TYPE Systematic Review

PUBLISHED 26 September 2022

DOI 10.3389/fmed.2022.950596

Efficacy and safety of methylene

OPEN ACCESS blue in patients with
vasodilatory shock: A systematic
EDITED BY
Jihad Mallat,
Cleveland Clinic Abu Dhabi, United
Arab Emirates

REVIEWED BY
review and meta-analysis
Giovanni Landoni,
San Raffaele Hospital (IRCCS), Italy
Osama Abou-Arab, Cong-Cong Zhao1 , Yu-Jia Zhai1 , Zhen-Jie Hu1 , Yan Huo1 ,
University Hospital Center (CHU) of
Amiens, France Zhi-Qiang Li2 and Gui-Jun Zhu1*
1
*CORRESPONDENCE Department of Intensive Care Unit, The Fourth Hospital of Hebei Medical University, Shijiazhuang,
Gui-Jun Zhu China, 2 Department of Intensive Care Unit, Affiliated Hospital of North China University of Science
[email protected] and Technology, Tangshan, China
SPECIALTY SECTION
This article was submitted to
Intensive Care Medicine and Background: The role of methylene blue (MB) in patients with vasodilatory
Anesthesiology,
a section of the journal
shock is unclear. The purpose of this systematic review and meta-analysis was
Frontiers in Medicine to evaluate the efficacy and safety of MB in patients with vasodilatory shock.
RECEIVED 23 May 2022 Methods: We searched MEDLINE at PubMed, Embase, Web of Science,
ACCEPTED 01 September 2022
PUBLISHED 26 September 2022
Cochrane, CNKI, CBM and Wanfang Medical databases for all observational
and intervention studies comparing the effect of MB vs. control in vasodilatory
CITATION
Zhao C-C, Zhai Y-J, Hu Z-J, Huo Y, shock patients. This study was performed in accordance with the PRISMA
Li Z-Q and Zhu G-J (2022) Efficacy and statement. There were no language restrictions for inclusion.
safety of methylene blue in patients
with vasodilatory shock: A systematic Results: A total of 15 studies with 832 patients were included. Pooled data
review and meta-analysis. demonstrated that administration of MB along with vasopressors significantly
Front. Med. 9:950596.
doi: 10.3389/fmed.2022.950596 reduced mortality [odds ratio (OR) 0.54, 95% confidence interval (CI) 0.34
COPYRIGHT
to 0.85, P = 0.008; I2 = 7%]. This benefit in mortality rate was also seen
© 2022 Zhao, Zhai, Hu, Huo, Li and in a subgroup analysis including randomized controlled trials and quasi-
Zhu. This is an open-access article randomized controlled trials. In addition, the vasopressor requirement was
distributed under the terms of the
Creative Commons Attribution License reduced in the MB group [mean difference (MD) −0.77, 95%CI −1.26 to −0.28,
(CC BY). The use, distribution or P = 0.002; I2 = 80%]. Regarding hemodynamics, MB increased the mean arterial
reproduction in other forums is
permitted, provided the original
pressure, heart rate and peripheral vascular resistance. In respect to organ
author(s) and the copyright owner(s) function, MB was associated with a lower incidence of renal failure, while in
are credited and that the original regards to oxygen metabolism, it was linked to reduced lactate levels. MB had
publication in this journal is cited, in
accordance with accepted academic no effect on the other outcomes and no serious side effects.
practice. No use, distribution or
Conclusions: Concomitant administration of MB and vasopressors improved
reproduction is permitted which does
not comply with these terms. hemodynamics, decreased vasopressor requirements, reduced lactate levels,
and improved survival in patients with vasodilatory shock. However, further
studies are required to confirm these findings.
Systematic review registration: Identifier: CRD42021281847.

KEYWORDS

methylene blue, vasodilatory shock, vasoplegic syndrome, septic shock, mortality,

meta-analysis

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Zhao et al. 10.3389/fmed.2022.950596

