Pharmacokinetics and safety of EVER206, a novel polymyxin antimicrobial, in healthy Chinese subjects.

EVER206 (also known as SPR206) is a novel polymyxin analog that has shown in vitro potency and in vivo efficacy against multidrug-resistant (MDR) Gram-negative pathogens. This randomized, double-blinded, placebo-controlled, Phase I study evaluated the safety, tolerability, and pharmacokinetics of EVER206 in healthy Chinese subjects. After single administration of 50-300 mg EVER206, the Cmax ranged from 3.94 to 25.82 mg/L, and the AUC0-inf ranged from 12.42 to 101.67 h·mg/L. The plasma exposure displayed a linear relationship with the dose administered. After administration of 75 and 100 mg of EVER206 every 8 hours (q8 hour), a steady state was achieved on Day 2. The accumulation ratios of Cmax and AUC from Day 1 to Day 7 were in the range of 1.12 to 1.3. The elimination half-lives ranged from 2.86 to 4.32 hours in the single-ascending-dose (SAD) study and 4.71 to 6.18 hours in the multiple-ascending-dose (MAD) study. The urinary excretion of unchanged EVER206 increased with the dose, with the mean cumulative fraction ranging from 23.70% to 47.10%. EVER206 was safe and well-tolerated in Chinese healthy subjects. No severe treatment emerging adverse events (TEAEs), serious adverse events, or TEAEs leading to discontinuation were reported. The results of the present study demonstrated a similar safety profile of EVER206 with data reported in an earlier study on SPR206-101. The exposure of EVER206 in Chinese healthy subjects was higher than that in Australian healthy subjects. These results could enable further clinical development of EVER206 in Chinese patients with severe MDR Gram-negative pathogen infections.CLINICAL TRIALSThis study was registered at the Chinese Clinical Trial Registry under identifier ChiCTR2200056692.

Acyltransferase AniI, a Tailoring Enzyme with Broad Substrate Tolerance for High-Level Production of Anisomycin.

Anisomycin (compound 1), a pyrrolidine antibiotic, exhibits diverse biological and pharmacologic activities. The biosynthetic gene cluster of compound 1 has been identified previously, and the multistep assembly of the core benzylpyrrolidine scaffold was characterized. However, enzymatic modifications, such as acylation, involved in compound 1 biosynthesis are unknown. In this study, the genetic manipulation of aniI proved that it encoded an indispensable acetyltransferase for compound 1 biosynthesis. Bioinformatics analysis suggested AniI as a member of maltose (MAT) and galactoside O-acetyltransferases (GAT) with C-terminal left-handed parallel beta-helix (LbH) subdomain, which were referred to as LbH-MAT-GAT sugar O-acetyltransferases. However, the biochemical assay identified that its target site was the hydroxyl group of the pyrrolidine ring. AniI was found to be tolerant of acyl donors with different chain lengths for the biosynthesis of compound 1 and derivatives 12 and 13 with butyryl and isovaleryl groups, respectively. Meanwhile, it showed comparable activity toward biosynthetic intermediates and synthesized analogues, suggesting promiscuity to the pyrrolidine ring structure of compound 1. These data may inspire new viable synthetic routes for the construction of more complex pyrrolidine ring scaffolds in compound 1. Finally, the overexpression of aniI under the control of strong promoters contributed to the higher productivities of compound 1 and its analogues. These findings reported here not only improve the understanding of anisomycin biosynthesis but also expand the substrate scope of O-acetyltransferase working on the pyrrolidine ring and pave the way for future metabolic engineering construction of high-yield strains. IMPORTANCE Acylation is an important tailoring reaction during natural product biosynthesis. Acylation could increase the structural diversity and affect the chemical stability, volatility, biological activity, and even the cellular localization of specialized compounds. Many acetyltransferases have been reported in natural product biosynthesis. The typical example of the LbH-MAT-GAT sugar O-acetyltransferase subfamily was reported to catalyze the coenzyme A (CoA)-dependent acetylation of the 6-hydroxyl group of sugars. However, no protein of this family has been characterized to acetylate a nonsugar secondary metabolic product. Here, AniI was found to catalyze the acylation of the hydroxyl group of the pyrrolidine ring and be tolerant of diverse acyl donors and acceptors, which made the biosynthesis more efficient and exclusive for biosynthesis of compound 1 and its derivatives. Moreover, the overexpression of aniI serves as a successful example of genetic manipulation of a modification gene for the high production of final products and might set the stage for future metabolic engineering.

