Study screening
The search strategy identified 3937 unique publications. After excluding 1439 duplicates and screening 2381 titles and abstracts, 117 studies were assessed in full text for eligibility. The full-text screening excluded 101 studies for the reasons shown in Fig. 1. Finally, 16 studies[9,11,23-36] were included in this meta-analysis (kappa = 0.803, P<0.01) Among these, 8 studies were published in Chinese, and the other 8 studies were published in English.
The characteristics of all the included studies are summarized in Table 1. In total, the included studies comprised 864 patients, and the number of patients per study was 20 to 120. The population included septic shock, vasoplegic syndrome, and ischemia reperfusion. Of the 16 included studies, 7 were RCTs, 4 were quasi-Randomized Controlled Trials (q-RCTs), and 5 were observational studies. Among the 11 interventional studies, only 1 study had a high risk of bias, and all the other 10 studies had a mild to moderate risk of bias. All 6 observational studies except for 2 had a mild risk of bias. The risk bias of the included studies is shown in Fig. 2 (kappa = 0.824, P<0.01).
Mortality
Nine (n=526, 257 in the MB group and 269 in the control group) of the 16 included studies reported mortality ranging from 0%-70% with different follow-up times, including 28 days, 30 days, 90 days and hospitalization. The pooled data showed that compared with the control group, MB significantly reduced mortality in patients with vasodilatory shock (OR 0.54, 95% CI 0.34 to 0.85, P = 0.008; Fig. 3), with low heterogeneity (I2 = 7%). No sign of significant publication bias was observed (Additional file 2: Figure S1).
This result was confirmed by the pooled analysis from RCTs and q-RCTs (OR=0.45, 95%CI 0.25 to 0.81, P=0.008; I2 = 1%; Additional file 3: Figure S2), rather than non-RCTs (OR 0.70, 95%CI 0.34 to 1.42, P=0.32; I2 = 29%; Additional file 3: Figure S2). Subgroup analyses of the population revealed a reduction in mortality in patients with septic shock (OR 0.43, 95%CI 0.22 to 0.87, P=0.02; I2 = 0%; Additional file 4: Figure S3), but the difference was not statistically significant in nonseptic shock patients (OR 0.63,95%CI 0.35 to 1.16, P=0.14; I2 = 42%; Additional file 4: Figure S3). Continuous infusion of MB significantly improved survival (OR 0.36, 95% CI 0.15 to 0.88, P=0.02; I2 = 0%; Additional file 5: Figure S4), while no significant difference was found between the intervention injection MB and control groups (OR 0.62, 95% CI 0.37 to 1.07, P=0.08; I2 = 19%; Additional file 5: Figure S4). The dosages of MB used in the included studies that reported mortality were relatively uniform, ranging from 1-2 mg/kg for intravenous injection and 0.25-2 mg/kg/h for continuous infusion. Therefore, we did not perform subgroup analyses based on the doses of MB.
Secondary outcomes
Vasopressor requirement
Fifteen of the 16 included studies used MB as an adjunct intervention to vasopressors, including norepinephrine, epinephrine, dopamine, and dobutamine. Four studies with 430 patients reported this outcome. Pooled data showed that MB significantly reduced the requirement for vasopressors compared with the control group (SMD -0.77, 95% CI -1.26 to -0.28, P = 0.002; I2 = 80%; Table 2).
Hemodynamic changes
Ten (n=472) of the 16 included studies reported MAP, which was significantly increased by MB (MD 5.01, 95% CI 3.28 to 6.74, P<0.001; I2 =33%; Table 2). Pooled data from 9 studies (n =428) revealed that MB significantly increased HR (MD 4.51, 95% CI 2.21 to 6.81, P<0.001; I2 = 69%; Table 2). Moreover, SVR (5 studies, n=226) was also higher in the MB group than in the control group (MD 181.87, 95% CI 39.30 to 324.44, P=0.01; I2=88%; Table 2). However, comprehensive data from 6 studies (n=340) revealed no significant difference in cardiac index between the two groups (MD 0.36, 95% CI -0.03 to 0.74, P=0.07; I2=95%; Table 2).
Oxygen metabolism
Six (n=240) of the 16 included studies reported lactate. The results showed that MB could significantly reduce the level of lactate (MD -0.93, 95% CI -1.30 to -0.56, P < 0.001; I2=69%; Table 2). However, only 3 studies reported DO2I or VO2I, and neither of them was significantly different between MB and the control groups (DO2I: MD -19.63, 95% CI -106.30 to 67.04, P=0.66; I2=98%; VO2I: MD 10.85, 95% CI -0.13 to 21.84, P=0.05; I2=63%; Table 2).
Other secondary outcomes
The effects of MB treatment on ICU LOS (6 studies, n=332) and hospital LOS (4 studies, n=264) were -0.41 days (95% CI -0.99 to 0.17, P = 0.16; I2=83%; Table 2) and -0.30 days (95% CI -9.82 to 9.23, P = 0.95; I2=87%; Table 2), respectively. Five studies (n=254) reported the mechanical ventilation duration. Compared with the control group, MB had no effect on the duration of mechanical ventilation (SMD -0.47, 95% CI -1.06 to 0.13, P=0.13; I2=78%; Table 2).
Adverse effects
No serious side effects were found in this study. The adverse effects of MB reported in the included studies were blue discoloration of the skin and urine and a temporary decrease in mixed venous oxygen saturation.