Effects of a single bolus of methylene blue on 24-hour hemodynamics in vasodilatory shock

Effects of a single bolus of methylene blue on 24-hour hemodynamics in vasodilatory shock | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of a single bolus of methylene blue on 24-hour hemodynamics in vasodilatory shock Leena Ramadan, Anthony Rowe, Michael McCurdy, Michael Mazzeffi, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8355315/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Methylene blue (MB) can cause transient hypertension in healthy subjects, but studies examining its efficacy over time in persistent shock states are lacking. Methods Adults in shock who received methylene blue from 2017 to 2021 were analyzed retrospectively. Hourly hemodynamics from 12 hours (h) before and after treatment were collected, and the difference and hourly change of mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and norepinephrine-equivalent dose (NED) were examined in mixed-effect models. Results This study included hemodynamic data points from 58 patients. In the linear mixed effects model, significant differences in MAP and NED existed 12-h after MB administration (EFE 4.0, p = 0.01 and EFE − 0.12 ug/kg/min, p = .04, respectively). However, the two-piecewise mixed model found that the hourly change in MAP, SBP, and DBP was not different from zero in either the pre-administration or post-administration segments. Conclusions MB administration has been observed to increase MAP and decrease vasopressor requirements in shock. Our results suggest that in refractory vasoplegia, MB may improve MAP and vasopressor requirement over 12 hours in the linear mixed model, but not the piecewise mixed model, suggesting that the positive hemodynamic changes of MB may not be uniform. Clinically, these findings reinforce that bolus-dose MB likely has an impactful, though transient, physiological effect when given in addition to standard pharmaceutical management of refractory shock. MB should be considered as an adjunct therapy in refractory shock. Methylene blue refractory shock hemodynamics vasopressors Figures Figure 1 Figure 2 Figure 3 Background Septic shock mortality ranges from 30% to 75% in catecholamine refractory shock 1,2 . The guiding principle for sepsis management is infectious primary source control with chemical (i.e. antimicrobials) and potentially mechanical (i.e. drainage or extraction) pathogen removal. Optimal supportive care is similarly important, including vasopressors, when fluid resuscitation fails to correct the shock 3 . Despite the use of standard-of-care vasopressor agents, some patients exhibit vasoplegia, resulting in an inability to restore sufficient blood flow to critical organs. Maintaining hemodynamic stability is important, as the duration of hypotension impacts outcomes, with mortality increasing from 39.7% to 54.1% when hypotension extends from 2–4 hours to 4–6 hours 4 . Catecholamines are used to treat shock, though their risk profile is burdensome, including an increased incidence of adverse cardiac events and digital/ limb ischemia 2,5,6 . Combining vasopressor drugs may ameliorate the development of these complications while stabilizing hemodynamics. As vasopressors escalate, adjuncts such as hydroxocobalamin and MB are occasionally implemented for rescue therapy 7 . Nitric oxide (NO) is produced via enzymatic activity of NO synthase, which can be upregulated during sepsis. NO induces vasodilation through guanylyl cyclase stimulation and cyclic guanosine monophosphate (cGMP) production. With a half-life of approximately 5.25 hours 8 , intravenous MB is a thiazide dye that inhibits nitric oxide synthase and guanylate cyclase, reducing nitric oxide-induced smooth muscle dilatation and inducing vasoconstriction 9–11 . Most of the evidence demonstrating decreased vasopressor burden and improved hemodynamics with MB comes from both randomized and non-randomized trials in post cardiopulmonary bypass vasoplegia 10,12–14 . Scant evidence supports the use of MB in refractory shock 15 . However, one recent randomized control trial on MB use in septic shock demonstrated faster vasopressor discontinuation, more vasopressor free days, and shorter intensive care unit (ICU) length of stay 16 . Meta-analyses found that MB potentially reverses vasodilatation in critically ill patients, leading to improved hemodynamics and mortality, even in septic shock subgroups 17,18 . We characterized the hemodynamic effects of MB over 12 hours after administration and hypothesized that MB would not be associated with improved hemodynamic parameters over a 24-hour period. Based on its short half-life, we also hypothesized that the rate of change in the hemodynamic parameters would similarly not improve over this time. Methods Patients This retrospective observational study was approved by the institutional review board (IRB) at the University of Maryland Baltimore. The study was conducted at a single tertiary care academic hospital in the United States. Patients admitted between February 2017 and February 2021 who were administered MB for shock were identified by pharmacy records. The dose of MB was 1.5 mg/kg delivered as a single bolus dose over 5 minutes. Patients were excluded if they were < 18 years old, pregnant, or the entry was for a repeated dose of MB. Demographics, past medical history, severity of illness, etiology of shock, hourly vasopressor dose, hourly vitals, other vasoconstrictive agent use, and outcomes were recorded for all patients. Study Outcomes The study’s primary outcome was the adjusted difference in the MAP from the 12 hours preceding and 12 hours following MB administration. The secondary outcome was the hourly rate of change in MAP during the same period. As exploratory endpoints, we also examined the mean difference in SBP, DBP, and NED, as well as the hourly rate of change in these variables during the twelve hours before and after medication administration. Statistical Analysis Data analysis was undertaken using RStudio (RStudio Team (2020). RStudio: Integrated Development for R. RStudio, PBC, Boston, MA URL http://www.rstudio.com/ ). Data interpretation was permitted by the tidyverse package. Cohort description was performed with measures of central tendency as appropriate based on normality of the sample, evaluated by the Shapiro-Wilk test. Paired hemodynamic data was compared by a paired t-test. Piecewise and mixed linear models were fit using the lmer package and model summaries are reported. Effect estimates are illustrated using the metafor and forestplot packages. Data visualization was accomplished with the ggplot2 package. Results Fifty-eight patients were included in the study. The median age was 60 (IQR 48–65) and 31% of the patients were female ( Table 1 ). Most patients had surgical admissions (65.5%). Comorbidities such as hypertension and chronic kidney disease were present in 37.9% and 8.6% of patients, respectively. The etiology of shock was most commonly sepsis (61.5%), followed by hemorrhage (10.3%), unknown (10.3%), and neurogenic (2.6%). 