Severe Thrombocytopenia Caused by Vancomycin in the Intensive Care Unit: A Case Report.

Thrombocytopenia can cause substantial morbidity and mortality in critically ill patients. There are multiple etiology factors and various mechanisms associated with thrombocytopenia, of which drug-induced thrombocytopenia (DITP) deserves attention. Herein, we describe a case of severe thrombocytopenia during intensive care unit (ICU) hospitalization that was likely to be associated with vancomycin. By revealing the process of identifying this case of DITP and reviewing relevant clinical studies, a risk alert of vancomycin-related severe hematotoxicity should be considered.

Impact of Shenfu injection on a composite of organ dysfunction development in critically ill patients with coronavirus disease 2019 (COVID-19): A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: This study aims to determine the protection provided by Shenfu injection (a traditional Chinese medicine) against development of organ dysfunction in critically ill patients with coronavirus disease 2019 (COVID-19). TRIAL DESIGN: This study is a multicenter, randomized, controlled, open-label, two-arm ratio 1:1, parallel group clinical trial. PARTICIPANTS: The patients, who are aged from 18 to 75 years old, with a confirmed or suspected diagnosis of severe or critical COVID-19, will be consecutively recruited in the study, according to the guideline on diagnosis and treatment of COVID-19 (the 7th version) issued by National Health Commission of the People's Republic of China. Exclusion criteria include pregnant and breastfeeding women, atopy or allergies to Shenfu Injection (SFI), severe underlying disease (malignant tumor with multiple metastases, uncontrolled hemopathy, cachexia, severe malnutrition, HIV), active bleeding, obstructive pneumonia caused by lung tumor, severe pulmonary interstitial fibrosis, alveolar proteinosis and allergic alveolitis, continuous use of immunosuppressive drugs in last 6 months, organ transplantation, expected death within 48 hours, the patients considered unsuitable for this study by researchers. The study is conducted in 11 ICUs of designated hospitals for COVID-19, located in 5 cities of China. INTERVENTION AND COMPARATOR: The enrolled patients will randomly receive 100 ml SFI (study group) or identical volume of saline (control group) twice a day for seven consecutive days. Patients in the both groups will be given usual care and the necessary supportive therapies as recommended by the latest edition of the management guidelines for COVID-19 (the 7th version so far). MAIN OUTCOMES: The primary endpoint is a composite of newly developed or exacerbated organ dysfunction. This is defined as an increase in the sequential organ failure assessment (SOFA) score of two or more, indicating sepsis and involvement of at least one organ. The SOFA score will be measured for the 14 days after enrolment from the baseline (the score at randomization). The secondary endpoints are shown below: • SOFA score in total • Pneumonia severity index score • Dosage of vasoactive drugs • Ventilation free days within 28 days • Length of stay in intensive care unit • Total hospital costs to treat the patient • 28-day mortality • The incidence of adverse drug events related to SFI RANDOMISATION: The block randomization codes were generated by SAS V.9.1 for allocation of participants in this study. The ratio of random distribution is 1:1. The sealed envelope method is used for allocation concealment. BLINDING (MASKING): The patients and statistical personnel analyzing study data are both blinded. The blinding of group assignment is not adopted for the medical staff. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study is expected to recruit 300 patients with COVID-19, (150 in each group). TRIAL STATUS: Protocol version 2.0, February 15, 2020. Patient recruitment started on February 25, and will end on August 31, 2020. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000030043. Registered February 21, 2020, http://www.chictr.org.cn/showprojen.aspx?proj=49866 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Predictive model for acute respiratory distress syndrome events in ICU patients in China using machine learning algorithms: a secondary analysis of a cohort study.

BACKGROUND: To develop a machine learning model for predicting acute respiratory distress syndrome (ARDS) events through commonly available parameters, including baseline characteristics and clinical and laboratory parameters. METHODS: A secondary analysis of a multi-centre prospective observational cohort study from five hospitals in Beijing, China, was conducted from January 1, 2011, to August 31, 2014. A total of 296 patients at risk for developing ARDS admitted to medical intensive care units (ICUs) were included. We applied a random forest approach to identify the best set of predictors out of 42 variables measured on day 1 of admission. RESULTS: All patients were randomly divided into training (80%) and testing (20%) sets. Additionally, these patients were followed daily and assessed according to the Berlin definition. The model obtained an average area under the receiver operating characteristic (ROC) curve (AUC) of 0.82 and yielded a predictive accuracy of 83%. For the first time, four new biomarkers were included in the model: decreased minimum haematocrit, glucose, and sodium and increased minimum white blood cell (WBC) count. CONCLUSIONS: This newly established machine learning-based model shows good predictive ability in Chinese patients with ARDS. External validation studies are necessary to confirm the generalisability of our approach across populations and treatment practices.