Three Recently Diverging Duplicated Methyltransferases Exhibit Substrate-Dependent Regioselectivity Essential for Xantholipin Biosynthesis.

Polycyclic xanthones are characterized by highly oxygenated, angular hexacyclic frameworks and exhibit diverse biological activities. Although many of them have been isolated and chemically synthesized, the detailed biosynthetic machinery awaits discovery. Recently, xanthone construction in the xantholipin (1) pathway was shown to involve cryptic demethoxylation. This suggested a rationale for the existence of three O-methyltransferase (OMT) genes in the gene cluster, although there are only two O-methyl groups in the structure of 1. Here, in vivo and in vitro analysis have been used to show that the three paralogous OMTs, XanM1-M3, introduce individual methyl groups at specific points in the biosynthetic pathway. Each OMT can to some extent take over the role of the other OMTs, although they exhibit highly substrate-dependent regiospecificity. In addition, phylogenetic analysis suggests their evolution from a common ancestor. Four putative ancestral proteins were constructed, and one of them performed all the functions of XanM1-M3, while the others possessed more limited catalytic functions. The results suggest that a promiscuous common ancestor may have been able to catalyze all three reactions prior to gene duplication and functional divergence. The characterization of XanM1-M3 expands the enzyme inventory for polycyclic xanthone biosynthesis and suggests novel directed evolution approaches to diversifying natural product pathways.

A LuxR family transcriptional regulator AniF promotes the production of anisomycin and its derivatives in Streptomyces hygrospinosus var. beijingensis.

The protein synthesis inhibitor anisomycin features a unique benzylpyrrolidine system and exhibits potent selective activity against pathogenic protozoa and fungi. It is one of the important effective components in Agricultural Antibiotic120, which has been widely used as naturally-originated agents for treatment of crop decay in China. The chemical synthesis of anisomycin has recently been reported, but the complex process with low productivity made the biosynthesis still to be a vital mainstay in efforts. The biosynthetic gene cluster (BGC) of anisomycin in Streptomyces hygrospinosus var. beijingensis has been identified in our previous work, while poor understanding of the regulatory mechanism limited the yield enhancement via regulation engineering of S. hygrospinosus var. beijingensis. In this study here, we characterized AniF as an indispensable LuxR family transcriptional regulator for the activation of anisomycin biosynthesis. The genetic manipulations of aniF and the real-time quantitative PCR (RT-qPCR) revealed that it positively regulated the transcription of the anisomycin BGC. Moreover, the overexpression of aniF contributed to the improvement of the production of anisomycin and its derivatives. Dissection of the mechanism underlying the function of AniF revealed that it directly activated the transcription of the genes aniR-G involved in anisomycin biosynthesis. Especially, one AniF-binding site in the promoter region of aniR was identified by DNase I footprinting assay and an inverted repeat sequence (5'-GGGC-3') composed of two 4-nt half sites in the protected region was found. Taken together, our systematic study confirmed the positive regulatory role of AniF and might facilitate the future construction of engineering strains with high productivity of anisomycin and its derivatives.

Characterization of the positive SARP family regulator PieR for improving piericidin A1 production in Streptomyces piomogeues var. Hangzhouwanensis.

Piericidin A1, a member of ɑ-pyridone antibiotic, exhibits various biological activities such as antimicrobial, antifungal, and antitumor properties and possesses potent respiration-inhibitory activity against insects due to its competitive binding capacity to mitochondrial complex I. The biosynthetic pathway of piericidin A1 has been reported in Streptomyces piomogeues var. Hangzhouwanensis, while the regulatory mechanism remains poorly understood. In this study, a Streptomyces antibiotic regulatory protein (SARP) family transcriptional regulator PieR was characterized. Genetic disruption and complementation manipulations revealed that PieR positively regulated the production of piericidin A1. Moreover, the overexpression of pieR contributed to the improvement of piericidin A1 productivity. The real-time quantitative PCR (RT-qPCR) was carried out and the data showed that pieR stimulated the transcription of all the biosynthesis-related genes for piericidin A1. In order to explore the regulatory mechanism, electrophoresis mobility shift assays (EMSA) and DNase I footprinting experiments have been conducted. A protected region covering 50 nucleotides within the upstream region of pieR was identified and two 5-nt direct repeat sequences (5'-CCGGA-3') in the protected region were found. These findings, taken together, set stage for transcriptional control engineering in the view of optimizing piericidin A1 production and thus provide a viable potent route for the construction of strains with high productivity.

