Is methylene blue a recommended non-catecholamine vasopressor to treat vasodilatory shock?
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Background
One common form of circulatory shock seen in patients admitted to an intensive care unit (ICU) is vasodilatory shock.1 Its clinical manifestation may result from lowered systemic vascular resistance (SVR) and modified oxygen delivery to cells.1, 2 Sepsis is the most frequent cause of vasodilatory shock, but other causes include anaphylaxis, spinal cord injury (also called neurogenic shock), acute pancreatitis-related systemic inflammatory response, postoperative vasoplegia, and direct vascular relaxation following general and neuraxial anesthesia. In all forms of vasodilatory shock, the renin-angiotensin-aldosterone system is triggered, plasma catecholamine concentrations are markedly raised, and eventually, vasodilation and hypotension lead to reduced oxygen supply to tissues.2 Hemodynamic stabilization with fluids and vasopressors is critically important for vasodilatory shock treatment. If left untreated, it can lead to reduced perfusion pressures resulting in insufficient cellular oxygen consumption, anaerobic metabolism, organ failure, and death.1
Guideline Recommendations
The 2021 Surviving Sepsis Campaign guidelines for treatment of septic shock recommend initial resuscitation with intravenous fluids followed by administration of vasopressors (if required) titrated to a target mean arterial pressures (MAP) of 65 mm Hg for hemodynamic management.3 Norepinephrine, a catecholamine vasopressor, is recommended as the first-line agent over other vasopressors (such as vasopressin, epinephrine, and angiotensin II). Relative to heart rate, norepinephrine primarily induces vasoconstriction and raised MAP because it is a potent agonist of α-1 and β-1 adrenergic receptors. Negative outcomes may arise from the stepwise vasopressor dosing strategy to treat vasodilatory shock due to the overall catecholamine burden. The achievement of the desired MAP often requires high doses of norepinephrine, which increases the risk of arrhythmias, death, and other complications due to the strong vasoconstrictive effects at α-adrenergic receptors and β-adrenergic receptor stimulation at the myocardium level. It also increases the risk of digital, mesenteric, and myocardial ischemia.1,4 Patients with septic shock may benefit from the alternate or supplemental use of non-catecholamine vasopressors, particularly those patients with catecholamine-resistant refractory shock.4 Methylene blue is a non-catecholamine vasopressor that works by inhibiting 2 different enzymes: guanylyl cyclase and nitric oxide synthase.5 The cytokines generated in response to shock have less of a vasodilatory effect as a result of this inhibition. The Surviving Sepsis Campaign guidelines recommend using norepinephrine as the first line agent over other non-catecholamine vasopressors, specifically listing out vasopressin and angiotensin II as comparator agents.3 The guidelines do state that for patients with septic shock on norepinephrine and inadequate MAP, vasopressin can be added instead of escalating norepinephrine dosing. Other non-catecholamine vasopressors such as methylene blue are not mentioned in the guidelines.
Efficacy of Methylene Blue in Vasodilatory Shock
In general, only a small number of randomized controlled trials (RCTs) and a few cohort studies and case reports support the use of non-catecholamine medications in the treatment of vasodilatory shock. Angiotensin II is the only FDA-approved non-catecholamine agent indicated for treatment of vasodilatory shock, and methylene blue has an off-label indication for use in septic shock or other vasodilatory shock states according to tertiary drug resources.6 The Table below summarizes relevant clinical efficacy data for use of methylene blue in patients with vasodilatory shock.
The 2023 meta-analysis by Brokmeier and colleagues compared hydroxobalamin and methylene blue in vasodilatory shock patients and found that both agents reported similar hemodynamic outcomes.7
The 2022 meta-analysis by Zhao and colleagues evaluated the effectiveness of methylene blue compared to placebo for treatment of vasodilatory shock.8 Most of the studies included in the meta-analysis utilized concomitant administration of vasopressors and methylene blue; concomitant administration improved hemodynamic parameters and minimized vasopressor requirements in the analyzed studies.
