine the risk factors for 28d and in-hospital mortality. RESULTS: A total of 143 patients were enrolled in this study. Compared with LVEF, GLS or MAPSE, TMAD exhibited the highest parameter acquisition rate, intra- and inter-observer reliability. The mean time for offline analyses with TMAD was significantly shorter than that with LVEF or GLS (p < 0.05). According to the AUROC analysis, TMADMid presented an excellent discriminatory value for predicting SICM (AUROC > 0.9). Patients with lower TMADMid (< 9.75 mm) had significantly higher 28d and in-hospital mortality (both p < 0.05). The multivariate Cox proportional hazards model revealed that BMI and SOFA were the independent risk factors for 28d and in-hospital mortality in sepsis cases, but TMAD was not. CONCLUSION: STE-based TMAD is a novel and feasible technology with promising discriminatory value for predicting SICM with LVEF < 50%.

Severe COVID-19 has a distinct phenotype from bacterial sepsis: a retrospective cohort study in deceased patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has caused more than 2 million deaths worldwide. Viral sepsis has been proposed as a description for severe COVID-19, and numerous therapies have been on trials based upon this hypothesis. However, whether the clinical characteristics of severe COVID-19 are similar to those of bacterial sepsis has not been elucidated. METHODS: We retrospectively compared the clinical data of non-surviving COVID-19 patients who were admitted to a 30-bed intensive care unit (ICU) in Wuhan Infectious Diseases Hospital (Wuhan, China) from 22 January 2020, to 28 February 2020, with those of non-surviving patients with bacterial sepsis who were admitted to the ICU in Zhongshan Hospital, Fudan University (Shanghai, China) from 3 July 2018, to 30 June 2020. RESULTS: A total of 53 COVID-19 patients and 26 septic patients were included in the analysis. The mean ages were 65.6 [standard deviation (SD): 11.1] and 70.4 (SD: 14.3) years in the COVID-19 cohort and sepsis cohort, respectively. The proportion of participants with hypertension was higher in non-survivors with COVID-19 than in non-survivors with sepsis (41.5% vs. 15.4%, P=0.020). The Sequential Organ Failure Assessment (SOFA) score of non-survivors with COVID-19 was lower than that of non-survivors with sepsis at ICU admission {4.0 [interquartile range (IQR): 3.0-6.0] vs. 7.5 [IQR: 5.8-11.0], P<0.001}. The clinical parameters at ICU admission assessed with principal component analysis and hierarchical cluster analysis showed that COVID-19 patients were distinct from bacterial septic patients. Compared with non-survivors with sepsis, non-survivors with COVID-19 had a higher neutrophil/lymphocyte ratio, total protein, globulin, lactate dehydrogenase (LDH), and D-dimer; a lower eosinophil count, procalcitonin, interleukin-6 (IL-6), total bilirubin, direct bilirubin, myohemoglobin, albumin/globulin ratio, activated partial thromboplastin time (APTT), prothrombin time (PT), and international normalization ratio (INR) at ICU admission. In addition, the levels of total protein, globulin, LDH, D-dimer, and IL-6 were significantly different between the two groups during the ICU stay. CONCLUSIONS: Patients with critical COVID-19 have a phenotype distinct from that of patients with bacterial sepsis. Therefore, caution should be used when applying the previous experience of bacterial sepsis to patients with severe COVID-19.

Comparative study of high flow nasal catheter device and noninvasive positive pressure ventilation for sequential treatment in sepsis patients after weaning from mechanical ventilation in intensive care unit.

BACKGROUND: The hypoxemia condition after mechanical ventilation (MV) weaning is not rare among sepsis patients, so we compared the efficacy in two different intervention groups: high-flow nasal cannula device group and non-invasive positive pressure ventilation (NPPV) group. METHODS: This is a retrospective cohort study. Participants were patients with sepsis receiving high-flow nasal catheter (HFNC) device or NPPV within 24 hours after weaning from MV. The primary outcome was tracheal re-intubation within 72 hours after extubation. Secondary outcomes included: oxygenation index, complication rate, patient comfort evaluation, HFNC/NPPV treatment time, ICU length of stay (LOS), ICU mortality, and in-hospital 28-day mortality. RESULTS: A total of 283 patients were included in the study with 167 in the HFNC group and 116 in the NPPV group. The re-intubation rates after extubation in both groups were respectively 4.2% and 5.2% without significant difference. Patients in the HFNC group experienced lower incidence of delirium, reflux aspiration, facial pressure ulcer and other complications, and higher score of patients comfort than that in the NPPV group. There was no significant difference in ICU LOS, ICU mortality and in-hospital 28-day mortality between the two groups. CONCLUSIONS: HFNC and NPPV have similar efficacy in the sequential treatment of sepsis patients after weaning from MV. Compared with NPPV, those extubated to HFNC had lower rate of complications such as reflux aspiration and facial pressure ulcers. The patients extubation to HFNC is more comfortable (and associated with less delirium) than to NPPV.