Ertapenem versus piperacillin/tazobactam for diabetic foot infections in China: a Phase 3, multicentre, randomized, double-blind, active-controlled, non-inferiority trial.

OBJECTIVES: Few randomized controlled studies have compared antibiotic regimens against diabetic foot infections (DFIs) in Chinese patients. We evaluated the efficacy and safety of ertapenem versus piperacillin/tazobactam for the treatment of DFIs in Chinese patients. METHODS: Patients with moderate to severe DFIs requiring parenteral antibiotics were randomized in a 1 : 1 ratio to receive ertapenem (1.0 g once daily) or piperacillin/tazobactam (4.5 g every 8 h) by 30 min intravenous (iv) infusions for ≥5 days. The primary outcome was favourable clinical response at discontinuation of iv therapy (DCIV). An evaluable-patient population was identified for primary analysis of non-inferiority at -15%. Safety was assessed. ClinicalTrials.gov: NCT01370616. RESULTS: Of 565 patients randomized, 443 patients (ertapenem = 219 and piperacillin/tazobactam = 224) were clinically evaluable for primary analysis. In the clinically evaluable population, the proportions of patients with favourable clinical response at DCIV were 93.6% (205/219) and 97.3% (218/224) in the ertapenem and piperacillin/tazobactam groups, respectively (difference: -3.8%, 95% CI: -8.3%, 0.0%). Ertapenem had a significantly lower favourable clinical response rate (91.5% versus 97.2%, 95% CI for difference: -12.1%, -0.3%) at DCIV in severe DFI patients. In the modified ITT population, 88.8% (237/267) and 90.6% (241/266) of patients in the ertapenem and piperacillin/tazobactam groups, respectively, had favourable clinical responses at DCIV (difference: -1.9%, 95% CI: -7.3%, 3.3%). Microbiological eradications of causative pathogens and adverse events were similar between treatment groups. CONCLUSIONS: Treatment with ertapenem was non-inferior to piperacillin/tazobactam in Chinese patients with DFIs. Ertapenem treatment resulted in a markedly lower rate of clinical resolution in severe DFIs.

Ertapenem prophylaxis of surgical site infections in elective colorectal surgery in China: a multicentre, randomized, double-blind, active-controlled study.

OBJECTIVES: Our purpose was to evaluate ertapenem versus ceftriaxone/metronidazole for prophylaxis of surgical site infections (SSIs) following elective colorectal surgery in Chinese adult patients. METHODS: Eligible Chinese adults aged 18-80 years scheduled to undergo elective colorectal surgery by laparotomy were randomized to receive a 30 min infusion of 1 g of ertapenem/metronidazole placebo or 2 g of ceftriaxone/500 mg of metronidazole within 2 h before initial incision. The study endpoint was the proportion of patients with successful prophylaxis at 4 weeks after treatment. The primary analysis was based on the evaluable population (PP population) and the pre-specified non-inferiority margin was set at -15%. ClinicalTrials.gov: NCT01254344. RESULTS: Of 599 patients randomized, 499 (251 ertapenem and 248 ceftriaxone) were eligible for inclusion in the PP population. The proportions of patients with successful prophylaxis in the ertapenem and ceftriaxone groups were 90.4% (227/251) and 90.3% (224/248), respectively. The difference in the proportion of successful outcomes was 0.1% (95% CI -5.2%, 5.5%). Unexplained antibiotic use was the most frequent reason for prophylaxis failure in both groups [ertapenem 4.8% (12/251), ceftriaxone 4.4% (11/248); difference 0.3%; 95% CI -3.6, 4.3]. Pathogen species isolated from SSI sources were consistent with previously conducted studies and the product package insert. The incidence of adverse events (AEs) was similar between the groups, with the most common AE being pyrexia [ertapenem 7.6% (22/290), ceftriaxone 5.7% (17/297)]. CONCLUSIONS: Ertapenem is as effective as ceftriaxone/metronidazole for SSI prophylaxis in patients undergoing elective colorectal surgery, and is well tolerated.