Introduction the lack of randomized controlled trials (RCTs) and divergent

patient subsets, the efficacy of MB on mortality is unclear.
Vasodilatory shock is defined as life-threatening acute Moreover, there is no consensus on several key issues, including
circulatory failure characterized by low arterial pressure, normal MB treatment time window, optimal dose and administration
or elevated cardiac output, and reduced systemic vascular mode. Some studies used MB as a last rescue therapeutic
resistance, resulting in inadequate oxygen utilization (1, 2). in refractory vasodilatory shock (15, 18, 19). This may limit
It can be related to various causes (i.e., sepsis, vasoplegic the effectiveness of MB due to the treatment time later than
syndrome, liver transplant, and allergy) and the final stage of the “window of opportunity” (20). The mode and dose of
other types of shock. Treatment is centered upon providing MB administration were inconsistent among all studies, which
adequate organ reperfusion and oxygen utilization by fluid ranged from 0.5 mg/kg/h to 4 mg/kg/h by intravenous injection
resuscitation and catecholamine vasopressors. However, high with or without continuous infusion (6). Thus, the role of MB in
doses of catecholamines increase the risk of adverse effects patients with vasodilatory shock remains unclear.
such as peripheral ischemia/dysfunction, tachyarrhythmia, Therefore, we performed a meta-analysis to evaluate the
myocardial depression, and others (3, 4). A recent study efficacy and safety of MB in vasodilatory shock patients.
reported that excessive doses of norepinephrine was associated Subgroup analyses were performed to explore the benefits of MB
with acute kidney injury (AKI) and intensive care unit for different populations, modes, and administration doses.
(ICU) mortality following cardiac surgery (5). Moreover, first-
line norepinephrine is inefficacious in some patients (6),
therefore, researchers are actively looking for catecholamine- Methods
sparing agents.
Methylene blue (MB), a water-soluble dye and an inhibitor
Study registration
of nitric oxide (NO), is an alternative method to restore vascular
This systematic review was registered at PROSPERO with
tone and improve perfusion (7). In vasodilatory shock, elevated
the registration number CRD42021281847. It was performed
levels of NO and activation of soluble guanylyl cyclase (sGC) are
according to the Preferred Reporting Items for Systematic
the main reasons for the mismatch between macrocirculation
Reviews and Meta-Analyses (PRISMA) guidelines (21).
and microcirculation (8). MB inhibits NO and selectively
inhibits inducible NO synthase generation. Additionally, MB
binds to the heme part of sGC, blocking the effect of sGC in
vascular smooth muscle, reducing the level of cyclic adenosine Data sources
monophosphate, and synergistically improving vasodilation
(9). Studies have reported that MB was able to significantly We searched the MEDLINE via the PubMed, Embase, Web
increase the mean arterial pressure (MAP) and systemic vascular of Science, Cochrane, CBM, CNKI, and Wanfang databases up
resistance (SVR) with no apparent major side effect (10, 11). In to April 10, 2022, using the key words (“Methylene blue”) AND
addition, MB administration was able to facilitate the weaning (“Shock” or “Septic” or “Vasoplegia” or “Hypotension”). There
of catecholamine vasopressors (12–14). Taken together, MB were no language restrictions. The search strategy in provided in
represents an option for catecholamine-sparing agents. more detail in the Supplementary material.
Although MB may improve vasodilation, a corresponding
mortality benefit was not seen overall. A recent retrospective
study found that MB responders had a lower mortality compared Study selection
to MB non-responders (15). Li et al. reported that compared
with norepinephrine monotherapy, MB combination therapy The initial and full-text reviews were performed
improved mortality in sepsis patients (16). However, the result independently by two authors (CCZ and YJZ). The inclusion
could not be reproduced in subsequent studies (17, 18). Due to criteria were as follows: 1) type of study: observational study or
interventional study (either randomized or non-randomized);
2) population: adult patients (≥18 years) suffering from
Abbreviations: MB, Methylene blue; OR, Odds ratio; CI, Confidence vasodilatory shock treated with routine fluid and catecholamine
interval; M-H, Mantel–Haenszel; MD, Mean difference; SMD, Standardized vasopressor therapy; 3) intervention: intravenous MB treatment
mean difference; NO, Nitric oxide; sGC, soluble Guanylyl cyclase; AKI, vs. placebo or blank; 4) outcomes: the primary outcome was
Aacute Kidney Injury; MAP, Mean arterial pressure; SVR, Systemic vascular mortality without time limits, and secondary outcomes were
resistance; HR, Heart rate; CI, Cardiac index; DO2 I, Oxygen delivery index; vasopressor requirement; hemodynamic changes [including
VO2 I, Oxygen consumption index; RCTs, Randomized controlled trials; mean arterial pressure (MAP); systemic vascular resistance
q-RCTs, quasi-Randomized controlled trials; NOS, Newcastle-Ottawa (SVR); heart rate (HR); and cardiac index (CI)]; oxygen
quality assessment scale; ICU, Intensive care unit; LOS, Length of stay. metabolism [including lactate, oxygen delivery (DO2 I), oxygen