10.3% of patients received MB in the peri-cardiopulmonary bypass period. Gram-negative, gram-positive, and fungal organisms (n = 54) were identified in 14.8%, 5.6%, and 5.6%, respectively, while cultures were negative 74.1% of the time, which is slightly higher than the 47–56% rate of culture-negative sepsis identified from the Nationwide Inpatient Sample and Prehospital Antibiotics Against Sepsis (PHANTASi) trial 19 . Patients with refractory shock were treated with therapies that are considered standard of care prior to being considered for MB administration. This includes fluid resuscitation, antibiotics, vasopressors, and source control when applicable. Most patients received steroids, with 89.7% receiving hydrocortisone and 15.5% receiving fludrocortisone. At baseline (Table 2), the median NED of vasopressors one hour prior to MB administration was 0.6 µg/kg/min (IQR 0.4–0.9) and the median intravenous fluid administration was 6.8 L (IQR 5.0-11.4 L) in the 24 hours prior to MB and 5.2 L (IQR 3.2–7.1 L) in the 24 hours post administration (p = 0.004). Once patients were requiring multiple vasopressors despite fluid administration and shock was deemed refractory, patients were considered for MB dosing. Time from hospital admission to MB administration was 4 days, while time from intensive care unit (ICU) admission to administration was 2 days. Prior to MB, patients had a median cardiac index of 2.5 L/min/m 2 (IQR 2.1–3.1) and a median central venous pressure (CVP) of 15 mm Hg (IQR 12–16). Hydrocortisone was used prior to MB in 89.7% of patients. The median lactate was 5.4 mmol/L. Overall, cohort mortality rate was 82.8%, with a median ICU length of stay of 10.5 days (IQR 2–25) and hospital length of stay of 14 days (LQR 4–33). Effect on Mean Arterial Pressure: Boxplots of unadjusted hemodynamic parameters for pre- and post-MB administration are depicted in Fig. 1 . The adjusted difference in MAP before and after MB administration was modeled with a linear mixed effects model to account for repeated measures of MAP within patients. There was a significant difference in the pre-administration and post-administration MAPs (66 mmHg [pre] vs 70 mmHg [post], estimated fixed effect [EFE] 4, p = 0.01). However, the change in MAP was modeled in the 12-hour period surrounding MB administration with a two-piecewise linear mixed model. MB had no significant effect in either the pre-administration segment (EFE − 0.7 mmHg, CI -2.3-0.9, p = 0.4), or the post administration segment (EFE 1.0 mmHg, CI -0.6-2.6, p = NS), indicating that MB was not associated with an hourly increase in MAP (Table 3 and Fig. 2A). Effect on Systolic and Diastolic Blood Pressure: The administration of MB did not significantly change SBP (EFE − 1 mmHg, CI 88.4–118, p = 0.1) or DBP (EFE 2 mmHg, CI 51–58, p = 0.08) (Fig. 1). The hourly rate of change was also not statistically significant from zero after MB administration for SBP (EFE − 6.4, CI -32.4-19.6, p = NS) or DBP (EFE 1.0, CI -0.5-2.5, p = NS) ( Table 3, Fig. 2A ). Effect on Norepinephrine-Equivalent Dose: In the linear mixed model, the adjusted pre-administration NED was 1.1 ug/kg/min, while the post administration NED was 1.0 ug/kg/min (EFE − 0.1 ug/kg/min, CI 0.7–1.3, p = 0.04). Despite this observation, the administration of MB was not associated with significant improvement in the slope of the NED (EFE − 0.11 ug/kg/min/h, CI -0.13—0.08, p = NS) ( Table 3, Fig. 2B ). Discussion Our study demonstrated that hemodynamics at the 24-hour mark post-MB administration did not change compared to pre-MB values. The linear mixed model, which allows for an overall estimate of treatment effect over 24 hours, demonstrated that patients who received MB required a lower cumulative dose of pressors and achieved higher MAPs. However, when the same data was examined in the piecewise linear mixed model, there was no significant improvement of NED or MAP. This difference indicates that the hemodynamic improvement seen from MB is not uniform but manifests early and disappears quickly. Our findings indicate the heterogeneity of response to MB boluses. This study differs from previous studies by accounting for repeated measures through linear mixed models and piecewise models to incorporate hourly measurements of hemodynamics into our analysis. Linear mixed models are used with hierarchical data that includes repeated measures of the same subjects over time, handling dependency of the data and individual variability/random effects while still estimating overall trends. Piecewise models are used when different linear relationships between variables in different ranges are expected, with each segment representing a distinct phase, making this analysis useful for patterns seen before and after an intervention. The use of this hybrid methodology models both within-person correlations and changes in slope, allowing for an increased number of sampling timepoints and increasing the power of each model. Nesting of observations within patients enabled each patient to contribute an individual slope and intercept to the overall model, whereas this was not possible with the previous analyses. In addition, the autoregressive structure of the piecewise models enabled us to account for the decreasing correlation between time points as the time interval increased. The human body has evolved intricate redundant neural, hormonal, and local autoregulatory systems that act synergistically to preserve vital perfusion during shock states. Sympathetic activation via catecholamine release increases systemic vascular resistance, the renin-angiotensin-aldosterone system promotes additional vasoconstriction, and parallel regulatory mechanisms such as nitric oxide modulation redistribute blood flow to critical areas to provide a multi-layered design that acts as a safety net to prevent cardiovascular collapse. Medical management of refractory shock has targeted these physiological redundancies through medications. Early studies of MB demonstrated hemodynamic improvement secondary to improved systemic vascular resistance 20,21 . MB shows promise as being integrated into a multimodal regimen that attenuates excessive nitric oxide signaling, restoring vascular tone, and allowing for lower cumulative vasopressor requirements. Two small randomized controlled trials from two decades ago that were performed in early septic shock indicated that continuous infusion