The HADS and the DT for screening psychosocial distress of cancer patients in Taiwan.

PURPOSE: This study assesses the sensitivity and specificity of Mandarin versions of two psychosocial screening tools for adjustment, anxiety and depressive disorders: the Hospital Anxiety and Depression Scale (HADS), and the Distress Thermometer (DT). METHODS: The two scales were used to screen 103 consecutive cancer patients seen for psychiatric evaluation at KF-SYSCC between May and November 2004 prior to their psychiatric interviews. Each scale was tested against clinical psychiatric diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition for their sensitivity and specificity. RESULTS: For the Mandarin version of the DT, receiver operating characteristic (ROC) analyses identified a DT score of 4 as the optimal cut-off, with sensitivity and specificity of 98 and 73%, respectively. For the Mandarin version of the HADS, ROC identified a score of 9 and 8 as the optimal cutoffs for the respective anxiety and depression subscales (HADS-a and HADS-d), with sensitivities and specificities of 84 and 73, 72 and 86%, respectively. For the full scale of the HADS (HADS-t), 15 was identified as the optimal cutoff, which yielded sensitivity and specificity of 84 and 68%, respectively. Using the frequency table, the concordance rate of the two scales was found to be 72-80% based on the above optimal cut-offs. CONCLUSION: The Mandarin versions of the HADS and the DT are efficacious for screening anxiety and depression for our population. Compared with the HADS-t, the DT appears to have not only higher sensitivity, but also higher specificity.

[The impact of positive end-expiratory pressure on cerebral perfusion pressure and hemodynamics in patients receiving lung recruitment maneuver].

OBJECTIVE: To explore the impact of lung recruitment maneuver (RM) on intracranial pressure (ICP), cerebral perfusion pressure (CPP) and mean arterial pressure (MAP). METHODS: RM was performed and ICP, MAP, central venous pressure (CVP), saturation of arterial oxygen (SpO2) were monitored continuously in 6 severe cerebral injury patients combined with lung injury, who were indicated for mechanical ventilation and meeting the criteria for intracranial pressure monitoring. RM included pressure control ventilation with stepwise increase in positive end-expiratory pressure (PEEP). RESULTS: RM was performed for 22 times in 6 patients, among them two were moribund due to sharp drop of blood pressure and CPP. In the remaining 20 attempts, the mean values of MAP, CVP, ICP, CPP measured at each PEEP level showed no significant difference compared with baseline values (all P>0.05). MAP was significantly correlated with CPP (r=0.706, P=0.000). In the remaining RMs, a correlation between MAP and CPP accounted for 85% (17/20) of total RMs, that between PEEP and CVP accounted for 75% (15/20), that between PEEP and ICP accounted for 75% (15/20), and that between PEEP and CPP existed in 40% (8/20). In a total of 22 cases, there were 6 patterns of response of MAP to alteration in PEEP: MAP maintained relatively stable in 8 case, MAP decreased when PEEP increased and increased when PEEP decreased in 6 case; in 2 cases MAP elevated with increase in PEEP, and drop to baseline with decrease in PEEP, in 2 cases it fell with increase in PEEP but it did not rise with decrease in PEEP, in 2 cases it rose with increase in PEEP but remained at a high level with PEEP decreased to baseline, in 2 cases, MAP dropped abruptly with increase in PEEP resulting in termination of RM. In 11 cases, ICP increased with increase in PEEP and decreased with lowering of PEEP. ICP maintained stable in 6 cases, and ICP maintained at a high level and did not return to baseline after RM in 3 cases. CPP decreased with increase in PEEP and increased when PEEP decreased, and it returned to baseline when PEEP was back to baseline in 12 case. CPP kept constant in 6 case. In 2 cases, CPP remained at a low level, and it returned to baseline 10-20 minutes after PEEP was lowered to baseline. CONCLUSION: There is considerable individual difference in impact of RM on MAP, ICP and CPP in patients with cerebral. ICP monitoring is helpful to assure safety of RM in patients with cerebral injury complicated with lung injury.

[The analysis of 252 episodes of recruitment maneuver during mechanical ventilation in surgery intensive care unit].

