Pathophysiological characteristics and therapeutic approaches for pulmonary injury and cardiovascular complications of coronavirus disease 2019.

The pandemic of coronavirus disease 2019 (COVID-19) has emerged as a major health crisis, with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) having infected over a million people around the world within a few months of its identification as a human pathogen. Initially, SARS-CoV-2 infects cells in the respiratory system and causes inflammation and cell death. Subsequently, the virus spreads out and damages other vital organs and tissues, triggering a complicated spectrum of pathophysiological changes and symptoms, including cardiovascular complications. Acting as the receptor for SARS-CoV entering mammalian cells, angiotensin converting enzyme-2 (ACE2) plays a pivotal role in the regulation of cardiovascular cell function. Diverse clinical manifestations and laboratory abnormalities occur in patients with cardiovascular injury in COVID-19, characterizing the development of this complication, as well as providing clues to diagnosis and treatment. This review provides a summary of the rapidly appearing laboratory and clinical evidence for the pathophysiology and therapeutic approaches to COVID-19 pulmonary and cardiovascular complications.

Improvement of Sepsis Prognosis by Ulinastatin: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Ulinastatin has been prescribed to treat sepsis. However, there is doubt regarding the extent of any improvement in outcomes to guide future decision making. Objectives: To evaluate the effects of ulinastatin on mortality and related outcomes in sepsis patients. Methods: Thirteen randomized controlled trials and two prospective studies published before September 1, 2018, that included 1358 patients with sepsis, severe sepsis, or septic shock were evaluated. The electronic databases searched in this study were PubMed, Medline, Embase, and China National Knowledge Infrastructure (CNKI) for Chinese Technical Periodicals. Results: Ulinastatin significantly decreased the all-cause mortality {odds ratio (OR) = 0.48, 95% confidence interval (CI) [0.35-0.66], p < 0.00001, I2 = 13%}, Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score {mean difference (MD) = -2.40, 95% CI [-4.37, -0.44], p = 0.02, I2 = 66%}, and reduced the incidence of multiple organ dysfunction syndrome (MODS) (OR = 0.3, 95% CI [0.18, 0.49], p < 0.00001, I2 = 0%). Ulinastatin also decreased the serum levels of IL-6 (MD = -88.5, 95% CI [-123.97, -53.04], p < 0.00001), TNF-α (MD = -56.22, 95% CI [-72.11, -40.33], p < 0.00001), and increased the serum levels of IL-10 (MD = 37.73, 95% CI [16.92, 58.54], p = 0.0004). Ulinastatin administration did not lead to any difference in the occurrence of adverse events. Conclusions: Ulinastatin improved all-cause mortality and other related outcomes in patients with sepsis or septic shock. The results of this meta-analysis suggest that ulinastatin may be an effective treatment for sepsis and septic shock.

Corrigendum: Improvement of Sepsis Prognosis by Ulinastatin: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

[This corrects the article DOI: 10.3389/fphar.2019.01370.].

Hemodynamic changes with manual and automated lateral turning in patients receiving mechanical ventilation.

BACKGROUND: Lateral turning of critical care patients receiving mechanical ventilation can adversely affect hemodynamic status. OBJECTIVE: To study hemodynamic responses to lateral turning. METHOD: A time-series design with automated signal processing and ensemble averaging was used to evaluate changes in heart rate, mean arterial pressure, and pulse pressure due to lateral turning in 13 adult medical-surgical critical care patients receiving mechanical ventilation. Patients were randomly assigned to the manual-turn or the automated-turn protocol for up to 7 consecutive days. Heart rate and arterial pressure were measured every 6 seconds for more than 24 hours, and pulse pressure was computed. RESULTS: A total of 6 manual-turn patients and 7 automated-turn patients completed the study. Statistically significant changes in heart rate, mean arterial pressure, and pulse pressure occurred with the manual turn. Return of the hemodynamic variables to baseline values required up to 45 minutes in the manual-turn patients (expected recovery time ≤ 5 minutes). However, clinically important changes dissipated within 15 minutes of the lateral turn. The steady-state heart rate response on the right side was slightly greater (3 beats per minute) than that on the back (P = .003). Automated turning resulted in no clinically important changes in any of the 3 variables. CONCLUSIONS: In medical-surgical critical care patients receiving mechanical ventilation, manual lateral turning was associated with changes in heart rate, mean arterial pressure, and pulse pressure that persisted up to 45 minutes.