An older meta-analysis from 2015 by Belletti and colleagues evaluated non-catecholamine vasopressors (e.g., vasopressin, methylene blue, terlipressin) compared to various comparator groups.9 The pooled estimates showed that non-catecholamine vasopressors significantly reduced mortality in patients with vasodilatory shock, however, individual agent analysis did not reveal statistically significant reduction in mortality.
An RCT by Ibarra-Estraca compared early adjunct methylene blue treatment to placebo in patients with septic shock.10 Methylene blue started within 24 hours of septic shock shortened the time needed to vasopressor discontinuation and increased the number of vasopressor-free days at 28 days.
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| Table. Meta-analyses and RCTs on the use of methylene blue for vasodilatory shock.7-10 | |||
|---|---|---|---|
| Study design and duration | Subjects | Interventions | Results |
| Meta-analyses | |||
| Brokmeier 2023 MA of 12 case reports, 9 case series, and 3 retrospective cohort studies For comparison to methylene blue, analysis limited to n=3 observational studies Follow-up duration: NR | N=123 adults with cardiac surgery vasoplegia | Hydroxocobalamin Methylene blue | Comparative outcomes Hydroxocobalamin was associated with a greater MAP at 1 hour compared to methylene blue (MD 7.80; 95% CI, 2.63 to 12.98) Vasopressor dosage at 1 hour was similar between both groups (MD -0.06; 95% CI, -0.21 to 0.09; I2 = 83%) No significant differences in the change in MAP or vasopressor dosage at 1 hour compared to baseline between hydroxocobalamin and methylene blue No difference in mortality between both groups (OR 0.92; 95% CI 0.42 to 2.0) |
| Zhao 2022 MA of 7 RCTs, 3 quasi-RCTs, and 5 observational cohort studies Follow-up duration: up to 90 days | N=832 adults who received methylene blue for vasodilatory shock | Methylene blue Control (placebo) | Primary Mortality (n=9 studies); methylene blue significantly reduced mortality compared to the control group (OR, 0.54; 95% CI 0.34 to 0.85; p = 0.008; I2 = 7%) Secondary Vasopressor requirements (n=4 studies); methylene blue significantly reduced vasopressor requirements compared to the control group (SMD, −0.77; 95% CI, −1.26 to −0.28; p = 0.002; I2 = 80%) Hemodynamic changes (n=9 studies); methylene blue significantly increased MAP compared to control (MD, 4.76; 95% CI, 2.99 to 6.54; p < 0.001; I2 = 33%). Other parameters such as HR (MD, 4.70; 95% CI 2.38 to 7.02; p < 0.001; I2= 71%) and SVR (MD, 181.87; 95% CI, 39.30 to 324.44; p= 0.01; I2 = 88%) were also significantly increased in the methylene blue group compared to control Oxygen metabolism (n=5 studies); methylene blue significantly reduced lactate levels compared to control (MD, −0.97; 95% CI, −1.34 to −0.59; p < 0.001; I2 = 72%) |
| Belletti 2015 MA of 20 RCTs | N=1608 adult patients treated with non-catecholamine vasopressors who had/ or were at risk for vasodilatory shock | Vasopressin Terlipressin Methylene blue Comparator group (e.g., placebo, norepinephrine, dopamine, standard treatment) | Primary Mortality (n=20 studies); pooled estimates on use of non-catecholamine vasopressors was associated with significantly reduced mortality (RR, 0.88; 95% CI, 0.79 to 0.98; p= 0.02; I2 = 0%) No individual non-catecholamine agent was associated with a statistically significant reduction in mortality |
| Randomized Controlled Trials | |||
| Ibarra-Estrada 2023 SC, DB, RCT Follow-up: up to 28 days | N= 308 adults with septic shock requiring norepinephrine to maintain MAP | Methylene blue 100 mg x 3 doses Placebo | Primary Time to vasopressor discontinuation: 69 hours in the methylene blue group compared to 94 hours in placebo group (MD, 29.4; 95% CI, 15.4 to 50.7; p < 0.001) Secondary Vasopressor-free days at day 28: the methylene blue group had 1.0 more vasopressor-free days compared to placebo (p=0.008) AEs: most common AE was green-blue urine staining occurring in 93% of the methylene blue group; methemoglobin saturation was significantly higher in the methylene blue group (2.9%) compared to placebo (0.5%) (p< 0.001) |