OBJECTIVE: To analyze the clinical effects of recruitment maneuver and the impacts on blood pressure and oxygen saturation in patients with mechanical ventilation. METHODS: To analyze all related data from 252 episodes of recruitment maneuver of 46 patients admitted from July 2005 to February 2007. Recruitment maneuver method: the drive pressure constant was kept at 15 cm H(2)O (1 cm H(2)O=0.098 kPa) and the positive end-expiratory pressure (PEEP) level was increased gradually. RESULTS: Of the 252 episodes of recruitment maneuver, this procedure was effective in 91% of the patients, with pneumothorax and pneumo-mediastinum occurred in a patient with legionnaire pneumonia, and no improvement of oxygen saturation in one patient with patent foramen ovale. The value of effective PEEP used ranged from a minimum of 8 cm H(2)O to a maximum of 30 cm H(2)O and the duration of satisfactory oxygen saturation ranged from a minimum of 0.4 hour to a maximum of 368 hours. On average, each patient received 5.48 episodes of recruitment maneuver with one of the patients received 16 episodes of recruitment maneuver. Twenty-three out of the 46 patients (50%) had experienced an episode of hypoxemia. One hundred and one episodes of hypoxemia occurred in 252 recruitment maneuver (40%) and the minimum PEEP inducing hypoxemia is 8 cm H(2)O, and the maximum PEEP was 22 cm H(2)O, with an average value of 12.7 cm H(2)O. Twenty-five of the 46 patients (54%) had experienced transient hypotension with 93 episodes of hypoxemia in 252 episodes of recruitment maneuver (37%), and the minimum PEEP inducing hypotension was 6 cm H(2)O and the maximum PEEP was 23 cm H(2)O, with an average value of 13.9 cm H(2)O. CONCLUSION: Recruitment maneuver could effectively improve oxygenation while the value of PEEP used should be individualized according to clinical condition.

[Effect of lung stress index on titration of positive end-expiratory pressure at post-recruitment in three canine acute respiratory distress syndrome models].

OBJECTIVE: To investigate the relationship of lung stress index and positive end-expiratory pressure (PEEP) at post-recruitment in different canine acute respiratory distress syndrome (ARDS) models. METHODS: The ARDS models were induced by intravenous oleic acid, saline lavage and hydrochloric acid aspiration in anesthetized dogs. During volume control ventilation with constant inspiratory flow, PEEP was set to obtain a b (stress index) value between 0.9 and 1.1 (b = 1) before and post recruitment maneuver (RM). PEEP was changed to obtain b < 1 (0.6 < b < 0.8) and b > 1 (1.1 < b < 1.3). Meanwhile, the recruited volume (RV) was measured and pulmonary mechanics and gas exchange were observed. RESULTS: At b = 1 after RM, PEEP were (10.8 +/- 2.3), (12.8 +/- 1.8) and (9.2 +/- 1.8) cm H2O in the oleic acid, saline-lavaged and hydrochloric acid aspiration groups, respectively. PEEP in saline-lavaged group was higher than that in hydrochloric acid aspiration group (P < 0.05). The ratio of partial arterial oxygen tension and fraction of inspiratory oxygen (PaO(2)/FiO(2)) at b = 1 without RM was lower than those post-RM in all three groups (P < 0.05). In oleic acid group, PaO(2)/FiO(2) at b = 1 post-RM was (399 +/- 61) mm Hg, which was higher than that at b < 1 [(307 +/- 71) mm Hg], but there was no difference between those at b = 1 and b > 1. At b = 1 after RM, PaO(2)/FiO(2) in the saline-lavaged group was higher than that in acid aspiration group, but no difference between saline-lavaged group and oleic acid group was found. At b = 1 post-RM, RV were higher than that at b = 1 before RM in all three groups (P < 0.01), but there was no significant difference among three groups. At b = 1 post-RM in three groups, pulmonary compliance were higher than those at b > 1, but airway plateau pressure were lower than those at b > 1. CONCLUSIONS: Lung stress index could be a good indicator for PEEP titration at post-RM.

[Assessment of stroke volume variation and intrathoracic blood volume index on the responsiveness to volume loading in mechanically ventilated canine with hemorrhagic shock].