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consumption (VO2 I)]; organ function; intensive care unit Results

(ICU) and hospital length of stay (LOS); mechanical ventilation
duration; as well as adverse effects. Study screening
The exclusion criteria were as follows: 1) oral administration
of MB or MB as a prophylactic treatment; 2) lack of a baseline The search strategy identified 3,937 unique publications.
condition or control group; 3) lack of data on any outcome; After excluding 1,439 duplicates and screening 2,381 titles and
and 4) review articles, cohort studies, case reports and studies abstracts, 117 studies were assessed in full text for eligibility. The
without full text, animal and in vitro studies. full-text screening excluded 102 studies for the reasons shown
in Figure 1. Finally, 15 studies (12, 16, 23–35) were included
in this meta-analysis. Among these, 7 studies were published in
Data extraction Chinese, and the other 8 studies were published in English.
The characteristics of all the included studies are
Two authors (CCZ and YJZ) independently extracted data summarized in Table 1. In total, the included studies comprised
from the included studies. The kappa coefficient was calculated 832 patients, and the number of patients per study was 20
as a measure of agreement about study selection and quality to 120. The population included septic shock, vasoplegic
appraisal. Any discrepancies were resolved by the third author syndrome, and ischemia reperfusion. Of the 15 included
(ZQL), and a decision was reached by consensus. studies, 7 were RCTs, 3 were quasi-Randomized Controlled
For each study, the following information was extracted: Trials (q-RCTs), and 5 were observational studies. Among
publication (last name of the first author, year of publication), the 10 interventional studies, only 1 study had a high risk of
participant characteristics (including patient source, diagnosis, bias, and all the other 9 studies had a mild to moderate risk
demographic data, clinical setting, and number of patients), of bias. All 5 observational studies except for 2 had a mild
details of the intervention (including MB dosage, route, and risk of bias. The risk bias of the included studies is shown in
duration), follow-up duration, and outcome data. Figure 2.

Assessment of risk of bias Mortality

Two authors independently assessed the risk of bias to Nine (n = 526, 257 in the MB group and 269 in the control
evaluate the quality of the included studies. The Cochrane group) of the 15 included studies reported mortality ranging
Collaboration tool (22) was used for RCTs, and the Newcastle– from 0–70% with different follow-up times, including 28 days,
Ottawa Scale (NOS) (23) was used for non-RCTs and 30 days, 90 days and hospitalization. The pooled data showed
observational studies. A funnel plot was used to evaluate that compared with the control group, MB significantly reduced
publication bias. mortality in patients with vasodilatory shock (OR 0.54, 95% CI
0.34 to 0.85, P = 0.008; Figure 3), with low heterogeneity (I2
= 7%). No sign of significant publication bias was observed
Statistical analysis (Supplementary Figure S1).
This result was confirmed by the pooled analysis from
SPSS 25.0 (IBM, Armonk, New York, USA) was used to RCTs and q-RCTs (OR = 0.45, 95%CI 0.25 to 0.81, P =
calculate the kappa coefficient. Data analysis was conducted 0.008; I2 = 1%; supplementary Figure S2), rather than
by RevMan 5.4 (The Nordic Cochrane Center, Rigs Hospitalet, non-RCTs (OR 0.70, 95%CI 0.34 to 1.42, P = 0.32; I2
Copenhagen, Denmark). The results are presented with forest = 29%; Supplementary Figure S2). Subgroup analyses
plots using odds ratio (OR) for dichotomous data and the of the population revealed a reduction in mortality in
mean differences (MD) for continuous data. If continuous data patients with septic shock (OR 0.43, 95%CI 0.22 to 0.87,
with different units, the standardized mean differences (SMD) P = 0.02; I2 = 0%; Supplementary Figure S3), but the
was used. All estimates were provided with 95% confidence difference was not statistically significant in non-septic
interval (CI). Heterogeneity was assessed by Cochran’s Q shock patients (OR 0.63,95%CI 0.35 to 1.16, P = 0.14; I2
statistic and the I2 -test. A P value > 0.1 or I2 statistic below 50% = 42%; Supplementary Figure S3). Continuous infusion of
indicated low levels of heterogeneity. In these cases, a fixed-effect MB significantly improved survival (OR 0.36, 95% CI 0.15
model was used. Otherwise, a random-effects model (Mantel– to 0.88, P = 0.02; I2 = 0%; Supplementary Figure S4), while
Haenszel method) was selected. P < 0.05 indicated statistical no significant difference was found between the intervention
significance. Several subgroup analyses were performed for injection MB and control groups (OR 0.62, 95% CI 0.37 to
mortality according to population (septic shock and non-septic 1.07, P = 0.08; I2 = 19%; Supplementary Figure S4). The
shock), mode (intravenous injection and continuous infusion) dosages of MB used in the included studies that reported
and the design of the trial (RCTs and non-RCTs). mortality were relatively uniform, ranging from 1–2 mg/kg