Neuroprotective Effect of the Inhibitor Salubrinal after Cardiac Arrest in a Rodent Model.

Cardiac arrest (CA) yields poor neurological outcomes. Salubrinal (Sal), an endoplasmic reticulum (ER) stress inhibitor, has been shown to have neuroprotective effects in both in vivo and in vitro brain injury models. This study investigated the neuroprotective mechanisms of Sal in postresuscitation brain damage in a rodent model of CA. In the present study, rats were subjected to 6 min of CA and then successfully resuscitated. Either Sal (1 mg/kg) or vehicle (DMSO) was injected blindly 30 min before the induction of CA. Neurological status was assessed 24 h after CA, and the cortex was collected for analysis. As a result, we observed that, compared with the vehicle-treated animals, the rats pretreated with Sal exhibited markedly improved neurological performance and cortical mitochondrial morphology 24 h after CA. Moreover, Sal pretreatment was associated with the following: (1) upregulation of superoxide dismutase activity and a reduction in maleic dialdehyde content; (2) preserved mitochondrial membrane potential; (3) amelioration of the abnormal distribution of cytochrome C; and (4) an increased Bcl-2/Bax ratio, decreased cleaved caspase 3 upregulation, and enhanced HIF-1α expression. Our findings suggested that Sal treatment improved neurological dysfunction 24 h after CPR (cardiopulmonary resuscitation), possibly through mitochondrial preservation and stabilizing the structure of HIF-1α.

Epidemiology, pathogenetic mechanism, clinical characteristics, and treatment of Vibrio vulnificus infection: a case report and literature review.

Vibrio vulnificus is a Gram-negative bacterium that belongs to the Vibrionaceae family. It represents a deadly opportunistic human pathogen which grows in water with the proper temperature and salinity, and is mostly acquired from seafood eating or direct contact. In susceptible individuals, a traumatic infection could be fatal, causing severe wound infection and even septic shock, and may require amputation. Global warming plays an important role in the geographical area expanding of Vibrio disease. The pathogenesis of Vibrio vulnificus-associated sepsis is very complex, including iron intake, cell injury, and adhesion-related protein and virulence regulation. Vibrio vulnificus infection mainly manifests clinical subtypes such as primary sepsis, traumatic infection, and gastroenteritis, with rapid symptom progression and signs of multiple organ dysfunction syndrome (MODS). It is important to assess these pathogenetic mechanisms in order to select more appropriate measures to prevent and treat Vibrio vulnificus infections, including antibiotic usage and surgical intervention. In this work, we report a typical case of successful treatment of necrotizing fasciitis caused by Vibrio vulnificus, and review the epidemiology, pathogenetic mechanism, clinical characteristics, and treatment of Vibrio vulnificus infection.

Value of the combination of renal resistance index and central venous pressure in the early prediction of sepsis-induced acute kidney injury.

PURPOSE: Early prediction of acute kidney injury (AKI) in septic patients is difficult. This study aimed to assess the values of renal resistive index (RI), central venous pressure (CVP), and their combination in the early prediction of sepsis-induced AKI. METHODS: A prospective cohort study was performed in septic patients. The variables potentially associated with AKI were recorded at admission and compared between the AKI and non-AKI groups. The variables independently associated with sepsis-induced AKI were identified using multivariable logistic regression, and the area under the receiver operating characteristic curve (AUROC) analysis was calculated. RESULTS: A total of 124 septic patients were included. Septic shock (OR, 3.28; P=0.002), high CVP (OR, 1.92; P=0.012) and renal RI (OR, 2.58; P=0.009), low diastolic perfusion pressure (DPP) (OR, 2.15; P=0.010) at admission were independent risk factors for sepsis-induced AKI. The AUROC value of the combination of RI and CVP was greater compared with either RI or CVP alone in predicting sepsis-induced AKI (AUROC=0.858, 0.811, and 0.780, respectively). CONCLUSIONS: The combination of RI and CVP was more valuable than either of the two parameters in the early prediction for sepsis-induced AKI.

Metformin can block precancerous progression to invasive tumors of bladder through inhibiting STAT3-mediated signaling pathways.