OBJECTIVE: To assess the significance of stroke volume variation (SVV) and intrathoracic blood volume index (ITBI) on the responsiveness to volume loading in mechanically ventilated canine with hemorrhagic shock. METHODS: Hemorrhagic shock canine model was established with the modified Wiggers' method. The heart rate (HR), mean artery pressure (MAP), central venous pressure (CVP), pulmonary artery wedge pressure (PAWP), intrathoracic blood volume index (ITBI) and stroke volume variation (SVV) were investigated by Swan-Ganz catheter or PiCCO monitor. Graded volume loading (VL) was performed. Successive responsive VLs were performed (increase in SV > 5% after VL) until continuous change in SV < 5% (unresponsive) was reached. RESULTS: Fourteen canines were studied and a total of 134 VLs were performed. In 94 VLs, an increase in SV of more than 5% was reached. In the other 40 VLs, increase in SV was less than 5%. The change of HR, MAP, ITBI, SVV in responsive were more than those of unresponsive after VL. The change of CVP, PAWP in responsive were less than those of unresponsive. Significant correlation was found between DeltaSV after VL and the baseline values of ITBI, SVV. No correlation was found between DeltaSV and HR, MAP, CVP, PAWP. Significant correlations were also found between DeltaSV and DeltaCVP, DeltaPAWP, DeltaITBI, DeltaSVV after fluid loading. No correlation was found between DeltaSV and DeltaHR, DeltaMAP. By using receiver operating characteristic analysis, the area under the curve were 0.872 for SVV and 0.689 for ITBI, more than those of HR, MAP, CVP, PAWP statistically. As SVV value of 9.5% or more will predict an increase in the SV of at least 5% in response to a VL with a sensitivity of 92.6% and a specificity of 82.5%. CONCLUSIONS: SVV and ITBI were more useful indicators than CVP and PAWP on the assessment of responsiveness to volume loading. SVV as a functional preload parameter and for on-line monitoring may help to improve the hemodynamic management.

[Relationship of stress index with lung recruitment and gas exchange in dogs with acute respiratory distress syndrome].

OBJECTIVE: To determine the relationship of stress index with lung recruitment and gas exchange in dogs with acute respiratory distress syndrome (ARDS). METHODS: The ARDS model was induced by infusion of oleic acid intravenously in anesthetized dogs. During volume control ventilation with constant inspiratory flow, the pressure-time (P-t) curve was fitted to a power equation: P = a.time(b)+c, where coefficient b (stress index) describes the shape of the curve: b = 1, straight curve; b < 1, progressive increase in slope; and b > 1, progressive decrease in slope. Tidal volume (V(T)) was 6 ml/kg, and positive end-expiratory pressure (PEEP) was set to obtain a b value between 0.9 and 1.1 before (b = 1) and after (b = 1 after recruiting maneuver) application of a recruiting maneuver (RM). PEEP was changed to obtain 0.6 < b < 0.8 and 1.1 < b < 1.3. Experimental condition sequence was random. Recruited volume (RV) was measured by static pressure-volume curve method. Hemodynamics, pulmonary mechanics and gas exchange were observed at the same time. RESULTS: At b = 1 without RM, the PEEP was (5.0 +/- 3.0) cm H2O, the RV was (27 +/- 15) ml, and the RV increased to (166 +/- 84) ml significantly at b = 1 after RM [PEEP (10.8 +/- 2.3) cm H2O (1 cm H2O = 0.098 kPa), q = 3.18, P < 0.01]. At 1.1 < b < 1.3 after RM, the PEEP was (16.8 +/- 1.1) cm H2O and the RV was (262 +/- 57) ml, which was higher than that at b = 1 after RM (q = 2.54, P = 0.023). At 0.6 < b < 0.8 after RM, the PEEP was (5.6 +/- 2.2) cm H2O and the RV was lower than that at b = 1 after RM (q = 2.85, P = 0.013). The partial pressure of oxygen in arterial blood (PaO2) in b = 1, 0.6 < b < 0.8 and 1.1 < b < 1.3 after RM were (319 +/- 49) mm Hg (1 mm Hg = 0.133 kPa), (246 +/- 57) mm Hg and (314 +/- 27) mm Hg respectively, which was higher than the PaO2 at b = 1 without RM [(153 +/- 64) mm Hg, all q = 2.81, all P < 0.05]. The PaO2 at 0.6 < b < 0.8 was lower than that at b = 1 after RM (q = 2.81, P = 0.005), while there was no significant difference between the PaO2 at 1.1 < b < 1.3 and that at b = 1 after RM. The peak airway pressure and plateau pressure at 1.1 < b < 1.3 were higher than those at b = 1 after RM (q = 6.02, 5.72, all P < 0.05). CONCLUSION: In the b = 1 after RM, there were better PaO2 and lower airway pressure, suggesting that b = 1 after RM may be a good indicator for PEEP titration.