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FIGURE 1
Study selection flow diagram according to the PRISMA guidelines.

for intravenous injection and 0.25–2 mg/kg/h for continuous HR (MD 4.70, 95% CI 2.38 to 7.02, P < 0.001; I2 = 71%;
infusion. Therefore, we did not perform subgroup analyses Table 2). Moreover, SVR (5 studies, n = 226) was also higher
based on the doses of MB. 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
Secondary outcomes significant difference in cardiac index between the two groups
(MD 0.36, 95% CI −0.03 to 0.74, P = 0.07; I2 = 95%;
Vasopressor requirement Table 2).
Four of the 15 included studies used MB in addition to
vasopressors, such as norepinephrine, epinephrine, dopamine,
and dobutamine. Four studies with 430 patients reported that
MB significantly reduced the requirement for vasopressors Oxygen metabolism
compared with the control group (SMD −0.77, 95% CI −1.26 Five (n = 208) of the 15 included studies reported lactate
to −0.28, P = 0.002; I2 = 80%; Table 2). values. The results showed that MB could significantly reduce
the level of lactate (MD −0.97, 95% CI −1.34 to −0.59,
P < 0.001; I2 = 72%; Table 2). However, only 3 studies
Hemodynamic changes reported DO2 I or VO2 I, and neither of them was significantly
Nine (n = 440) of the 15 included studies reported MAP, different between MB and the control groups (DO2 I: MD
which was significantly increased by MB (MD 4.76, 95% CI −19.63, 95% CI −106.30 to 67.04, P = 0.66; I2 = 98%; VO2 I:
2.99 to 6.54, P < 0.001; I2 = 33%; Table 2). Pooled data from MD 10.85, 95% CI −0.13 to 21.84, P = 0.05; I2 = 63%;
8 studies (n = 396) revealed that MB significantly increased Table 2).

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TABLE 1 Characteristics of included studies.

Study Country Design Setting Participants MB intervention Control Outcomes

Kirov et al. (12) Russia RCT ICU Septic shock Time: after diagnosis Placebo 1, 2, 3, 4, 5, 6, 8, 9,
n = 20 Dose: 2 mg/kg (iv) +0.25–2.00 11,12,13, 14, 15,16
mg/kg/h (iv 4 h)
Koelzow et al. UK RCT Surgery Ischemia reperfusion Time: 1 min before Placebo 1, 2, 5, 6, 7,11
(31) syndrome graft reperfusion
n = 38 Dose: 1.5 mg/kg (iv)
Memis et al. (24) Turkey RCT Anesthesiology Septic shock Time: after diagnosis Placebo 1, 2, 3,11,12,13,
n = 30 Dose: 0.5 mg/kg/h (iv 6 h) 15,16
Levin et al. (33) Argentina RCT Surgery Vasoplegic syndrome Time: after diagnosis Placebo 1,10,16
French n = 56 Dose: 1.5 mg/kg/h (iv 1h)
Swiss
Maslow et al. (32) USA RCT Surgery Vasoplegic syndrome Time: after the onset of Placebo 2, 3, 4, 6, 7, 16
n = 30 cardiopulmonary bypass
Dose: 3 mg/kg (iv)
Habib et al. (25) Egypt Observational CSICU Vasoplegic syndrome Time: after diagnosis Blank 1, 6, 10, 13, 14, 15
study n = 56 Dose: 2 mg/kg (iv) +0.5–1
mg/kg/h (iv, if needed)
Saha et al. (26) USA Observational ICU Vasoplegic syndrome Time: after diagnosis Blank 1, 13, 14
study n = 68 Dose: 1–2 mg/kg (iv) +1–2 mg/kg
(iv, if >1h)
Kofler et al. (35) USA Observational Anesthesiology Vasoplegic syndrome Time: after diagnosis Blank 1, 2, 6, 11,12,13, 14,
study n = 120 Dose: 2 mg/kg (iv) 15
Xiong et al. (27) China RCT Anesthesiology Septic shock Time: after diagnosis Blank 2, 3, 4, 5, 7, 8, 9
n = 40 Dose: 0.5–1.0 mg/kg/h (iv)
Li (36) China Observational ICU Septic shock Time: after diagnosis Blank 2, 4, 5
study n = 86 Dose: 4 mg/kg (iv)
Zhang and Wu China Observational ICU Septic shock Time: after diagnosis Blank 3, 5
(28) study n = 90 Dose: 2 mg/kg (iv) + 0.25–2
mg/kg/h (iv 24h)
Lu et al. (29) China RCT ICU Septic shock Time: after diagnosis Placebo 1, 3, 6, 7
n = 54 Dose: 2 mg/kg (iv) /+ 2 mg/kg/h
(iv 24 h)
Ma et al. (34) China RCT Anesthesiology Vasoplegic syndrome Time: 10 min before Placebo 2, 3, 7, 13, 15
n = 28 CPB shutdown
Dose: 2 mg/kg (iv)
Li (16) China q-RCT ICU Septic shock Time: after diagnosis Blank 1, 3, 5, 13
n = 66 Dose: 2 mg/kg (iv)
Zhang et al. (30) China RCT Surgery Vasoplegic syndrome Time: after diagnosis Dose: 2 Blank 2, 3, 4, 8, 9
n = 50 mg/kg (iv 3–4 h)