BACKGROUND: Metformin is the first line of oral antidiabetic drug in the biguanide class for treatment of type 2 diabetes. Increasing evidence has suggested that it is a potential anti-tumor drug. However, the mechanisms underlying inhibiting tumor development remain elusive, especially in bladder tumors. METHODS: T24 and J82 cell lines were used as an in vitro model, and 24 female SD rats were used to build an N-methyl-N-nitrosourea (MNU)-induced orthotopic rat bladder cancer model. Transfection of lentivirus-based shRNA was used to construct the STAT3-KNOCKDOWN T24 cell line. After metformin treatment, the viability of bladde cancer cells was determined by CCK8. Cell cycle distribution and apoptosis were assessed by flow cytometry. The migration and invasion abilities of cells were evaluated by wound healing and transwell asssays. The inactivation of stat3 pahtway was examined by qRTPCR, western blot and Immunofluorescence. RESULTS: Metformin can effectively inhibit precancerous progression to invasive cancer in an MNU-induced rat orthotopic bladder tumor model, although it could not completely suppress normal cells transforming into tumor cells. While the MNU could induce 50 % rats (4/8) to develop invasive bladder cancers, the rats co-administrated with metformin failed to develop invasive tumors but retained at precancerous or non-invasive stages, exhibiting as dysplasia, papillary tumor and/or carcinoma in situ (CIS). Accordingly, phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is a well known oncogene, was significantly inhibited in the tumors of rats treated with metformin. In vitro experiments revealed that the metformin could efficiently inhibit STAT3 activation, which was associated with the cell cycle arrest, reduction of cell proliferation, migration and invasiveness, and increase in apoptotic cell death of bladder cancer cell lines. CONCLUSIONS: These findings provide for the first time the evidence that metformin can block precancerous lesions progressing to invasive tumors through inhibiting the activation of STAT3 pathway, and may be used for treatment of the non-invasive bladder cancers to prevent them from progression to invasive tumors.

AEG-1 is associated with tumor progression in nonmuscle-invasive bladder cancer.

Astrocyte elevated gene-1 (AEG-1), a novel oncoprotein, has been implicated in oncogenesis and cancer progression in various types of human cancers. Here, immunohistochemistry was used to detect AEG-1 expression in nonmuscle-invasive bladder cancer (NMIBC), and these data were examined for correlation with clinicopathological parameters, and prognosis. Immunohistochemical analysis revealed that AEG-1 expression was significantly higher in bladder cancer tissues than that in normal tissues. High expression of AEG-1 was found in 45 % of bladder cancers and significantly associated with tumor grade (P = 0.002) and progression (P = 0.028). The Kaplan-Meier survival analysis demonstrated that AEG-1 expression was significantly associated with shorter progression-free survival (P = 0.0011). Multivariate analysis further demonstrated that AEG-1 was an independent prognostic factor for patients with BC. AEG-1 protein may contribute to the malignant progression of bladder cancer, and present as a novel marker to predict the progression of NMIBC.

Effects of hyperbaric oxygen on aggressive periodontitis and subgingival anaerobes in Chinese patients.

OBJECTIVE: To investigate the effects of hyperbaric oxygen (HBO2) on aggressive periodontitis (AgP), and subgingival obligate anaerobes in Chinese patients. MATERIALS AND METHODS: Sixty cases of Chinese patients with AgP were randomly divided into two groups -the HBO2 group (30 cases) and the control group (30 cases). Study teeth were divided into four groups -: the HBO2 therapy, the HBO2 + scaling scaling group, the scaling group and the control group. Subgingival anaerobic organisms were measured with anaerobic culture, and number of obligate anaerobes and facultative anaerobes and Bacteroides melaninogenicus was counted. Comparisons of changes in the clinical indices, and subgingival anaerobes were made between the groups. RESULTS: Highly significant differences in gingival index (GI), probing depth (PD), attachment loss (AL), and Plaque index (PLI), and tooth odontoseisis (TO) were seen in the HBO2, the HBO2 + scaling and the scaling groups when compared with the control group (P<0.01). The number of subgingival anaerobes as well as the types of obligate anaerobes and facultative anaerobes and the number of Bacteroides melaninogenicus were reduced markedly in these three treatment groups. Highly statistical differences in clinical indices, subgingival anaerobe number and types of obligate anaerobes and facultative anaerobes and Bacteroides melaninogenicus were found when comparisons were made between the HBO2 + scaling and the HBO2 groups, as well as between the HBO2 + scaling and the scaling groups. Clinical follow-ups indicated that the GI, PD, AL, TO, PLI and subgingival anaerobes number of the three therapeutic groups were reduced more severely than the control group. CONCLUSIONS: HBO2 had good therapeutic effects on Chinese patients with AgP. HBO2 therapy combined with scaling and root planing was the most beneficial in the treatment of AgP. The therapeutic effect of HBO2 on AgP is most likely through inhibition of the growth of subgingival anaerobes. Clinical follow-ups suggest that the effect could last more than 2 years.

