Methylene blue in the critical care setting

Table 1 Summary of individual studies on methylene blue for shock and vasoplegic syndromes

Author	Type of study	Indication	Dose for studies	Results
Zhu et al[24], 2008	Prospective study (animal study)	Septic shock	2 mg/kg IV	Higher MAP and lower plasma levels of TNF alpha, IL-6, IL-8, NO; and LA were observed in the MB group
				12-hour survival rates were not statistically significant
Kirov et al[17], 2001	RCT	Septic shock	2 mg/kg IV bolus for 2 hours, followed by stepwise infusion of 0.25 mg/kg/hour, 0.5 mg/kg/hour, 1 mg/kg/hour, and 2 mg/kg/hour, that were maintained for 1 hour each	MB increased mean arterial pressure; vasopressor use decreased 87%, 81%, 40% respectively (P < 0.001)
				MB also reduced the body temperature and the plasma concentration of nitrates/nitrites and leukocytes
Luis-Silva et al[20], 2024	RCT	Septic shock	loading dose of MB (3 mg/kg) and maintenance (0.5 mg/kg/hour) for 48 hours	The MB group showed an immediate reduction in vasopressor use and higher IL-10 levels compared to the control group
Juffermans et al[16], 2010	RCT	Septic shock	1 mg/kg, 3 mg/kg, or 7 mg/kg over 20 minutes	Methylene blue had a dose-dependent effect on cardiac index, mean arterial, mean pulmonary artery and pulmonary artery occlusion pressures, left ventricular function, O(2) delivery and consumption and lactate levels
				Higher dose reduced splanchnic perfusion
Rajbanshi et al[31], 2023	Prospective study	Septic shock	Bolus dose with 2 mg/kg dose in 20 minutes	MAP in MB group increased (P = 0.005); vasopressor-free time increased (OR = 4.02, 95%CI: 1.18-13.68)
				No significant difference in terms of mortality, length of ICU stays, ventilator free days, and incidence of AKI
Hiruy et al[32], 2023	Retrospective cohort study	Vasoplegic shock post-cardiopulmonary bypass	Median bolus dose of methylene blue was 1.2 mg/kg. For patients administered a continuous infusion, the median dose was 0.25 mg/kg/hour for a median duration of 10 hours	Great reduction in vasopressor requirements and an increase in MAP were noted in the hydroxocobalamin group compared with the methylene blue group (P < 0.001)
Leyh et al[58], 2003	Prospective observational study	Norepinephrine-refractory vasoplegic shock after cardiopulmonary bypass	2 mg/kg IV over 20 minutes	SVR increased; norepinephrine use decreased (P < 0.05)
Mazzeffi et al[36], 2017	Retrospective cohort study	Post-cardiopulmonary bypass vasoplegic syndrome	MB doses were between 1 mg/kg and 2 mg/kg given as bolus over 10 minutes	MAP increased by 8 mmHg in MB group (P = 0.004)
Mehaffey et al[19], 2017	Retrospective study	Vasoplegic syndrome post - cardiopulmonary bypass	Bolus dose of 2 mg/kg IV MB followed by 12-hour infusion at 0.5 mg/kg/hour	Early MB uses improved survival and reduces the risk-adjusted rate of major adverse events in these patients (OR = 0.35, P = 0.037)
Shaker et al[2], 2025	RCT	Vasoplegic syndrome in cardiac surgery	MB bolus of 1 mg/kg or MB bolus of 4 mg/kg	Decreased time to vasopressor termination, and vasopressor-free days at 28 days
			Followed by 0.25 mg/kg/hour infusion of MB for 72 hours after the bolus dose	The 4 mg/kg bolus dose group was protective against mortality with a hazard ratio of 0.29
Maslow et al[38], 2006	RCT	Hypotension during cardiopulmonary bypass and cardioplegic arrest	3 mg/kg IV	MAP increased, SVR increased, vasopressor use decreased (P < 0.05)
				Serum lactate levels were lower in MB patients
Ozal et al[37], 2005	Prospective study	Prevention of vasoplegic syndrome in coronary artery bypass graft surgery	2 mg/kg IV pre-op for more than 30 minutes	Reduces the incidence and severity of vasoplegic syndrome (0% vs 26%, P < 0.001); shortens both ICU and hospital stays
Huang et al[30], 2023	RCT	Hypotension in obstructive jaundice surgery	2 mg/kg IV	Noradrenaline use decreased (P = 0.017)
Luppi et al[23], 2024	RCTAnimal study	Animal study - hemorrhagic shock	Not specified	MAP recovery with MB + BT vs blood transfusion alone was significant (P < 0.05)
Ghiassi et al[25], 2004	RCTAnimal study	Refractory hemorrhagic shock	Not specified	Improved survival (P < 0.05), MAP increased, CO increased, and lactate decreased