RCT, Randomized controlled trial; q-RCT, quasi-Randomized controlled trial; ICU, Intensive care unit; CSICU, Cardiac surgical intensive care unit; MB, Methylene blue; CPB,
Cardiopulmonary bypass; iv, intravenous injection; Outcomes: 1 Mortality; 2 Mean arterial pressure; 3 Heart rate; 4 Systemic vascular resistance; 5 Cardiac index; 6 Vasopressor
Requirement; 7 Lactate; 8, Oxygen delivery; 9, Oxygen consumption; 10, Renal failure; 11, Creatinine; 12, Alanine aminotransferase; 13 Intensive care unit length of stay; 14 Hospital
length of stay; 15 Duration of Mechanical Ventilation; 16 Adverse Reaction.

Organ function of renal failure (OR = 0.14, 95%CI 0.03 to 0.58, P = 0.007;
Among the 15 included studies, two studies (n = 112) I2 = 0%; Table 2), but had no effect on the level of creatinine
reported the incidence of renal failure, and three studies (n (SMD 0.37, 95% CI −0.84 to 0.57, P = 0.55; I2 = 90%;
= 163) reported the effect of MB on creatinine. The pooled Table 2). Moreover, three studies (n = 168) reported the data
data showed that MB was associated with a lower incidence of alanine aminotransferase. The pooled data showed that MB