CYP3A4 * 1G Genetic Polymorphism Influences Metabolism of Fentanyl in Human Liver Microsomes in Chinese Patients.

PURPOSE: This study aimed to investigate whether CYP3A4*1G genetic polymorphism influences the metabolism of fentanyl in human liver microsomes in Chinese patients. METHODS: The human liver microsomes were obtained from 88 hepatobiliary surgery patients who accepted liver resection surgery in this study. A normal liver sample (confirmed by the Department of Pathology) was taken from the outer edge of the resected tissue. The metabolism of fentanyl in human liver microsomes was studied. The concentration of fentanyl was measured by high performance liquid chromatography. The CYP3A4*1G variant allele was genotyped using the PCR restriction fragment length polymorphism method. RESULTS: The frequency of the CYP3A4*1G variant allele was 0.188 in the 88 Chinese patients who had received hepatobiliary surgery. The metabolic rate of fentanyl in patients homozygous for the *1G/*1G variant (0.85 ± 0.37) was significantly lower than that in patients bearing the wild-type allele *1/*1 (1.89 ± 0.58) or in patients heterozygous for the *1/*1G variant (1.82 ± 0.65; p < 0.05). There were no gender-related differences in the metabolic rate of fentanyl (p > 0.05) nor was there any correlation between age and metabolic rate of fentanyl (p > 0.05). Results from different hepatobiliary diseases showed no significant difference in the metabolic rate of fentanyl (p > 0.05). The difference of CYP3A4 mRNA among different CYP3A4*1G variant alleles was significant (p < 0.05). There was positive correlation between CYP3A4 mRNA and metabolic rate of fentanyl (p < 0.01). CONCLUSIONS: CYP3A4*1G genetic polymorphism decreases the metabolism of fentanyl. There is a positive correlation between CYP3A4 mRNA level and metabolism of fentanyl.

Inhaled unfractionated heparin improves abnormalities of alveolar coagulation, fibrinolysis and inflammation in endotoxemia-induced lung injury rats.

BACKGROUND: Acute lung injury/acute respiratory distress syndrome presents with not only local inflammation, but also pulmonary coagulopathy which is characterized by an alveolar procoagulant response, anticoagulant inhibition, fibrinolytic supression and fibrin deposition. We thus had hypothesized that if aerosolized unfractionated heparin was inhaled into alveolar spaces, it could block the procoagulant tendency, lessen depletion of coagulation factors, and even influence the inflammatory response. We also assessed the effects of different administration regimens of heparin. METHODS: Male Wistar rats were given inhaled heparin starting 30 minutes before (prophylactic heparin) or 2 hours after (therapeutic heparin) intravenous lipopolysaccharide (LPS) was administered at 6-hour intervals; control groups received inhaled normal saline with or without being exposed to LPS. Thrombin-antithrombin complexes, activated protein C, tissue type and urokinase type plasminogen activators (t-PA/u-PA), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-α, interleukin-6 in bronchoalveolar lavage, and lung tissue myeloperoxidase activity, and histology score were measured at three time-points. PAI-1/(t-PA + u-PA) was calculated based on the before-mentioned parameters. Statistical analysis was made using one-way analysis of variance (ANOVA) with post hoc test or Student's t test in the case of heterogeneity of variance. RESULTS: An alveolar procoagulant reaction, depressed fibrinolysis, and inflammatory response occurred in endotoxemia-induced lung injury. Local prophylactic application of heparin attenuated coagulation and early inflammation, promoted fibrinolysis, and reduced the histology score. Therapeutic application of heparin had similar, but weaker effects. CONCLUSIONS: Intrapulmonary application of unfractionated heparin by inhalation might inhibit alveolar procoagulant reaction and the early inflammatory response, promote fibrinolysis, and alleviate pulmonary pathology in endotoxemia-induced lung injury rats. Administration of heparin before LPS challenge was more efficacious.

[The effects of three dosages of nebulized unfractionated heparin on alveolar coagulation and tissue inflammation injury in endotoxin-induced acute lung injury rat model].