| Abbreviations: AEs=adverse events; CI=confidence interval; DB=double-blind; HR=heart rate; MA=meta-analysis; MAP=mean arterial pressure; MD=mean difference; NR=not reported; OR=odds ratio; RCT=randomized controlled trial; RR=risk ratio; SC=single center; SMD: standardized mean difference; SVR=systemic vascular resistance | |||
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Conclusion
Vasodilatory shock is primarily caused by sepsis but can also result from various other conditions such as postoperative vasoplegia, anaphylaxis, and spinal cord injury.1,2 The Surviving Sepsis guidelines recommend that intravenous fluids be used first-line for fluid resuscitation, and that vasopressors such as norepinephrine be used to regulate hemodynamics.3 Vasopressor selection is patient-specific and excessive vasopressor dosages might have serious side effects. Non-catecholamine vasopressors such as vasopressin and angiotensin II, along with other agents like methylene blue and hydroxocobalamin, may be helpful for individuals experiencing refractory shock and to reduce the catecholamine burden.4 Non-catecholamine vasopressor usage (other than vasopressin and angiotensin II) are not mentioned in the Surviving Sepsis guidelines.3 While there are a few meta-analyses and RCTs on methylene blue treatment for vasodilatory shock, there is substantial variability amongst studies in dosage, study design, and study populations. To validate the effectiveness and utility of methylene blue in vasodilatory shock, more robust evidence and comparative data is required.
References
- Wieruszewski PM, Khanna AK. vasopressor choice and timing in vasodilatory shock. Crit Care. 2022;26(1):76. Published 2022 Mar 22. doi:10.1186/s13054-022-03911-7
- Lahiry S, Thakur S, Chakraborty DS. Advances in vasodilatory shock: A concise review. Indian J Crit Care Med. 2019;23(10):475-480. doi:10.5005/jp-journals-10071-23266
- Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47:1181–247
- Zhong L, Ji XW, Wang HL, Zhao GM, Zhou Q, Xie B. Non-catecholamine vasopressors in the treatment of adult patients with septic shock-evidence from meta-analysis and trial sequential analysis of randomized clinical trials. J Intensive Care. 2020;8(1):83. Published 2020 Oct 31. doi:10.1186/s40560-020-00500-0
- Heyman HM, Serrano RA. Vasoplegic syndrome and noncatecholamine therapies. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from:
- Lexi-Drugs. Lexicomp Online. Lexicomp; 2024. Accessed August 2024. https://online.lexi.com
- Brokmeier HM, Seelhammer TG, Nei SD, et al. Hydroxocobalamin for vasodilatory hypotension in shock: a systematic review with meta-analysis for comparison to methylene blue. J Cardiothorac Vasc Anesth. 2023;37(9):1757-1772. doi:10.1053/j.jvca.2023.04.006
- Zhao CC, Zhai YJ, Hu ZJ, Huo Y, Li ZQ, Zhu GJ. Efficacy and safety of methylene blue in patients with vasodilatory shock: A systematic review and meta-analysis. Front Med (Lausanne). 2022;9:950596. Published 2022 Sep 26. doi:10.3389/fmed.2022.950596
- Belletti A, Musu M, Silvetti S, et al. Non-Adrenergic vasopressors in patients with or at risk for vasodilatory shock. A systematic review and meta-analysis of randomized trials. PLoS One. 2015;10(11):e0142605. Published 2015 Nov 11. doi:10.1371/journal.pone.0142605
- Ibarra-Estrada M, Kattan E, Aguilera-González P, et al. Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial. Crit Care. 2023;27(1):110. Published 2023 Mar 13. doi:10.1186/s13054-023-04397-7
Prepared by:
Faria Munir, PharmD, MS, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
September 2024
The information presented is current as August 21, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.