[Effects and holding time of hyperbaric oxygen on human severe periodontitis].

OBJECTIVE: This paper studied the therapeutic effects and holding time of hyperbaric oxygen (HBO) on human severe periodontitis. METHODS: 30 cases with periodontitis were selected and randomly divided into 2 groups, i.e. the HBO group and control group. For HBO group, they were exposed to a pressure of 0.25 MPa. For control group, they were rinsed with gargle. Gingival indices (GI), sulcus bleeding indices (SBI), plaque index (PLI), probing depth (PD), attachment loss (AL) and gingival crevicular fluid (GCF) were measured during both the first and last clinical visits, and 1 year after HBO therapy. The gingival blood flow (GBF) were measured by Laser Doppler Flowmeter. RESULTS: HBO can decrease GI of patients with periodontitis by 1.1 decrease SBI by 1.2, lower PD and AL by 0.7 mm, decrease the volume of GCF by 2.0, and significant differences could be seen in the above indices between pre and post HBO therapy. The GBF had a 1.8 folds increase after HBO exposure. GI and SBI one year after HBO therapy were larger than that of the time after HBO therapy. There were no significant differences in the PLI, PD, AL, GCF, GBF between post HBO therapy and 1 year after HBO therapy. CONCLUSION: HBO had good therapeutic effects on human severe periodontitis, the effects can keep more than 1 year.

Effects and mechanism of hyperbaric oxygen on prostaglandins in alveolar bone and gingival of experimental periodontitis in animal.

OBJECTIVE: To study the effects and the therapeutic mechanism of hyperbaric oxygen (HBO) on prostaglandin E(2) (PGE(2)) in alveolar bone and gingiva of experimental periodontitis in animal. METHODS: Experimental periodontitis was produced by silk thread sutures combined with high content sugar diet. For HBO therapy, they were exposed to a pressure of 0.25 MPa (2.5ATA), breathing pure oxygen one session a day for 60 min. The treatment course was 2 weeks. The value of PGE(2) in gingiva and alveolar bone was analyzed by enzyme immunoassay (EIA). RESULTS: The value of PGE(2) in gingiva of control group was 3.21 ng/g, and that of PGE(2) in alveolar bone was 3.22 ng/g. The contents of PGE(2) in gingiva (13.96 ng/g) and alveolar bone (13.32 ng/g) of periodontitis group increased markedly than control group (P < 0.01). The contents of PGE(2) in gingiva (5.21 ng/g) of HBO group were 62.7% which was lower than that of periodontitis group, and the value of PGE(2) in alveolar bone (4.05 ng/g) were 69.6% lower than that of periodontitis group. The difference of PGE(2) in gingiva or alveolar bone was significant for the HBO group and periodontitis group (P < 0.01). CONCLUSIONS: The contents of PGE(2) in alveolar bone and gingiva increased markedly when experimental periodontitis has formed. The value of PGE(2) in alveolar bone and gingiva reduce markedly after HBO exposure, and the decreased rate of PGE(2) in alveolar bone is more evident than that of PGE(2) in gingiva after HBO therapy.

[Effects of fast decompression on prostaglandins content in cerebral tissue of guinea pigs].

Objective. To investigate the effect of fast decompression on prostaglandins in cerebral tissue. Method. 26 guinea pigs were divided into 2 groups randomly. The animals in group FDC (group 1) were treated with fast decompression and formed decompression sickness, but those in control group (group 2) were not treated with decompression. The contents of prostaglandin E2 (PGE2), 6-keto-prostaglandin F1a (6-K-PGF1a) and thromboxane B2 (TXB2) in cerebral tissue of the animals were determined by enzyme immunoassay. Result. The content of PGE2 in cerebral tissue of FDC animals was twice as much as that in control animals. The content of TXB2 in cerebral tissue of FDC animals was 3 times as high as that in control animals, and that of 6-K-PGF1a in cerebral tissue of FDC animals was 2.6 times as that in control animals. It showed very significant differences as compared with control group (P<0.01). Conclusion. The content of PGs in cerebral tissue increased markedly after fast decompression, and may cause cerebral injury.