OBJECTIVE: To observe the effects of three dosages of nebulized unfractionated heparin (UFH) on alveolar coagulation, inflammation and lung histology in endotoxin-induced acute lung injury rat model, and investigate the appropriated dose of local UFH in managing intrapulmonary coagulopathy. METHODS: Twenty-nine male Wistar rats were divided into control (n=5) and UFH group (n=24) in table of random number, which were duplicated to be endotoxin-induced ALI rat model with lipopolysaccharide (LPS) injecting by intravenous route. The UFH group was divided into three subgroups, which were administered once with 6, 12 and 18 U/g aerosolized UFH in 10 ml at 2 hours after challenge, respectively, while the control group was simply nebulized with normal saline. All rats were sacrificed at 6 hours after intravenous administration of LPS, bronchoalveolar lavage was performed, and the fluid was collected. Enzyme-linked immune sorbent assay (ELISA) was used to measure the level of thrombin-antithrombin complex (TATc), tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid (BALF), and lung wet/dry (W/D) weight ratio, histology score were recorded. RESULTS: At 6 hours after LPS-induced lung injury, the levels of TATc and TNF-α, lung W/D weight ratio and histology score in 6 U/g and 12 U/g group were all lower than those of control group significantly (TATc: 0.959±0.681 µg/L, 1.165±0.854 µg/L vs. 2.141±0.791 µg/L, TNF-α: 4.449±5.054 ng/L, 9.096±4.099 ng/L vs. 18.184±3.869 ng/L, W/D weight ratio: 7.018±1.137, 7.367±0.349 vs. 8.472±0.614, histology score: 16.0±1.0, 16.5±1.5 vs. 19.6±0.4, P<0.05 or P<0.01). There was no significant difference in the comparisons between the subgroups of UFH in TATc level in BALF and lung histology score. For the TNF-αlevel in BALF, 18 U/g group evidently exceeded that of 6 U/g group (15.503±8.753 ng/L vs. 4.449±5.054 ng/L, P<0.01), and lung W/D weight ratio in 18 U/g group was also significantly higher comparing to 6 U/g (8.850±1.157 vs. 7.018±1.137, P<0.05) and 12 U/g group (8.850±1.157 vs. 7.367±0.349, P<0.05). CONCLUSION: It was appropriate for the dose of nebulized UFH to be administered no more than 12 U/g in ALI treatment, which was enough to inhibit alveolar coagulant cascade, decrease early inflammatory response and alleviate lung tissue injury.

[Effect of inhalation of aerosolized unfractioned heparin on peri alveolar coagulability and inflammatory response in endotoxin induced acute lung injury rat model].

OBJECTIVE: To observe the local changes in alveoli in intravenous endotoxin induced acute lung injury (ALI) rat model after inhalation of aerosolized unfractioned heparin (UFH), and to observe its effects on coagulability, fibrinolysis and inflammatory response. METHODS: Eighty seven male Wistar rats were divided into groups according to table of random number: sham, model, heparin therapy (HT) and heparin prophylaxis (HP). Endotoxin induced ALI model was reproduced by intravenous administration of lipopolysaccharide (LPS). Rats in HP and HT groups received aerosolized UFH before and after injection with LPS respectively, while rats in both sham and model groups inhaled aerosolized normal saline. Rats in each group were respectively sacrificed at 6, 12 and 24 hours after intravenous administration of LPS, and bronchoalveolar lavage fluid (BALF) was collected. Enzyme linked immunosorbent assay was used to measure the level of thrombin antithrombin (TAT), tissue type plasminogen activator (t-PA), urokinase type plasminogen activator (u-PA), plasminogen activator inhibitor 1 (PAI-1), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) in BALF. RESULTS: At 6 hours after injury, the level of TAT (µg/L) in model group (3.346±0.585) was highest, that in HT group (2.764±0.100) was higher, and that in HP group (2.564±0.216) was lowest in BALF (all P<0.05). The t-PA (µg/L) concentration in HP group (3.037±0.524) was highest, that in HT group (2.494±0.191) was higher, and that in model group (1.716±0.125) was lowest (all P<0.05). Compared with model group, u-PA (µg/L) level in HP group dramatically enhanced (0.411±0.118 vs. 0.303±0.049, P<0.05). The concentration of PAI-1 (µg/L) in HP group was significantly lower than that of HT and model groups (2.296±0.246 vs. 2.597±0.425, 2.834±0.198, both P<0.05). In HP group, it was still lower than that in HT group at 12 hours (1.273±0.441 vs. 1.817±0.252, P<0.05). TNF-α (ng/L) levels in HT and HP groups were markedly lower compared with model group (68.154±3.915, 36.990±6.539 vs. 77.001±4.485) at 6 hours, and the level in HP group was lower than that in HT group (all P<0.05). TNF-α concentration in HP group was still the lowest at 12 hours (15.287±4.754), and there was significant difference compared with HT and model groups (26.756±5.336, 23.674±4.398, both P<0.05). The levels of IL-6 were not distinctively different among model, HT and HP groups at various time points. CONCLUSION: It was proved that inhalation of aerosolized UFH resulted in lowering local coagulability, alleviating fibrinolytic depression, improving fibrinolysis , and attenuating inflammation in endotoxin induced ALI rat model. More prominent results will be obtained when it was use as a prophylactic measure. The optimal time of usage is 6 hours after endotoxin injection.