of MB increased MAP and decreased vasopressor requirements without adverse effects 22,23 . Since these trials, momentum for MB use in refractory shock slowed until a recent randomized trial found decreased time to vasopressor discontinuation 16 . More recent meta-analyses furthermore show both improved hemodynamics and a significant reduction in mortality 17,18 . No studies to date have meaningfully examined patient centered outcomes with MB. The principle of combining vasoactive agents is to decrease catecholamine burden. This strategy was most recently demonstrated by ATHOS-3 24 . Trials that leverage non-adrenergic agents investigate how to use a multipronged therapeutic approach for managing hypotension, thereby replicating the body’s natural redundant hemodynamic pathways, impacting outcomes compared to escalation of a single agent alone. As demonstrated by Sessler et al., the longer the duration of hypotension, the higher the risk of end-organ dysfunction and therefore increased mortality 25–27 . It is therefore important to achieve MAP targets rapidly rather than tolerate prolonged hypotension. This can be done by using adjunctive pharmaceutical agents, such as MB, in conjunction with conventional therapies for management of refractory hypotension. Deploying alternative, targeted salvage therapies for shock may lead to a more rapid resumption of end-organ perfusion. Examples of such adjuncts include corticosteroids, immunomodulating agents, MB, and hydroxycobalamin 7 . The reported experiences regarding MB timing, modes of administration, quantified concomitant vasopressor burden, and outcomes are inconsistent. Due to its short half-life and lack of a steady state, bolus-dose MB alone may not counteract vasoplegia over longer periods. The recent randomized control trial that showed improvement in hemodynamics with MB administration used a MB infusion. The most recent meta-analysis showed an improvement in hemodynamics and mortality; however, studies included were a combination of bolus and infusion dosing 16–18 . There are several limitations to this study. This is a retrospective study at a single center. Linear mixed models, while well suited for repeated measures data, may oversimplify the complex hemodynamic responses that occur in critically ill patients. The statistical models used in this study can demonstrate associations, but do not necessarily capture the temporal effects of a drug administration at a certain time point. Both linear and piecewise linear mixed models do not establish causality and therefore can only suggest a hemodynamic improvement with MB. While hemodynamic parameters were analyzed, the effect of MB on mortality was not examined. Conclusion MB has remained a “kitchen sink” option for severe shock due to its low level of supporting evidence, relegated to the role of salvage therapy. Given the high mortality in refractory shock, investigation into drugs that combat vasoplegia are important and give the opportunity to add MB to the arsenal of available treatments for these complex patients. Given emerging evidence and its safety profile, MB should be shifted from rescue therapy to adjunctive therapy, though larger-scale, prospective, international randomized trials are needed. Further research should define the utility of targeting overlapping pathways in shock. Abbreviations MB Methylene blue MAP Mean arterial pressure SBP Systolic blood pressure DBP Diastolic blood pressure NED Norepinephrine-dose equivalent NO Nitric oxide CGMP Cyclic guanosine monophosphate CVP Central venous pressure Declarations Ethics approval and consent to participate: The need for ethics approval and consent was waived given the retrospective nature of this study. Consent for publication: Not applicable. Funding: No funding sources are utilized for this research. Author Contribution LeR and AR were responsible for data collection. MH and LiR conducted statistical analyses and prepared figures and tables. All authors reviewed and edited the manuscript. Acknowledgements: Not applicable. Data Availability The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. References Brown SM, Lanspa MJ, Jones JP, et al. Survival after shock requiring high-dose vasopressor therapy. Chest . 2013;143(3):664–671. doi:10.1378/chest.12-1106 Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ. Two decades of mortality trends among patients with severe sepsis: A comparative meta-Analysis. Crit Care Med . 2014;42(3):625–631. doi:10.1097/CCM.0000000000000026 Levy MM, Evans LE, Rhodes A. Sepsis Bundle 2018. Crit Care Med . 2018;46(6):997–1000. Vincent JL, Nielsen ND, Shapiro NI, et al. Mean arterial pressure and mortality in patients with distributive shock: a retrospective analysis of the MIMIC-III database. Ann Intensive Care . 2018;8(1). doi:10.1186/s13613-018-0448-9 Schmittinger CA, Torgersen C, Luckner G, Schröder DCH, Lorenz I, Dünser MW. Adverse cardiac events during catecholamine vasopressor therapy: A prospective observational study. Intensive Care Med . 2012;38(6):950–958. doi:10.1007/s00134-012-2531-2 Bostick D, McCurdy M. Catecholamine-induced Ischemic Necrosis of the Hand. Clin Pract Cases Emerg Med . 2017;1(3):270–271. doi:10.5811/cpcem.2017.4.33513 Ritter LA, Maldarelli M, McCurdy MT, et al. Effects of a single bolus of hydroxocobalamin on hemodynamics in vasodilatory shock. J Crit Care . 2022;67:66–71. doi:10.1016/j.jcrc.2021.09.024 Peter C, Hongwan D, Küpfer A, Lauterburg B. Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol . 2000;56(3):247–250. Hiruy A, Ciapala S, Donaldson C, Wang L, Hohlfelder B. Hydroxocobalamin Versus Methylene Blue for the Treatment of Vasoplegic Shock Associated With Cardiopulmonary Bypass. J Cardiothorac Vasc Anesth . 2023;37(11):2228–2235. doi:10.1053/j.jvca.2023.07.015 Mazzeffi M, Hammer B, Chen E, Caridi-Scheible M, Ramsay J, Paciullo C. Methylene blue for postcardiopulmonary bypass vasoplegic syndrome: A cohort study. Ann Card Anaesth . 2017;20(2):178–181. doi:10.4103/aca.ACA_237_16 Tchen S, Sullivan JB. Clinical utility of midodrine and methylene blue as catecholamine-sparing agents in intensive care unit patients with shock. J Crit Care . 2020;57:148–156. doi:10.1016/j.jcrc.2020.02.011 Levin RL, Degrange MA, Bruno GF, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg . 2004;77(2):496–499. doi:10.1016/S0003-4975(03)01510-8 Mehaffey JH, Johnston LE, Hawkins RB, et al. Methylene Blue for Vasoplegic Syndrome After Cardiac Operation: Early Administration Improves Survival. Ann Thorac Surg . 2017;104(1):36–41. doi:10.1016/j.athoracsur.2017.02.057 Pasin L, Umbrello M, Greco T, et al. Methylene Blue as a Vasopressor: A Meta-Analysis of Randomised Trials . www.jficm.anzca.edu.au/aaccm/journal/publi- Busse LW, Barker N, Petersen C. Vasoplegic syndrome following cardiothoracic surgery-review of pathophysiology and update of treatment options. Crit Care . 