Amniotic cells protect and repair mouse brain cells following ischemia-reperfusion injury / 中国组织工程研究

BACKGROUND:Amniotic cells are mainly composed of amniotic epithelial cells and amniotic mesenchymal cells, which have multi-differentiation potential and can be transformed into neurons as wel as synthesize and release biological y active substances and neurotrophic factors. In preliminary studies, amniotic cells that are transplanted into the brain can significantly promote the regeneration of brain neurons. OBJECTIVE:To explore the role of amniotic cells in mouse brain cells after ischemia-reperfusion injury. METHODS:The model of cerebral ischemia-reperfusion injury was established in Babl/c mice using occlusion of bilateral common carotid arteries, and then brain cells were separated from mice. Amniotic cells were isolated from mouse placenta. Brain cells from Balb/C mice co-cultured with amniotic cells served as experimental group, and brain cells cultured with PBS as control group. RESULTS AND CONCLUSION:The viability of brain cells in the experimental group was significantly higher than that in the control group (P0.05);after 48 hours co-culture, however, the necrotic rate of brain cells was significantly lower in the experimental group than the control group (P<0.05). In cellcycle, the experiment group showed increased S phase cells;while, the control group exhibited increased G 1 phase cells and decreased S phase cells. G 2 phase cells had no changes in number in both two groups. Through the above results, amnion cells can be proved to protect and promote the regeneration of brain cells of Balb/C mice with ischemia-reperfusion injury, and inhibit cellnecrosis and apoptosis.

A phase 2 randomized, double-blind, placebo-controlled study of the safety and efficacy of talactoferrin in patients with severe sepsis.

OBJECTIVES: Lactoferrin is a glycoprotein with anti-infective and anti-inflammatory properties found in secretions and immune cells. Talactoferrin alfa, a recombinant form of human lactoferrin, has similar properties and plays an important role in maintaining the gastrointestinal mucosal barrier integrity. In experimental animal models, administration of talactoferrin reduces translocation of bacteria from the gut into the systemic circulation and mortality from sepsis. Our objective was to determine if talactoferrin could reduce 28-day all-cause mortality in patients with severe sepsis and to assess its safety. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multicenter phase 2 trial. SETTING: Adult ICUs and emergency departments in the United States. PATIENTS: One hundred ninety-four adults within 24 hrs of the onset of severe sepsis. INTERVENTIONS: Enterally administered talactoferrin 1.5g or placebo every 8 hrs for up to 28 days or until discharge from the ICU. MEASUREMENTS AND MAIN RESULTS: Modified intention-to-treat analysis was used to assess the primary (28-day all-cause mortality) and secondary endpoints. The all-cause mortality at 28 days was 26.9% in the placebo group and 14.4% in the talactoferrin group (two-sided p = 0.052), representing a 12.5% absolute and a 46.5% relative reduction in mortality, meeting the protocol-specified primary endpoint. Reduction in all cause mortality was sustained at 6 months (p = 0.039). These reductions in mortality were observed across a wide spectrum of subgroups. The drug was well tolerated with a safety profile similar to that of placebo. CONCLUSIONS: Enteral administration of talactoferrin reduced 28-day all-cause mortality in patients with severe sepsis. This reduction in mortality was sustained at 6 months. Talactoferrin was very well tolerated.

Acute lung inflammatory response and injury after hemorrhagic shock are more severe in postpartum rabbits.

OBJECTIVE: The acute respiratory distress syndrome may complicate postpartum hemorrhagic shock and resuscitation, but its mechanisms are not yet well defined. We studied the lung inflammatory response to postpartum hemorrhagic shock and resuscitation in a rabbit model and the role of the nuclear factor-κB pathway. DESIGN: Randomized, controlled, prospective study. SETTING: University hospital laboratory. SUBJECTS: Nonobstetric (not pregnant nor postpartum) and obstetrical (within 2 hrs postpartum) rabbits. INTERVENTIONS: Nonobstetric and obstetric female New Zealand white rabbits underwent fixed-pressure or fixed-volume hemorrhagic shock for 30 mins and then were rapidly resuscitated with the shed blood and Ringer's solution. Finally, they were either monitored for survival time or euthanized by exsanguination for lung tissue examination 24 hrs after hemorrhage. MEASUREMENTS AND MAIN RESULTS: After hemorrhagic shock and resuscitation, median survival time in obstetric rabbits (3 days) was significantly shorter (p<.05) than that in nonobstetric rabbits (5 days). Compared with nonobstetric rabbits, obstetric rabbits had more severe lung injury as indicated by alveolar and interstitial fluid accumulation and marked neutrophil sequestration and greater lung injury score, myeloperoxidase activity, expression of intercellular adhesion molecule-1, serum tumor necrosis factor-α levels, and nuclear factor-κB activation, and lower serum interleukin-10 levels (p<.05 for all). CONCLUSIONS: After hemorrhage and resuscitation, obstetric rabbits had significantly shorter survival time and more severe lung injury than nonobstetric rabbits. The mechanism may be through upregulation of the signal transductions of the nuclear factor-κB pathways.

Increased survival with hypotensive resuscitation in a rabbit model of uncontrolled hemorrhagic shock in pregnancy.