[A study on the effect of recruitment maneuver imposed on extravascular lung water in patients with acute respiratory distress syndrome].

OBJECTIVE: To investigate the possible effects of recruitment maneuver (RM) imposing on extravascular lung water (EVLW) in patients with acute respiratory distress syndrome (ARDS). METHODS: Twenty patients with ARDS who were eligible for the study were randomized to two groups, one group of which received regular therapy+RM (RM group), and to the other group only regular therapy was given (control group). Mechanical ventilation of all the patients was performed on the principles of lung protective ventilation. RM was carried out in bi-level positive airway passage (BIPAP) mode, and repeated every 8 hours per day until on the 7th day or before weaning of mechanical ventilation. The treatment was same between the two groups except RM. Baseline data and the influencing factors of EVLW were all recorded, which included everyday EVLW, extravascular lung water index (EVLWI) after RM, respiratory mechanics, oxygenation parameters, central venous pressure (CVP), plasma colloid osmotic pressure (COP), dosage of corticosteroid and adrenergic drugs, 24-hour net fluid balance. RESULTS: EVLW and EVLWI in RM and control group showed a tendency of decrease with passage of time, but the difference between both groups had no statistical significance (all P>0.05). The comparisons between the influencing factors of the groups, consisting of CVP, COP, noradrenaline and hydrocortisone, had no significant difference either (all P>0.05). Dopamine dosage in RM group on the 4th day was smaller than that of control group (P<0.05). Net fluid balance in RM group on the 7th day was negative, whereas it was positive in control group (P<0.05). Mean airway pressure [Pmean, RM group (18.8+/-3.2) cm H(2)O (1 cm H(2)O=0.098 kPa) vs. control group (16.6+/-3.9) cm H(2)O] and lung quasi-static compliance [Cstat, RM group (36.5+/-14.5) ml/cm H(2)O vs. control group (29.3+/-12.0) ml/cm H(2)O] in RM group were higher than those in control group (both P<0.05). Cstat on the 5th day was higher than that on the 2nd and 3rd day in RM group (both P<0.05). But oxygenation index (PaO(2)/FiO(2)) showed no distinct difference between the groups (all P>0.05). CONCLUSION: RM for the patients with ARDS can merely improve lung mechanics without obvious effect on EVLW. Neither of the influencing factors involved in the study has impact on emergence and clearance of EVLW.

[Effects of transection of cervical spinal cord on lipopolysaccharide induced acute lung injury in rat].

OBJECTIVE: To investigate the effects of transection of cervical spinal cord (TCSC) on acute lung injury (ALI) and its potential mechanism in rat. METHODS: Seventy-two rats were randomly divided into three groups: normal control group (NC, n=8), endotoxemia group (ET, n=32) and endotoxemia with TCSC group (TCSC, n=32), and the latter two groups were divided into four subgroups respectively according to different time intervals (n=8). Endotoxemia model was established by injecting lipopolysaccharide (LPS, 10 mg/kg) intravenously, and the spinal cord at 7th cervical spine of rats was transected in TCSC group. Samples of blood and lung were collected at different time intervals. The plasma levels of norepinephrine (NE) and interleukin-6 (IL-6) were measured by high performance liquid chromatography (HPLC) and enzyme-lined immunosorbent assay (ELISA) respectively, and arterial blood oxygen pressure (PaO2) was determined by blood-gas analyser. The changes in histopathology and lung wet/dry weight (W/D) ratio were also observed in every group. RESULTS: The changes in the levels of NE and lung W/D ratio of the TCSC group was significantly decreased than those of ET group, but PaO2 of TCSC group was increased obviously than that of ET group (all P<0.05), and the degree of lung injury was less intensive in the TCSC group. At all the time points, the level of IL-6 of TCSC group was lower compared with ET group (all P<0.05). The results of correlation analysis suggested that there was a positive correlation between plasma NE and IL-6 concentration (r=0.458, P<0.05), a negative correlation between NE and PaO2 (r= -0.528, P<0.05). CONCLUSION: Sympathectomy as a result of TCSC at 7th cervical spine may palliate the degree of ALI and improve oxygenation in rats with endotoxemia by inhibiting excessive activation of adrenoceptor.

