Norepinephrine is the 1st line vasopressor but at high doses can have increased adverse effects including tachyarrhythmias, myocardial disfunction, and peripheral ischemia. Higher doses and longer duration of exposure to vasopressors can be associated with increased risk of organ failure, and death [5]. Adding catecholamine-sparing agents such as methylene blue (MB) “earlier” in treatment may reduce the norepinephrine exposure (both dose and duration).
MB decreases nitric oxide levels by inhibiting inducible nitric oxide synthase (iNOS) and soluble guanylate cyclase (sGC). Through these mechanisms it restores vasoregulation. Most of the research on the use of MB has been in patients with vasoplegia following cardiopulmonary bypass. Limited, small studies on its use in septic shock do not make a clear argument for use.
Paper: Ibarra-Estrada, M et al. Early Adjunctive Methylene Blue in Patients with Septic Shock: A Randomized Controlled Trial. Crit Care 2023. PMID: 36915146 [Access on Read by QxMD]
Clinical Question: Does adjunctive methylene blue reduce time to vasopressor discontinuation in patients with septic shock?
What They Did:
- Single-center, parallel, double blind, randomized controlled trial performed in a medical-surgical ICU (Mexico)
- Both groups received:
- Adjunctive vasopressin initiated at a dose of 0.03 IU/min if norepinephrine dose reached ≥0.25mcg/kg/min
- Evaluation of volume responsiveness repeated at least 3x/day as long as vasopressors were needed
- Hydrocortisone 200mg/day by continuous infusion
- Nurse-led vasopressor tapering protocol with titration of vasopressors at 15 to 20min intervals to maintain MAP between 65 and 75mmHg until complete discontinuation
- Vasopressin was progressively withdrawn by 0.005UI/min each hour only after complete discontinuation of norepinephrine
- Methemoglobin capillary saturation was continuously monitored along the intervention timeframe by pulse co-oximetry
- Patients with septic shock according to Sepsis-3 criteria randomized to:
- Methylene Blue (MB): IV infusion of 100mg of MB in 500mL of 0.9% NaCl over 6hrs once daily x3 doses
- Placebo: 500mL of 0.9% NaCl without MB
Outcomes:
- Primary: Time to vasopressor discontinuation(Defined as discontinuation of all vasopressors for at least 48 consecutive hours)
- Key Secondary Outcomes:
- Vasopressor-free days at 28d
- Days on mechanical ventilator
- Length of stay in ICU
- Length of stay in Hospital
- 28d Mortality
Inclusion:
- Adult patients (≥18 years of age)
- Septic shock as defined by Sepsis-3 criteria
- Highly suspected or confirmed infection
- Requiring norepinephrine to maintain a MAP≥65mmHg
- Serum lactate >2mmol/L after adequate fluid resuscitation
Exclusion:
- >24hr since initiation of norepinephrine
- Pregnancy
- High probability of death within 48hrs
- Concurrent hemorrhagic, obstructive, or hypovolemic shock
- Pending damage control surgery
- Major burn injury
- Personal or familiar history of glucose-6-phosphate dehydrogenase deficiency
- Allergy to methylene blue, phenothiazines, or food dyes
- Recent intake (4wks) of selective serotonin re-uptake inhibitors
- Refusal of patient or decision maker to participate
- During the COVID-19 pandemic, data safety monitoring board did not allow recruitment of patients with COVID-19 due to unknown pathophysiologic underpinnings and unknown response to MB
Results:
- 308 patients evaluated for eligibility
- 216 not eligible (Most common reason was diagnosis of COVID-19)
- 92 patients underwent randomization
- Took over 5 years (2017 to 2022) to recruit these patients
- 1 patient withdrew in the MB group leaving 91 patients with data available for analysis
- Characteristics of Patients:
- Median Age ≈46years
- Source of Infection: PNA ≈50%; Intra-Abdominal ≈38%; UTI ≈9%
- Shock Diagnosis to Intervention ≈8hrs
- Positive Fluid Response at Enrollment ≈46%
- Norepinephrine Dose ≈0.41mcg/kg/min
- Vasopressin Use ≈76%
- Serum Lactate ≈5.6mmol/L
- Mechanical Ventilation ≈87%
- ARDS ≈75%
- Ejection Fraction ≈60%
- SOFA Score = 10
- APACHE II Score ≈22
- No other vasopressors (phenylephrine, angiotensin II, epinephrine, midodrine) or inotropes (milrinone, dobutamine) were used in this study
- Time to vasopressor discontinuation at 28d (Primary Outcome)
- MB: 69hrs (Range 59 to 83hr)
- Placebo: 94hrs (Range 74 to 141hrs)
- Median difference: 29.4; 95% CI 15.4 to 50.7; P<0.001
- Norepinephrine dose requirement decreased more pronouncedly in the MB group as compared to placebo over the first 4 days
- 5/45 (11%) patients in MB group and 13/46 (28%) patients required re-initiation of NE within 48hrs after discontinuation (p = 0.06)
- Early adjunctive MB compared to placebo also led to:
- One more vasopressor-free day at day 28 (P = 0.008)
- Lower cumulative fluid balance by 741mL (p = 0.001)
- Shorter ICU length of stay by 1.5 days (P = 0.039)
- Shorter hospital length of stay by 2.7d (P = 0.027)
- No difference in days on mechanical ventilation and mortality between groups
- No serious adverse events related to MB administration
- Most common adverse effect was green-blue discoloration of urine in 42/45 (93%) of patients
Strengths:
- Patients, clinicians, investigators, and outcome assessors were blinded to the treatment received
- To avoid visual identification, all infusion bags and polyvinylchloride lines were prepared at a central pharmacy with opaque envelopes
- Baseline characteristics of patients were similar between groups
- Largest RCT comparing MB to placebo in patients with septic shock
- Treatments outside of the intervention were standardized across groups by protocol.