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could significantly reduce the level of alanine aminotransferase In contrast to our study, Furnish et al. (18) showed that as a
(SMD −0.60, 95% CI −0.92 to −0.28, P < 0.001; I2 = 19%; rescue therapy for vasoplegic syndrome, there was no significant
Table 2). difference in mortality between the MB and hydroxocobalamin
groups. The meta-analysis by Pasin et al. (38) included 5 studies
with a total of 174 hypotensive patients and indicated that
Other secondary outcomes MB showed no detrimental effect on survival. The inconsistent
The effects of MB treatment on ICU LOS (6 studies, n = 332) effects of MB on mortality may be attributable to some potential
and hospital LOS (4 studies, n = 264) were −0.41 days (95% CI confounding factors, including different patients, methods and
−0.99 to 0.17, P = 0.16; I2 = 83%; Table 2) and −0.30 days (95% dosages of MB administration. Therefore, subgroup analyses
CI −9.82 to 9.23, P = 0.95; I2 = 87%; Table 2), respectively. Five were performed. We identified a significant difference between
studies (n = 254) reported the mechanical ventilation duration. groups favoring continuous infusion MB with a dosage of 0.25–
Compared with the control group, MB had no effect on the 2 mg/kg/h in septic shock patients. This result can be attributed
duration of mechanical ventilation (SMD −0.47, 95% CI −1.06 to several reasons. First, a possible “window of opportunity”
to 0.13, P = 0.13; I2 = 78%; Table 2). (the first 8 h) for MB’s effectiveness in sepsis has been proposed
(39), which indicated that MB was less effective as a late
rescue therapy (20). In most of the included studies, MB was
Adverse effects used in the early stage of vasodilatory shock patients (Table 1).
Second, MB acts rapidly after intravenous injection, with a
No serious side effects were found in this study. The terminal plasma half-life of 5–6 h (7). Considering the short-
adverse effects of MB reported in the included studies were blue acting effects of MB, continuous infusion for a longer time may
discoloration of the skin and urine and a temporary decrease in be more effective. Third, Juffferman et al. (40) found that the
mixed venous oxygen saturation. infusion of 1–3 mg/kg MB could improve circulation without
increasing the gastric mucosa-arterial carbon dioxide partial
pressure difference. Although the high dose of methylene blue (7
Discussion mg/kg) will further increase the systemic blood flow, splanchnic
blood perfusion may be compromised. In summary, our study
This systematic review and meta-analysis examined the suggests that MB use in early septic shock may benefit patients
effect of MB in 15 studies including more than 800 vasodilatory more, that continuous infusion is preferred, and that it starts
shock patients with various causes, including septic shock, with low effective doses.
vasoplegic syndrome, and ischemia reperfusion injury. The Our study further analyzed the possible mechanisms by
main finding is that MB as a catecholamine-sparing agent which MB improved mortality. First, it is worth noting that
may improve the survival of patients with vasodilatory shock. almost all of the included studies used MB as an adjunct
For secondary outcomes, MB significantly decreased the intervention to catecholamine vasopressor, which is the first
requirement for vasopressors. MB also had the beneficial effect choice for the treatment of vasodilatory shock (41). Although
on hemodynamic changes, organ function, and lactate level. catecholamine vasopressors increase blood pressure and cardiac
However, MB had no effect on mechanical ventilation duration, output, high doses may be responsible for several complications,
ICU LOS or hospital LOS. such as peripheral ischemia, dysrhythmias, and increased
In vasodilatory shock, elevated levels of NO and activation myocardial oxygen consumption, all of which were associated
of sGC are the main reasons for vasodilation. As an with an increased risk of death (42). This study showed that
NO inhibitor, MB has the ability to restore vascular tone compared with the control group, the vasopressor requirement
and increase blood pressure (6). Although MB represents in the MB group was significantly reduced. Second, NO leads to
another option of catecholamine-sparing agents, its role in severe hypoxia and organ failure by its direct cytotoxicity and
patients with vasodilatory shock is still inconsistent due to mediated hypotension (43). MB, as a NO inhibitor, improved
insufficient evidence. hemodynamics, including elevated MAP, HR, and SVR. Third,
Our review found that compared with placebo, MB MB reduced organ failure. The pooled data showed that MB was
treatment significantly reduced the mortality of patients with associated with a lower incidence of renal failure, also reduced
vasodilatory shock. Consistently, Levin et al. reported that MB the level of alanine aminotransferase. Fourth, vasoplegia for
was associated with a lower mortality and potentially faster more than 36–48 h is associated with a higher risk of multiple
reversal of vasoplegia compared to placebo in vasoplegic patients organ failure and death (44). Compared to conventional therapy,
(33). A recent meta-analysis by Perdhana et al. reported that MB administration reduced the duration of vasoplegia by 3
compared with placebo and hydroxocobalamin, administration times (33). As a result, the survival rate was improved. In
of MB significantly reduced mortality for vasoplegic syndrome summary, hemodynamic restoration is a crucial determinant
in cardiopulmonary bypass surgery patients (37). in survival probability. The consequence of classic stepwise

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FIGURE 2
Risk of bias summary assessments for included studies.

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FIGURE 3
Pooled mortality regarding the longest available time period within each study, odds ratio, methylene blue treatment vs. control; M-H,
Mantel–Haenszel; CI, Confidence interval.

TABLE 2 Secondary results of this meta-analysis.