MB: Methylene blue; IV: Intravenous; MAP: Mean arterial pressure; TNF: Tumor necrosis factor; IL-6: Interleukin-6; IL-8: Interleukin-8; NO: Nitric oxide; LA: Lactic acid; RCT: Randomized controlled trial; CI: Confidence interval; OR: Odds ratio; SVR: Systemic vascular resistance; ICU: Intensive care unit; AKI: Acute kidney injury; CO: Cardiac output; BT: Blood transfusion; Pre-op: Pre-operative..

Table 2 Summary of systematic reviews and meta-analyses on the use of methylene blue in shock and vasoplegic syndromes

Author	Type of study	Indication	Dose for studies	Results
Cadd et al[33], 2024	4 retrospective studies	263	Vasoplegic shock post-cardiopulmonary bypass	Hydroxocobalamin vs MB: Hydroxocobalamin was associated with a significant improvement in mean arterial pressure at 1 hour (MD: 5.30 mmHg, 95%CI: 2.98-7.62), total vasopressor dose at 1 hour (MD: -0.13 mcg/kg/minute NEE, 95%CI: -0.25 to -0.01) and total vasopressor dose at 6 hours (MD: -0.15 mcg/kg/minute NEE, 95%CI: -0.21 to -0.08) compared to MB
				No differences were observed in SVR or mortality between groups
Huang et al[39], 2024	6 RCTs	265	Septic shock, vasoplegic syndrome after cardiac surgery and ischemic reperfusion	MB reduced the duration of mechanical ventilation (MD: -0.68; 95%CI: -1.23 to -0.14), ICU LOS and (MD: -1.54, 95%CI: -2.61 to -0.48); hospital LOS (MD: -1.97; 95%CI: -3.92 to -0.11)
			Syndrome due to liver transplantation	No significant difference in mortality between the MB and placebo groups (ORs = 0.59; 95%CI: 0.32 to -1.06)
Zhao et al[4], 2022	10 RCT	832	Septic shock, vasoplegic syndrome and ischemic reperfusion	Mortality decreased (OR = 0.54, 95%CI: 0.34-0.85, P = 0.008); vasopressor use decreased (MD: -0.77, 95%CI: -1.26 to -0.28, P = 0.002)
	5 observational studies			MB increased MAP, HR and SVR. MB was associated with a lower incidence of renal failure. MB was linked to reduced lactate levels
Brokmeier et al[34], 2023	3 retrospective cohort studies	-	Vasoplegic shock post-cardiopulmonary bypass	Hydroxocobalamin vs MB: Hydroxocobalamin was associated with a higher MAP at 1 hour (MD: 7.80, 95%CI: 2.63-12.98); no difference in mortality (OR = 0.92, 95%CI: 0.42-2.03)
Ng et al[26], 2025	5 RCTs	257	Septic shock	MAP increased (MD: 8.4 mmHg, 95%CI: 5.01-11.75); mortality decreased (OR = 0.49, 95%CI: 0.27-0.88) reduced LOS (MD: -1.94 days, 95%CI: -3.79 to -0.08, P = 0.04, and increased PaO2/FiO2 (MD: 34.78, 95%CI: 8.94 to 60.61, P = 0.008)
Alkazemi et al[27], 2024	15 (5 RCTs, 10 observational studies)	441	Septic shock	Mortality decreased (OR = 0.52, 95%CI: 0.38-0.66, P < 0.001); ICU LOS decreased in 1 study; MAP increased post-infusion in 3 studies
Ballarin et al[12], 2024	3 RCTs	141	Septic shock	ICU LOS decreased (MD: -1.58, 95%CI: -2.97 to -0.20, P = 0.03); ventilation days decreased (MD: -0.72, 95%CI: -1.26 to -0.17, P = 0.01); time to vasopressor discontinuation decreased (MD: -31.49 hours, 95%CI: -46.02 to -16.96, P < 0.0001)

MB: Methylene blue; MAP: Mean arterial pressure; MD: Mean difference; CI: Confidence interval; NEE: Norepinephrine equivalent; SVR: Systemic vascular resistance; ICU: Intensive care unit; LOS: Length of stay; OR: Odds ratio; RCT: Randomized controlled trial; HR: Heart rate; PaO₂/FiO₂: Ratio of arterial oxygen partial pressure to fraction of inspired oxygen.