AIM: We sought to compare the effects of conservative hypotensive and aggressive normotensive resuscitation strategies on blood loss, fluid requirements, blood lactate and survival rate in a clinically relevant model of uncontrolled hemorrhagic shock in pregnancy. METHOD: 60 anesthetized New Zealand white rabbits at late gestation underwent uncontrolled hemorrhagic shock by transecting a small artery in the mesometrium, followed by blood withdrawal via the carotid artery, to a mean arterial pressure (MAP) of 40-45mmHg. They were randomly divided into six groups (n=10 per group): sham shock (group SS); shock without resuscitation (group SH); hypotensive resuscitation in the simulated prehospital phase with Ringer's solution to MAP of 50, 60, or 70mmHg, respectively (groups RE50, RE60, RE70); and aggressive resuscitation in the prehospital phase with Ringer's solution to MAP of 80mmHg (group RE80). Finally, in the simulated hospital phase, animals in the resuscitated groups underwent surgical control of bleeding and were fully resuscitated with half of the heparinized shed blood and Ringer's solution to MAP of 80mmHg. RESULTS: Hypotensive resuscitation significantly decreased blood loss and subsequent volume infusion, leading to higher hematocrit, lower lactate concentration, and shorter prothrombin time and activated partial thromboplastin time. Median survival time in group RE60 (4.3+/-0.6 days) was significantly longer than that in groups RE50 (2.7+/-0.4 days), RE70 (2.3+/-0.3 days), and RE80 (1.7+/-0.3 days) (P<0.05). CONCLUSIONS: We conclude that in this rabbit model of uncontrolled hemorrhage in pregnancy, hypotensive resuscitation to MAP of 60mmHg may be an optimal target MAP before hemorrhage can be controlled by surgical intervention.

Administration of the nitric oxide synthase inhibitor NG-methyl-L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002).

OBJECTIVE: To assess the safety and efficacy of the nitric oxide synthase inhibitor 546C88 in patients with septic shock. The predefined primary efficacy objective was resolution of shock, defined as a mean arterial pressure > or =70 mm Hg in the absence of both conventional vasopressors and study drug, determined at the end of the 72-hr treatment period. DESIGN: Multicentered, randomized, placebo-controlled, safety and efficacy study. SETTING: Forty-eight intensive care units in Europe, North America, and Australia. PATIENTS: A total of 312 patients with septic shock diagnosed within 24 hr before randomization. INTERVENTIONS: Patients were randomly allocated to receive either 546C88 or placebo (5% dextrose) by intravenous infusion for up to 72 hrs. Conventional vasoactive therapy was restricted to norepinephrine, dopamine, and dobutamine. Study drug was initiated at 0.1 mL/kg/hr (5 mg/kg/hr 546C88) and titrated according to response up to a maximum rate of 0.4 mL/kg/hr with the objective to maintain mean arterial pressure at 70 mm Hg while attempting to withdraw any concurrent vasopressor(s). MEASUREMENTS AND MAIN RESULTS: Requirement for vasopressors, systemic hemodynamics, indices of organ function and safety (including survival up to day 28) were assessed. The median mean arterial pressure for both groups was maintained >70 mm Hg. Administration of 546C88 was associated with a decrease in cardiac index while stroke index was maintained. Resolution of shock at 72 hr was achieved by 40% and 24% of the patients in the 546C88 and placebo cohorts, respectively (p =.004). There was no evidence that treatment with 546C88 had any major adverse effect on pulmonary, hepatic, or renal function. Day 28 survival was similar for both groups. CONCLUSIONS: In this study, treatment with the nitric oxide synthase inhibitor 546C88 promoted the resolution of shock in patients with severe sepsis. This was associated with an acceptable overall safety profile.

Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis.

OBJECTIVE: To determine the safety and efficacy of filgrastim (r-metHuG-CSF) in combination with intravenous antibiotics to reduce the rate of mortality in patients with pneumonia and sepsis. DESIGN: This study was multicenter, double-blind, and randomized. SETTING: Intensive care units PATIENTS Adult patients with bacterial pneumonia, either acquired or nosocomial, as confirmed by chest radiograph and positive culture or Gram-negative stain, and severe sepsis, defined as sepsis-induced hypotension or organ dysfunction. INTERVENTIONS: Standard antibiotic therapy with or without filgrastim (300 microg/day) or placebo administered as a 30-min intravenous infusion. The study drug was started within 24 hrs of enrollment and was continued for 5 days or until the white blood cell count reached >75.0 x 10(9) cells/L. MEASUREMENTS AND MAIN RESULTS: The primary end point was the occurrence of mortality through day 29; secondary end points included occurrence of subsequent organ dysfunction, time to discharge from intensive care unit, number of days on mechanical ventilatory support, and time to death. Study-related observations were recorded through day 10 and included vital signs, onset of organ dysfunction, clinical laboratory variables, and adverse events. Filgrastim increased the white blood cell count to a median peak of 31.7 x 10(9) cells/L from a baseline of 12.3 x 10(9) cells/L. The two groups were well matched and did not differ significantly with regard to severe adverse events, time to death, occurrence of end-organ dysfunction, days of intensive care unit hospitalization, or days on mechanical ventilatory support. Mortality was low in both treatment groups; the mortality rate in patients with adult respiratory distress syndrome was similar between the two groups. CONCLUSIONS: The addition of filgrastim to the antibiotic and supportive care treatment of patients with pneumonia complicated by severe sepsis appeared to be safe, but not efficacious in reducing mortality rates or complications from this infection.