2020;24(1). doi:10.1186/s13054-020-2743-8 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). doi:10.1186/s13054-023-04397-7 Pruna A, Bonaccorso A, Belletti A, et al. Methylene Blue Reduces Mortality in Critically Ill and Perioperative Patients: A Meta-Analysis of Randomized Trials. J Cardiothorac Vasc Anesth . 2024;38(1):268–274. doi:10.1053/j.jvca.2023.09.037 Mallat J, Landoni G, Zhu G-J, et al. Efficacy and Safety of Methylene Blue in Patients with Vasodilatory Shock: A Systemic Reviw and Meta-Analysis .; 2022. Panday RSN, Lammers EMJ, Alam N, Nanayakkara PWB. An overview of positive cultures and clinical outcomes in septic patients: A sub-analysis of the Prehospital Antibiotics Against Sepsis (PHANTASi) trial. Crit Care . 2019;23(1). doi:10.1186/s13054-019-2431-8 Gachot B BJVBWMRB. Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock. Intensive Care Med . 1995;21(12):1027–1031. Schneider F LPHMSJTJ. Methylene blue increases systemic vascular resistance in human septic shock. Preliminary observations. Intensive Care Med . 1992;18(5):309–311. Kirov MY, Evgenov O V, Evgenov N V, et al. Infusion of Methylene Blue in Human Septic Shock: A Pilot, Randomized, Controlled Study .; 2001. http://journals.lww.com/ccmjournal Memis D, Karamanlioglu B, Yuksel M, Gemlik I, Pamukcu Z. The Influence of Methylene Blue Infusion on Cytokine Levels During Severe Sepsis . Vol 30.; 2002. Wieruszewski PM, Bellomo R, Busse LW, et al. Initiating angiotensin II at lower vasopressor doses in vasodilatory shock: an exploratory post-hoc analysis of the ATHOS-3 clinical trial. Crit Care . 2023;27(1):1–10. doi:10.1186/s13054-023-04446-1 Walsh M, Devereaux PJ, Garg AX, et al. MAP Clinical Outcomes. Anesthesiology . 2013;(119(3)):507–515. Salmasi V, Maheshwari K, Yang D, et al. Relationship between Intraoperative Hypotension, Defined by Either Reduction from Baseline or Absolute Thresholds, and Acute Kidney and Myocardial Injury after Noncardiac Surgery. Anesthesiology . 2017;126(1):47–65. doi:10.1097/ALN.0000000000001432 Wesselink EM, Kappen TH, Torn HM, Slooter AJC, van Klei WA. Intraoperative hypotension and the risk of postoperative adverse outcomes: a systematic review. Br J Anaesth . 2018;121(4):706–721. doi:10.1016/j.bja.2018.04.036 Tables Table 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files MethyleneBlueTables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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16:33:10","extension":"html","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":53943,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8355315/v1/006d54647e618570d637ff3c.html"},{"id":99218223,"identity":"433835c9-346d-4ee7-a686-49341c6e8483","added_by":"auto","created_at":"2025-12-30 09:17:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":55329,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplots of unadjusted hemodynamics one hour pre and one hour post methylene blue administration.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8355315/v1/75208c8adad670ca0e46f66a.png"},{"id":99218226,"identity":"2f575802-483a-411f-895a-746b42769523","added_by":"auto","created_at":"2025-12-30 09:17:05","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":138884,"visible":true,"origin":"","legend":"\u003cp\u003e2A: Trend of SBP, DBP, and MAP from 12 hours prior to MB administration and 12 hours post MB administration.\u003c/p\u003e\n\u003cp\u003e2B: Trend of NED from 12 hours prior to MB administration and 12 hours post MB administration.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8355315/v1/536e78339ebcf5753d065f91.png"},{"id":99317938,"identity":"65114633-bc25-491f-ab6b-c4f53374a2c7","added_by":"auto","created_at":"2025-12-31 16:30:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":42449,"visible":true,"origin":"","legend":"\u003cp\u003eMean Differences (mmHg) of hemodynamic parameters pre and post administration, and in NED (mcg/kg/min).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8355315/v1/03edd02c06da5eb352d2ac69.png"},{"id":100949287,"identity":"a4ee76c2-4af4-42b4-9f59-da78754baf7c","added_by":"auto","created_at":"2026-01-23 06:57:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":725861,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8355315/v1/5dc8d758-0ecf-4e4a-b806-a435d45da0ad.pdf"},{"id":99218222,"identity":"343e32c0-c44f-4b59-b37e-8151ac3fff5b","added_by":"auto","created_at":"2025-12-30 09:17:05","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20489,"visible":true,"origin":"","legend":"","description":"","filename":"MethyleneBlueTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8355315/v1/f1bca39464af2a5c072ee9e1.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of a single bolus of methylene blue on 24-hour hemodynamics in vasodilatory shock","fulltext":[{"header":"Background","content":"\u003cp\u003eSeptic shock mortality ranges from 30% to 75% in catecholamine refractory shock\u003csup\u003e1,2\u003c/sup\u003e. The guiding principle for sepsis management is infectious primary source control with chemical (i.e. antimicrobials) and potentially mechanical (i.e. drainage or extraction) pathogen removal. Optimal supportive care is similarly important, including vasopressors, when fluid resuscitation fails to correct the shock\u003csup\u003e3\u003c/sup\u003e. Despite the use of standard-of-care vasopressor agents, some patients exhibit vasoplegia, resulting in an inability to restore sufficient blood flow to critical organs. Maintaining hemodynamic stability is important, as the duration of hypotension impacts outcomes, with mortality increasing from 39.7% to 54.1% when hypotension extends from 2\u0026ndash;4 hours to 4\u0026ndash;6 hours\u003csup\u003e4\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCatecholamines are used to treat shock, though their risk profile is burdensome, including an increased incidence of adverse cardiac events and digital/ limb ischemia\u003csup\u003e2,5,6\u003c/sup\u003e. Combining vasopressor drugs may ameliorate the development of these complications while stabilizing hemodynamics. As vasopressors escalate, adjuncts such as hydroxocobalamin and MB are occasionally implemented for rescue therapy\u003csup\u003e7\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNitric oxide (NO) is produced via enzymatic activity of NO synthase, which can be upregulated during sepsis. NO induces vasodilation through guanylyl cyclase stimulation and cyclic guanosine monophosphate (cGMP) production. With a half-life of approximately 5.25 hours\u003csup\u003e8\u003c/sup\u003e, intravenous MB is a thiazide dye that inhibits nitric oxide synthase