[Effects of cervical chordotomy on systemic inflammatory response and the outcome in rats with endotoxic shock induced by lipopolysaccharide].

OBJECTIVE: To investigate the effects of cervical chordotomy on systemic inflammatory response and the outcome in rats with endotoxemia induced by lipopolysaccharide (LPS). METHODS: Ninety-two Sprague Dawley (SD) rats were randomly divided into three groups: normal control group (group I, n=8) , endotoxemia group (group II, n=42) and endotoxemia with cervical chordotomy (group III, n=42). Endotoxemia was induced by intra-peritoneal injection of LPS 10 mg/kg. In group III, "cervical chordotomy" was attained by transection of spinal cord at C7 immediately before intra-peritoneal LPS administration. Ten rats of group II and III each were observed for 48-hour survival. The other rats were further divided into four subgroups of 8 animals each, according to the time when the animals were sacrificed . The animals were sacrificed at 3, 6, 12, and 48 hours after intra-peritoneal LPS injection. Heart blood samples were obtained for determination of plasma concentration of norepinephrine [NE, by high performance liquid chromatography (HPLC)] and plasma concentration of interleukin-10 (IL-10) and IL-6 [by enzyme linked immunosorbent assay (ELISA)]. RESULTS: Plasma NE concentration were significantly increased after intra-peritoneal LPS injection in group II and III as compared with group I and were significantly lower in group III than in group II starting from 6 hours after LPS (all P<0.05). Plasma IL-10 concentration was significantly lower at 3 hours and 6 hours while plasma IL-6 concentration was significantly higher after LPS challenge in group II than in group I at all time points (all P<0.05). High transection of spinal cord significantly elevated plasma IL-10 level at 12 hours and 48 hours, lowered IL-6 release at 3, 6, and 12 hours (all P<0.05), and improved 48-hour survival (20% vs. 70%) in group III as compared with group II. CONCLUSION: Transection of spinal cord at C7 level can ameliorate the systemic inflammatory response induced by endotoxemia thus improving the outcome through elevation in IL-10 level, decreases in IL-6 release, and improves 48-hour survival. This might be attributable to loss of sympathetic nerve function.

ent-Kaurene diterpenoids from Isodon oresbius.

Three new ent-kaurene diterpenoids, oreskaurins A-C (1-3), together with ten known ent-kaurene diterpenoids, enmenin monoacetate (4), effusanin E (5), adenolin B (6), maoecrystal G (7), enmelol (8), trichokaurin (9), sodoponin (10), trichorabdal A (11), nodosin (12), enmein (13), and a flavonoid, vitexin (14), were isolated from Isodon oresbius. Their structures were determined by spectroscopic means. Compound 12 showed inhibitory activity toward K562 cells with IC(50)=1.43 microg/ml.

Cytotoxic ent-kauranoids from Isodon leucophyllus.

Two new compounds, baiyecrystals D and E (1, 2), together with eight known analogues, xerophilusin B (4), macrocalin B (5), oridonin (6), rosthorin A (7), lasiocarpanin (8), rabdoternin A (9) and phyllostachysin A (10) and B (11), were isolated from the aerial parts of Isodon leucophyllus. The structures of 1 and 2 and 4-11 were elucidated on the basis of spectroscopic methods, especially the 2D NMR spectral analysis. Compounds 2, 6-8 and 10 were evaluated for their antineoplastic activities in vitro. Among them, lasiocarpanin (8) showed significant inhibitory activities against K562 and Bcap37 cells, with the IC50 values of 0.13 and 1.26 microg mL(-1), respectively, which were lower than those of the positive control.