[Comparison of single-indicator thermodilution versus gravimetric measurement in determination of extra-vascular lung water in dogs with acute respiratory distress syndrome].

OBJECTIVE: To compare the measurement of extra-vascular lung water (EVLW) by a single-indicator dilution technique and measurement obtained by gravimetry in different types of acute respiratory distress syndrome (ARDS). METHODS: Thirty-three dogs were randomly assigned to three groups: control group, oleic acid group and hydrochloric acid group. ARDS was reproduced by either intravenous injection of oleic acid or intratracheal instillation of hydrochloric acid. EVLW was measured before ARDS, at the onset of ARDS and 10 hours after ARDS by a single indicator dilution technique. Ten hours after ARDS, dogs were sacrificed and then EVLW was quantitated by a gravimetric measurement (golden standard). Hemodynamics and pulmonary gas exchange were determined. RESULTS: There was a close positive correlation (r=0.8820, P<0.05) between single indicator dilution and gravimetric measurements. However, the measurement with the single indicator dilution was consistently higher than the gravimetric measurement. In the control group, there was a positive correlation (r=0.9870, P<0.05) between the values of EVLW as measured by single indicator dilution and by gravimetric measurements. In the oleic acid group, there was also a significant correlation (r=0.9360, P<0.05) between the values of EVLW as measured by single indicator dilution and by gravimetric measurements. In the hydrochloric acid group, correlation (r=0.7950, P<0.05) was also found between EVLW as measured by the two methods. However, the correlation found was lower in the hydrochloric acid group than those in other two groups. Hydrochloric acid instillation resulted in a significant increase in shunting and the partial pressure of carbon dioxide in artery (PaCO(2)) compared with oleic acid group at 10 hours after ARDS. CONCLUSION: The results of measuring EVLW using single indicator dilution measurement are closely related with those of gravimetric measurement in ARDS, however, the correlations varies with the methods of reproduction of ARDS.

[Effect of hydroxyethyl starch and Ringer's solution on splanchnic perfusion in dogs with septic shock].

OBJECTIVE: To investigate the effect of 6% hydroxyethyl starch (HES) and Ringer's solution (RS) on splanchnic perfusion in dogs with septic shock. METHODS: Twenty-four mongrel dogs with septic shock induced by lipopolysaccharides (LPS) were randomly divided into two groups: HES group and RS group. Dogs of each group received an intravenous infusion of HES or RS (1 mlxkg(-1)xmin(-1)) for 60 minutes, followed by normal saline for 180 minutes with same infusion speed. Parameters of hemodynamics, oxygen dynamic, and splanchnic perfusion were monitored at 0, 30, 60, 120, 180, 240 minutes after basic measurements (pre-LPS). RESULTS: (1) After LPS infusion, mean arterial pressure (MAP) and cardiac index (CI) lowered significantly (P<0.05). Compared to that of 0 minutes, MAP and CI were elevated by fluid therapy in both groups, but there was no difference between HES and RS group. (2) Compared with pre-LPS, oxygen delivery (DO(2)) was reduced, arterial blood pH lowered and arterial lactate level increased markedly at 0 minutes (P<0.05). DO(2) increased by fluid therapy in both groups, but DO(2) was higher in HES group at the same time points (P<0.05). Compared to 0 minutes, arterial lactate levels were lowered at 180 minutes in both groups. (3) Mesenteric blood flow decreased after LPS infusion in all animals (P<0.05). Mesenteric blood flow increased after HES infusion, at the same time intramucosal pH (pHi) was elevated and Pg-aCO(2) decreased significantly (all P<0.05), but they showed no difference in RS group. At the same time, mesenteric blood flow and pHi was higher in HES group than that in RS group. CONCLUSION: Both HES and RS could improve MAP and DO(2) in dogs with septic shock, but the effect of HES was better than RS on splanchnic perfusion.