and guanylate cyclase, reducing nitric oxide-induced smooth muscle dilatation and inducing vasoconstriction\u003csup\u003e9\u0026ndash;11\u003c/sup\u003e. Most of the evidence demonstrating decreased vasopressor burden and improved hemodynamics with MB comes from both randomized and non-randomized trials in post cardiopulmonary bypass vasoplegia\u003csup\u003e10,12\u0026ndash;14\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eScant evidence supports the use of MB in refractory shock \u003csup\u003e15\u003c/sup\u003e. However, one recent randomized control trial on MB use in septic shock demonstrated faster vasopressor discontinuation, more vasopressor free days, and shorter intensive care unit (ICU) length of stay\u003csup\u003e16\u003c/sup\u003e. Meta-analyses found that MB potentially reverses vasodilatation in critically ill patients, leading to improved hemodynamics and mortality, even in septic shock subgroups\u003csup\u003e17,18\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe characterized the hemodynamic effects of MB over 12 hours after administration and hypothesized that MB would not be associated with improved hemodynamic parameters over a 24-hour period. Based on its short half-life, we also hypothesized that the rate of change in the hemodynamic parameters would similarly not improve over this time.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis retrospective observational study was approved by the institutional review board (IRB) at the University of Maryland Baltimore. The study was conducted at a single tertiary care academic hospital in the United States. Patients admitted between February 2017 and February 2021 who were administered MB for shock were identified by pharmacy records. The dose of MB was 1.5 mg/kg delivered as a single bolus dose over 5 minutes. Patients were excluded if they were \u0026lt;\u0026thinsp;18 years old, pregnant, or the entry was for a repeated dose of MB. Demographics, past medical history, severity of illness, etiology of shock, hourly vasopressor dose, hourly vitals, other vasoconstrictive agent use, and outcomes were recorded for all patients.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy Outcomes\u003c/h3\u003e\n\u003cp\u003eThe study\u0026rsquo;s primary outcome was the adjusted difference in the MAP from the 12 hours preceding and 12 hours following MB administration. The secondary outcome was the hourly rate of change in MAP during the same period. As exploratory endpoints, we also examined the mean difference in SBP, DBP, and NED, as well as the hourly rate of change in these variables during the twelve hours before and after medication administration.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eData analysis was undertaken using RStudio (RStudio Team (2020). RStudio: Integrated Development for R. RStudio, PBC, Boston, MA URL \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.rstudio.com/\u003c/span\u003e\u003cspan address=\"http://www.rstudio.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e).\u003c/span\u003e Data interpretation was permitted by the tidyverse package. Cohort description was performed with measures of central tendency as appropriate based on normality of the sample, evaluated by the Shapiro-Wilk test. Paired hemodynamic data was compared by a paired t-test. Piecewise and mixed linear models were fit using the lmer package and model summaries are reported. Effect estimates are illustrated using the metafor and forestplot packages. Data visualization was accomplished with the ggplot2 package.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFifty-eight patients were included in the study. The median age was 60 (IQR 48\u0026ndash;65) and 31% of the patients were female (\u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e). Most patients had surgical admissions (65.5%). Comorbidities such as hypertension and chronic kidney disease were present in 37.9% and 8.6% of patients, respectively. The etiology of shock was most commonly sepsis (61.5%), followed by hemorrhage (10.3%), unknown (10.3%), and neurogenic (2.6%). 10.3% of patients received MB in the peri-cardiopulmonary bypass period. Gram-negative, gram-positive, and fungal organisms (n\u0026thinsp;=\u0026thinsp;54) were identified in 14.8%, 5.6%, and 5.6%, respectively, while cultures were negative 74.1% of the time, which is slightly higher than the 47\u0026ndash;56% rate of culture-negative sepsis identified from the Nationwide Inpatient Sample and Prehospital Antibiotics Against Sepsis (PHANTASi) trial\u003csup\u003e19\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePatients with refractory shock were treated with therapies that are considered standard of care prior to being considered for MB administration. This includes fluid resuscitation, antibiotics, vasopressors, and source control when applicable. Most patients received steroids, with 89.7% receiving hydrocortisone and 15.5% receiving fludrocortisone. At baseline (Table\u0026nbsp;2), the median NED of vasopressors one hour prior to MB administration was 0.6 \u0026micro;g/kg/min (IQR 0.4\u0026ndash;0.9) and the median intravenous fluid administration was 6.8 L (IQR 5.0-11.4 L) in the 24 hours prior to MB and 5.2 L (IQR 3.2\u0026ndash;7.1 L) in the 24 hours post administration (p\u0026thinsp;=\u0026thinsp;0.004). Once patients were requiring multiple vasopressors despite fluid administration and shock was deemed refractory, patients were considered for MB dosing.\u003c/p\u003e \u003cp\u003eTime from hospital admission to MB administration was 4 days, while time from intensive care unit (ICU) admission to administration was 2 days. Prior to MB, patients had a median cardiac index of 2.5 L/min/m\u003csup\u003e2\u003c/sup\u003e (IQR 2.1\u0026ndash;3.1) and a median central venous pressure (CVP) of 15 mm Hg (IQR 12\u0026ndash;16). Hydrocortisone was used prior to MB in 89.7% of patients. The median lactate was 5.4 mmol/L. Overall, cohort mortality rate was 82.8%, with a median ICU length of stay of 10.5 days (IQR 2\u0026ndash;25) and hospital length of stay of 14 days (LQR 4\u0026ndash;33).\u003c/p\u003e\n\u003ch3\u003eEffect on Mean Arterial Pressure:\u003c/h3\u003e\n\u003cp\u003eBoxplots of unadjusted hemodynamic parameters for pre- and post-MB administration are depicted in \u003cb\u003eFig.\u0026nbsp;1\u003c/b\u003e. The adjusted difference in MAP before and after MB administration was modeled with a linear mixed effects model to account for repeated measures of MAP within patients. There was a significant difference in the pre-administration and post-administration MAPs (66 mmHg [pre] vs 70 mmHg [post], estimated fixed effect [EFE] 4, p\u0026thinsp;=\u0026thinsp;0.01). However, the change in MAP was modeled in the 12-hour period surrounding MB administration with a two-piecewise linear mixed model. MB had no significant effect in either the pre-administration segment (EFE \u0026minus;\u0026thinsp;0.7 mmHg, CI -2.3-0.9, p\u0026thinsp;=\u0026thinsp;0.4), or the post administration segment (EFE 1.0 mmHg, CI -0.6-2.6, p\u0026thinsp;=\u0026thinsp;NS), indicating that MB was not associated with an hourly increase in MAP (Table\u0026nbsp;3 and Fig.