RESUMO
Objective To investigate the clinical efficacy of methylene blue in the treatment of refractory hypotension caused by vascular paralysis during the course of vasodilatory shock. Methods The related articles were searched by retrieving the terms using methylene blue, vascular paralysis, hemodynamics, hypotension, vasodilatory shock in CNKI, China Biomedical Literature database, Wanfang database, PubMed, Springer Link, and BIOSIS Previews database. The retrieval time was from January 1994 to June 2017. The randomized clinical trials (RCTs) which using methylene blue as the experimental group, normal saline or catecholamine as the control in the treatment of refractory hypotension caused by vascular paralysis during the course of vasodilatory shock were collected. The primary end points were mean arterial pressure (MAP) immediately or 1 hour after the methylene blue administration, and the mortality at the longest follow-up available; the secondary end point was serum lactic acid (Lac) 1 hour after the methylene blue administration. Literature screening, data extraction and quality evaluation were carried out by two researchers. Meta analysis was performed using RevMan 5.3 software. The sensitivity analysis was performed in two trials with low risk of bias. The funnel plot for MAP was performed in five relative trials to analyze the research and publication bias. Results Totally 269 relative articles were collected, according to the inclusion and exclusion criteria, finally 6 RCTs with 214 patients were enrolled, 108 in methylene blue group, and 106 in control group. Four of the studies were considered to have mild to moderate risk of bias, two studies of high risk of bias. The Meta-analysis demonstrated that compared with the control group, methylene blue could significantly improve MAP [mean difference (MD) = 4.87, 95% confidence interval (95%CI) = 2.61 to 7.13, P < 0.000 1], reduce the serum Lac levels (MD = -1.06, 95%CI = -1.98 to -0.14, P = 0.02), and the mortality was decreased without statistical difference [odds ratio (OR) = 0.58, 95%CI = 0.25 to 1.31, P = 0.19]. Sensitivity analysis was performed in two trials with low risk of bias, which demonstrated methylene blue could exactly increase MAP (MD = 8.93, 95%CI = 1.55 to 16.32, P = 0.02). Funnel plot for MAP was performed in five relative trials which found no obvious publication bias. Conclusions Methylene blue could significantly increase MAP in the patients with refractory hypotension caused by vascular paralysis during the course of vasodilatory shock, decrease the Lac levels, and does not increase the risk of death. Therefore, methylene blue should be a potential and safe vasoconstrictor.
RESUMO
Objective To observe the effect of methylene blue on the expression of liver inducible nitric oxide synthase (iNOS) in rats with different stages of sepsis.Methods One hundred and twenty-six adult female Wistar rats were randomly divided into three groups: sham operation group, sepsis group and methylene blue group, each group was again subdivided into 0, 6, 12, 18, 24, 30, 36 hours subgroups, each subgroup6 rats. The model of sepsis was established by cecal ligation and puncture (CLP) method, and in the sham operation group, the abdominal incision was performed and the intestinal mesentery was separated only, without ligation and perforation. In methylene blue group, 15 mg/kg methylene blue was injected into a caudal vein at 0, 6, 12, 18, 24, 30, 36 hours after CLP in the rats in corresponding subgroups, respectively; in the sepsis and sham operation subgroups, the same amount of 0.9% normal saline was given. After administration for 6 hours in various groups, the rats were sacrificed and the liver tissue was harvested immediately. The expression of iNOS mRNA of liver tissues was determined by the real-time fluorescent quantitative reverse transcription-polymerase chain reaction (qRT-PCR),and the protein expression of iNOS was determined by Western Blot.Results Compared with sham operation group, the liver tissue expression of iNOS mRNA was significantly up-regulated in sub-sepsis groups at 0, 6, 12 and 18 hours after CLP (2-ΔΔCt: 16.66±2.81 vs. 1.00±0.36, 12.26±5.78 vs. 1.00±0.30, 6.08±1.33 vs. 1.00±0.18, 2.42±0.64 vs. 1.00±0.12, allP < 0.01), after 24 hours the expression of iNOS mRNA had no significant change; the liver tissue expression of iNOS protein was obviously up-regulated in sub-sepsis groups at 6, 12 ,18 and 36 hours after CLP (gray value: 0.350±0.011 vs. 0.210±0.005, 1.460±0.085 vs. 0.090±0.005, 0.230±0.012 vs. 0.18±0.008, 0.310±0.017 vs. 0.200±0.010, allP < 0.01). Compared with sepsis group, the expression of the liver tissue iNOS mRNA was down-regulated in methylene blue subgroups at 0, 12 and 18 hours after CLP (2-ΔΔCt: 9.90±3.06 vs. 16.66±2.81, 1.56±0.58 vs. 6.08±1.33, 1.11±0.15 vs. 2.42±0.64, allP < 0.05), and the expression of iNOS protein was down regulated in methylene blue subgroups at 6, 12, 18 and 36 hours after CLP (gray value: 0.150±0.008 vs. 0.350±0.011, 0.950±0.009 vs. 1.460±0.085, 0.150±0.007 vs. 0.230±0.012, 0.170±0.009 vs. 0.310±0.017, allP < 0.05).Conclusion Zero-24 hours after CLP, the expressions of mRNA iNOS and protein in liver of septic rats are significantly increased; methylene blue can markedly inhibit the expressions of iNOS mRNA and protein in the liver of rats with sepsis.