Covariate Studies MD/SMD/OR LCI UCI P I2

Vasopressor requirement 4 −0.77 −1.26 −0.28 0.002 80

MAP 9 4.76 2.99 6.54 <0.001 33
HR 8 4.70 2.38 7.02 <0.001 71
SVR 5 181.87 39.30 324.44 0.01 88
CI 6 0.36 −0.03 0.74 0.07 95
Lactate 5 −0.97 −1.34 −0.59 <0.001 72
DO2 I 3 −19.63 −106.30 67.04 0.66 98
VO2 I 3 10.85 −0.13 21.84 0.05 63
Renal failure 2 0.14 0.03 0.58 0.007 0
Creatinine 3 0.37 −0.84 0.57 0.55 90
Alanine minotransferase 3 −0.60 −0.92 −0.28 <0.001 19
ICU LOS 6 −0.41 −0.99 0.17 0.16 83
Hospital LOS 4 −0.30 −9.82 9.23 0.95 87
Mechanical ventilation duration 5 −0.47 −1.06 0.13 0.13 78

P < 0.05 represented in bold OR, Odds ratio; MD, Mean deviation; SMD, standardized mean difference; LCI, Lower 95% confidence interval; UCI, Upper 95% confidence interval; MAP,
Mean arterial pressure; HR, Heart rate; SVR, Systemic vascular resistance; CI, Cardiac index; DO2I, Oxygen delivery; VO2I, Oxygen consumption; ICU, Intensive care unit; LOS, Length
of stay.

vasopressor approach is excessive catecholamine administration was no difference in oxygen delivery or oxygen consumption.
which leads to several complications and poor outcome. An early Considering the limited number of included studies, small
multimodal vasopressor therapy may be a better choice (45). sample size, and relatively high heterogeneity of this result, the
In addition, our study found that MB had a beneficial effect effect of MB on oxygen metabolism needs to be further verified
on oxygen metabolism, manifested as a decrease in lactate. by more studies.
Consistently, a recent meta-analysis (46) reported that serum No serious side effects were found in the included studies
lactate was significantly decreased after MB administration in in this meta-analysis. The main adverse effect of MB was blue
patients with refractory hypotension. Lactate can reflect tissue discoloration of the skin and urine. It should be noted that
oxygen metabolism and microcirculation perfusion, and its MB has been found to lead to local skin necrosis, increased
increase is closely related to high mortality (47). However, there pulmonary vascular resistance, arrhythmias, and decreased

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oxygen saturation (48). Moreover, Martino et al. reported 3 Data availability statement
cases of life-threatening serotonin toxicity, including coma, in
patients who undergoing chronic selective serotonin reuptake The original contributions presented in the study are
inhibitor therapy and received MB for vasoplegic syndrome (49). included in the article/Supplementary materials, further
Most side effects are dose-related, and the application of MB is inquiries can be directed to the corresponding author/s.
relatively safe when the dose does not exceed 2 mg/kg (50).
To our knowledge, the present study is the most extensive
systematic review and meta-analysis on the role of MB in Author contributions
patients with vasodilatory shock, with a broad search strategy,
inclusion of extensive studies and the latest research with The study was designed by G-JZ. C-CZ and Y-JZ acquired
high methodological quality. Moreover, we performed various the data, performed the analysis, and wrote the manuscript.
subgroup analyses for mortality, the main outcome of this study, Z-QL helped with the search criteria. Z-JH corrected and
and generated new hypotheses for practical applications. In contributed to the manuscript. Tables were produced by YH. All
addition, this study was the first to analyze the effect of MB on authors read and approved the final manuscript.
oxygen metabolism.
Several limitations should be considered when interpreting
the findings of this study. First, many included studies
Conflict of interest
were observational studies. The evidence level was not high
The authors declare that the research was conducted in the
enough. However, a subgroup analysis for RCTs was also
absence of any commercial or financial relationships that could
performed in this meta-analysis. Second, the etiology of
be construed as a potential conflict of interest.
shock, severity of illness and MB intervention were diverse
in the included studies. These can be a risk of bias
and weaken the strength of the evidence. Third, although Publisher’s note
the number of included studies was large, all of them
were restricted to small sample sizes. Therefore, large- All claims expressed in this article are solely those of the
scale clinical trials are needed to clarify the findings of authors and do not necessarily represent those of their affiliated
this study. organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
Conclusion or endorsed by the publisher.

In conclusion, this meta-analysis suggests that the

adjunction of continuous administration of MB to vasopressors Supplementary material
may be associated with lower mortality in patients with
vasodilatory shock with no severe side effects. Further The Supplementary Material for this article can be
large-scale RCTs are required to ascertain MB efficacy found online at: https://www.frontiersin.org/articles/10.3389/
and safety. fmed.2022.950596/full#supplementary-material

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