\u0026nbsp;2A).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eEffect on Systolic and Diastolic Blood Pressure:\u003c/h2\u003e \u003cp\u003eThe administration of MB did not significantly change SBP (EFE \u0026minus;\u0026thinsp;1 mmHg, CI 88.4\u0026ndash;118, p\u0026thinsp;=\u0026thinsp;0.1) or DBP (EFE 2 mmHg, CI 51\u0026ndash;58, p\u0026thinsp;=\u0026thinsp;0.08) (Fig.\u0026nbsp;1). The hourly rate of change was also not statistically significant from zero after MB administration for SBP (EFE \u0026minus;\u0026thinsp;6.4, CI -32.4-19.6, p\u0026thinsp;=\u0026thinsp;NS) or DBP (EFE 1.0, CI -0.5-2.5, p\u0026thinsp;=\u0026thinsp;NS) (\u003cb\u003eTable\u0026nbsp;3, Fig.\u0026nbsp;2A\u003c/b\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEffect on Norepinephrine-Equivalent Dose:\u003c/h3\u003e\n\u003cp\u003eIn the linear mixed model, the adjusted pre-administration NED was 1.1 ug/kg/min, while the post administration NED was 1.0 ug/kg/min (EFE \u0026minus;\u0026thinsp;0.1 ug/kg/min, CI 0.7\u0026ndash;1.3, p\u0026thinsp;=\u0026thinsp;0.04). Despite this observation, the administration of MB was not associated with significant improvement in the slope of the NED (EFE \u0026minus;\u0026thinsp;0.11 ug/kg/min/h, CI -0.13\u0026mdash;0.08, p\u0026thinsp;=\u0026thinsp;NS) (\u003cb\u003eTable\u0026nbsp;3, Fig.\u0026nbsp;2B\u003c/b\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study demonstrated that hemodynamics at the 24-hour mark post-MB administration did not change compared to pre-MB values. The linear mixed model, which allows for an overall estimate of treatment effect over 24 hours, demonstrated that patients who received MB required a lower cumulative dose of pressors and achieved higher MAPs. However, when the same data was examined in the piecewise linear mixed model, there was no significant improvement of NED or MAP. This difference indicates that the hemodynamic improvement seen from MB is not uniform but manifests early and disappears quickly. Our findings indicate the heterogeneity of response to MB boluses.\u003c/p\u003e \u003cp\u003eThis study differs from previous studies by accounting for repeated measures through linear mixed models and piecewise models to incorporate hourly measurements of hemodynamics into our analysis. Linear mixed models are used with hierarchical data that includes repeated measures of the same subjects over time, handling dependency of the data and individual variability/random effects while still estimating overall trends. Piecewise models are used when different linear relationships between variables in different ranges are expected, with each segment representing a distinct phase, making this analysis useful for patterns seen before and after an intervention. The use of this hybrid methodology models both within-person correlations and changes in slope, allowing for an increased number of sampling timepoints and increasing the power of each model. Nesting of observations within patients enabled each patient to contribute an individual slope and intercept to the overall model, whereas this was not possible with the previous analyses. In addition, the autoregressive structure of the piecewise models enabled us to account for the decreasing correlation between time points as the time interval increased.\u003c/p\u003e \u003cp\u003eThe human body has evolved intricate redundant neural, hormonal, and local autoregulatory systems that act synergistically to preserve vital perfusion during shock states. Sympathetic activation via catecholamine release increases systemic vascular resistance, the renin-angiotensin-aldosterone system promotes additional vasoconstriction, and parallel regulatory mechanisms such as nitric oxide modulation redistribute blood flow to critical areas to provide a multi-layered design that acts as a safety net to prevent cardiovascular collapse. Medical management of refractory shock has targeted these physiological redundancies through medications.\u003c/p\u003e \u003cp\u003eEarly studies of MB demonstrated hemodynamic improvement secondary to improved systemic vascular resistance\u003csup\u003e20,21\u003c/sup\u003e. MB shows promise as being integrated into a multimodal regimen that attenuates excessive nitric oxide signaling, restoring vascular tone, and allowing for lower cumulative vasopressor requirements. Two small randomized controlled trials from two decades ago that were performed in early septic shock indicated that continuous infusion of MB increased MAP and decreased vasopressor requirements without adverse effects\u003csup\u003e22,23\u003c/sup\u003e. Since these trials, momentum for MB use in refractory shock slowed until a recent randomized trial found decreased time to vasopressor discontinuation\u003csup\u003e16\u003c/sup\u003e. More recent meta-analyses furthermore show both improved hemodynamics and a significant reduction in mortality\u003csup\u003e17,18\u003c/sup\u003e. No studies to date have meaningfully examined patient centered outcomes with MB.\u003c/p\u003e \u003cp\u003eThe principle of combining vasoactive agents is to decrease catecholamine burden. This strategy was most recently demonstrated by ATHOS-3\u003csup\u003e24\u003c/sup\u003e. Trials that leverage non-adrenergic agents investigate how to use a multipronged therapeutic approach for managing hypotension, thereby replicating the body\u0026rsquo;s natural redundant hemodynamic pathways, impacting outcomes compared to escalation of a single agent alone. As demonstrated by Sessler et al., the longer the duration of hypotension, the higher the risk of end-organ dysfunction and therefore increased mortality\u003csup\u003e25\u0026ndash;27\u003c/sup\u003e. It is therefore important to achieve MAP targets rapidly rather than tolerate prolonged hypotension. This can be done by using adjunctive pharmaceutical agents, such as MB, in conjunction with conventional therapies for management of refractory hypotension.\u003c/p\u003e \u003cp\u003eDeploying alternative, targeted salvage therapies for shock may lead to a more rapid resumption of end-organ perfusion. Examples of such adjuncts include corticosteroids, immunomodulating agents, MB, and hydroxycobalamin\u003csup\u003e7\u003c/sup\u003e. The reported experiences regarding MB timing, modes of administration, quantified concomitant vasopressor burden, and outcomes are inconsistent. Due to its short half-life and lack of a steady state, bolus-dose MB alone may not counteract vasoplegia over longer periods. The recent randomized control trial that showed improvement in hemodynamics with MB administration used a MB infusion. The most recent meta-analysis showed an improvement in hemodynamics and mortality; however, studies included were a combination of bolus and infusion dosing\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere are several limitations to this study. This is a retrospective study at a single center. Linear mixed models, while well suited for repeated measures data, may oversimplify the complex hemodynamic responses that occur in critically ill patients. The statistical models used in this study can demonstrate associations, but do not necessarily capture the temporal effects of a drug administration at a certain time point. Both linear and piecewise linear mixed models do not establish causality and therefore can only suggest a hemodynamic improvement with MB. While hemodynamic parameters were analyzed, the effect of MB on mortality was not examined.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eMB has remained a \u0026ldquo;kitchen sink\u0026rdquo; option for severe shock due to its low level of supporting evidence, relegated to the role of salvage therapy. Given the high mortality in refractory shock, investigation into drugs that combat vasoplegia are important and give the opportunity to add MB to the arsenal of available treatments for these complex patients. Given emerging evidence and its safety profile, MB should be shifted from rescue therapy to adjunctive therapy, though larger-scale, prospective, international randomized trials are needed. Further research should define the utility of targeting overlapping pathways in shock.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMethylene blue\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMAP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMean arterial pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSBP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSystolic blood pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDBP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDiastolic blood pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNED\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNorepinephrine-dose equivalent\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNitric oxide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCGMP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCyclic guanosine monophosphate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCVP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCentral venous pressure\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e \u003cp\u003e The need for ethics approval and consent was waived given the retrospective nature of this study.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication:\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eNo funding sources are utilized for this research.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eLeR and AR were responsible for data collection. MH and LiR conducted statistical analyses and prepared figures and tables. All authors reviewed and edited the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBrown SM, Lanspa MJ, Jones JP, et al. Survival after shock requiring high-dose vasopressor therapy. \u003cem\u003eChest\u003c/em\u003e. 2013;143(3):664\u0026ndash;671. doi:10.1378/chest.12-1106\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ. Two decades of mortality trends among patients with severe sepsis: A comparative meta-Analysis. \u003cem\u003eCrit Care Med\u003c/em\u003e. 2014;42(3):625\u0026ndash;631. doi:10.1097/CCM.0000000000000026\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevy MM, Evans LE, Rhodes A. Sepsis Bundle 2018. \u003cem\u003eCrit Care Med\u003c/em\u003e. 2018;46(6):997\u0026ndash;1000.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVincent JL, Nielsen ND, Shapiro NI, et al. Mean arterial pressure and mortality in patients with distributive shock: a retrospective analysis of the MIMIC-III database. \u003cem\u003eAnn Intensive Care\u003c/em\u003e. 2018;8(1). doi:10.1186/s13613-018-0448-9\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchmittinger CA, Torgersen C, Luckner G, Schr\u0026ouml;der DCH, Lorenz I, D\u0026uuml;nser MW. Adverse cardiac events during catecholamine vasopressor therapy: A prospective observational study. \u003cem\u003eIntensive Care Med\u003c/em\u003e. 2012;38(6):950\u0026ndash;958. doi:10.1007/s00134-012-2531-2\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBostick D, McCurdy M. Catecholamine-induced Ischemic Necrosis of the Hand. \u003cem\u003eClin Pract Cases Emerg Med\u003c/em\u003e. 2017;1(3):270\u0026ndash;271. doi:10.5811/cpcem.2017.4.33513\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRitter LA, Maldarelli M, McCurdy MT, et al. Effects of a single bolus of hydroxocobalamin on hemodynamics in vasodilatory shock. \u003cem\u003eJ Crit Care\u003c/em\u003e. 2022;67:66\u0026ndash;71. doi:10.1016/j.jcrc.2021.09.024\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeter C, Hongwan D, K\u0026uuml;pfer A, Lauterburg B. Pharmacokinetics and organ distribution of intravenous and oral methylene blue. \u003cem\u003eEur J Clin Pharmacol\u003c/em\u003e. 2000;56(3):247\u0026ndash;250.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiruy A, Ciapala S, Donaldson C, Wang L, Hohlfelder B. Hydroxocobalamin Versus Methylene Blue for the Treatment of Vasoplegic Shock Associated With Cardiopulmonary Bypass. \u003cem\u003eJ Cardiothorac Vasc Anesth\u003c/em\u003e. 2023;37(11):2228\u0026ndash;2235. doi:10.1053/j.jvca.2023.07.015\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMazzeffi M, Hammer B, Chen E, Caridi-Scheible M, Ramsay J, Paciullo C. Methylene blue for postcardiopulmonary bypass vasoplegic syndrome: A cohort study. \u003cem\u003eAnn Card Anaesth\u003c/em\u003e. 2017;20(2):178\u0026ndash;181. doi:10.4103/aca.ACA_237_16\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTchen S, Sullivan JB. Clinical utility of midodrine and methylene blue as catecholamine-sparing agents in intensive care unit patients with shock. \u003cem\u003eJ Crit Care\u003c/em\u003e. 2020;57:148\u0026ndash;156. doi:10.1016/j.jcrc.2020.02.011\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevin RL, Degrange MA, Bruno GF, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. \u003cem\u003eAnn Thorac Surg\u003c/em\u003e. 2004;77(2):496\u0026ndash;499. doi:10.1016/S0003-4975(03)01510-8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMehaffey JH, Johnston LE, Hawkins RB, et al. Methylene Blue for Vasoplegic Syndrome After Cardiac Operation: Early Administration Improves Survival. \u003cem\u003eAnn Thorac Surg\u003c/em\u003e. 2017;104(1):36\u0026ndash;41. doi:10.1016/j.athoracsur.2017.02.057\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePasin L, Umbrello M, Greco T, et al. \u003cem\u003eMethylene Blue as a Vasopressor: A Meta-Analysis of Randomised Trials\u003c/em\u003e. www.jficm.anzca.edu.au/aaccm/journal/publi-\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBusse LW, Barker N, Petersen C. Vasoplegic syndrome following cardiothoracic surgery-review of pathophysiology and update of treatment options. \u003cem\u003eCrit Care\u003c/em\u003e. 2020;24(1). doi:10.1186/s13054-020-2743-8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIbarra-Estrada M, Kattan E, Aguilera-Gonz\u0026aacute;lez P, et al. Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial. \u003cem\u003eCrit Care\u003c/em\u003e. 2023;27(1). doi:10.1186/s13054-023-04397-7\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePruna A, Bonaccorso A, Belletti A, et al. Methylene Blue Reduces Mortality in Critically Ill and Perioperative Patients: A Meta-Analysis of Randomized Trials. \u003cem\u003eJ Cardiothorac Vasc Anesth\u003c/em\u003e. 2024;38(1):268\u0026ndash;274. doi:10.1053/j.jvca.2023.09.037\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMallat J, Landoni G, Zhu G-J, et al. \u003cem\u003eEfficacy and Safety of Methylene Blue in Patients with Vasodilatory Shock: A Systemic Reviw and Meta-Analysis\u003c/em\u003e.; 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePanday RSN, Lammers EMJ, Alam N, Nanayakkara PWB. An overview of positive cultures and clinical outcomes in septic patients: A sub-analysis of the Prehospital Antibiotics Against Sepsis (PHANTASi) trial. \u003cem\u003eCrit Care\u003c/em\u003e. 2019;23(1). doi:10.1186/s13054-019-2431-8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGachot B BJVBWMRB. Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock. \u003cem\u003eIntensive Care Med\u003c/em\u003e. 1995;21(12):1027\u0026ndash;1031.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchneider F LPHMSJTJ. Methylene blue increases systemic vascular resistance in human septic shock. Preliminary observations. \u003cem\u003eIntensive Care Med\u003c/em\u003e. 1992;18(5):309\u0026ndash;311.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKirov MY, Evgenov O V, Evgenov N V, et al. \u003cem\u003eInfusion of Methylene Blue in Human Septic Shock: A Pilot, Randomized, Controlled Study\u003c/em\u003e.; 2001. http://journals.lww.com/ccmjournal\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMemis D, Karamanlioglu B, Yuksel M, Gemlik I, Pamukcu Z. \u003cem\u003eThe Influence of Methylene Blue Infusion on Cytokine Levels During Severe Sepsis\u003c/em\u003e. Vol 30.; 2002.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWieruszewski PM, Bellomo R, Busse LW, et al. Initiating angiotensin II at lower vasopressor doses in vasodilatory shock: an exploratory post-hoc analysis of the ATHOS-3 clinical trial. \u003cem\u003eCrit Care\u003c/em\u003e. 2023;27(1):1\u0026ndash;10. doi:10.1186/s13054-023-04446-1\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalsh M, Devereaux PJ, Garg AX, et al. MAP Clinical Outcomes. \u003cem\u003eAnesthesiology\u003c/em\u003e. 2013;(119(3)):507\u0026ndash;515.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalmasi V, Maheshwari K, Yang D, et al. Relationship between Intraoperative Hypotension, Defined by Either Reduction from Baseline or Absolute Thresholds, and Acute Kidney and Myocardial Injury after Noncardiac Surgery. \u003cem\u003eAnesthesiology\u003c/em\u003e. 2017;126(1):47\u0026ndash;65. doi:10.1097/ALN.0000000000001432\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWesselink EM, Kappen TH, Torn HM, Slooter AJC, van Klei WA. Intraoperative hypotension and the risk of postoperative adverse outcomes: a systematic review. \u003cem\u003eBr J Anaesth\u003c/em\u003e. 2018;121(4):706\u0026ndash;721. doi:10.1016/j.bja.2018.04.036\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Methylene blue, refractory shock, hemodynamics, vasopressors","lastPublishedDoi":"10.21203/rs.3.rs-8355315/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8355315/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMethylene blue (MB) can cause transient hypertension in healthy subjects, but studies examining its efficacy over time in persistent shock states are lacking.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAdults in shock who received methylene blue from 2017 to 2021 were analyzed retrospectively. Hourly hemodynamics from 12 hours (h) before and after treatment were collected, and the difference and hourly change of mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and norepinephrine-equivalent dose (NED) were examined in mixed-effect models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThis study included hemodynamic data points from 58 patients. In the linear mixed effects model, significant differences in MAP and NED existed 12-h after MB administration (EFE 4.0, p\u0026thinsp;=\u0026thinsp;0.01 and EFE \u0026minus;\u0026thinsp;0.12 ug/kg/min, p\u0026thinsp;=\u0026thinsp;.04, respectively). However, the two-piecewise mixed model found that the hourly change in MAP, SBP, and DBP was not different from zero in either the pre-administration or post-administration segments.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eMB administration has been observed to increase MAP and decrease vasopressor requirements in shock. Our results suggest that in refractory vasoplegia, MB may improve MAP and vasopressor requirement over 12 hours in the linear mixed model, but not the piecewise mixed model, suggesting that the positive hemodynamic changes of MB may not be uniform. Clinically, these findings reinforce that bolus-dose MB likely has an impactful, though transient, physiological effect when given in addition to standard pharmaceutical management of refractory shock. MB should be considered as an adjunct therapy in refractory shock.\u003c/p\u003e","manuscriptTitle":"Effects of a single bolus of methylene blue on 24-hour hemodynamics in vasodilatory shock","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-30 09:17:00","doi":"10.21203/rs.3.rs-8355315/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b1f6e9f0-d818-4183-adae-e5b09c9cf0ee","owner":[],"postedDate":"December 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-11T11:24:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-30 09:17:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8355315","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8355315","identity":"rs-8355315","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}