Limitations:
- Green-blue discoloration of urine could have led to unblinding of groups
- Non-patient centered primary outcome
- Decreased generalizability due to numerous exclusions
- Decreased generalizability due to small number of enrolled patients over a long interval time
- Single-center study performed in Mexico which may have different practice patterns than other facilities and countries, which could limit generalizability
- These patients had dynamic testing of fluid responsiveness quite frequently, which may not be possible in settings outside the ICU
- Patients with COVID-19 were excluded in this study and its results can not be extrapolated to this population
- Study was underpowered to make any real conclusions on mortality. Larger studies would be needed to confirm the results of this trial
Discussion:
- All fluid resuscitation of septic shock was guided by dynamic tests for prediction of volume responsiveness. Most common methods were:
- Aortic velocity-time integral change after passive leg raise (Cut-off 10%)
- Arterial pulse pressure variation (Cut-off 13%)
- Tidal volume challenge (Cut-off 3.5%)
- Respiratory variation of carotid peak flow velocity (Cut-off 14%)
- Adequate fluid resuscitation was defined as at least 500mL bolus of balanced crystalloids followed by negative volume responsiveness by at least 2 different methods
- Performed a sample size calculation with an expected mean vasopressor duration of 97 +/- 69hrs (Mean 83hrs), and considering a decrease of 24hrs as clinically relevant, the calculated sample size was 88 for the trial to provide a statistical power of 80%
- Previous Evidence:
- Kirov et al 2001 [2]: 20 patients with septic shock randomized to placebo or a bolus injection of 2mg/kg of MB, followed by a continuous 4hr infusion to a total dose of 5.75mg/kg
- More patients died in placebo group (7 vs 3)
- Duration of vasopressor support shorter in MB group (71hr vs 93hr)
- Both outcomes not statistically significant
- Memis et al 2002 [3]: 30 patients with septic shock randomized to placebo vs MB 3mg/kg over 6hrs
- No difference in cytokine levels
- Significant but transient increase in MAP in patients of MB group
- Most common use of MB is in patients after cardiopulmonary bypass
- 50% of patients will develop vasoplegia, but typically this is limited to a few hours
- Sepsis on the other hand has a less predictable inflammatory insult and can last for several days
- Doses <2mg/kg rarely present with adverse effects (i.e worsening oxygenation from pulmonary vasoconstriction, methemoglobinemia)
- In this study, patients received 100mg vials over 6hours 1x/day which is the equivalent of 1mg/kg in a 100kg patient Total cumulative dose of 3.6mh/kg over 54 hours)
- This dose reduced vasopressor support with no detrimental effects
- Methemoglobin levels were higher in the MB group (2.9% (Range 2.2. to 3.3) vs 0.5% (Range 0.4 to 0.7) BUT significantly lower than the clinically relevant threshold of 10%
- Kirov et al 2001 [2]: 20 patients with septic shock randomized to placebo or a bolus injection of 2mg/kg of MB, followed by a continuous 4hr infusion to a total dose of 5.75mg/kg
Author Conclusion: “In patients with septic shock, MB initiated within 24h reduced time to vasopressor discontinuation and increased vasopressor-free days at 28 days. It also reduced length of stay in ICU and hospital without adverse effects. Our study supports further research regarding MB in larger randomized clinical trials.”
Clinical Take Home Point: This small, single-center RCT found that adjunctive MB administered within 24hrs of septic shock reduced time to vasopressor discontinuation. The study was too small to make strong conclusions about adverse events. Without larger studies and a patient centered outcome, the addition of methylene blue within 24 hours of septic shock should still not be part of a general approach but rather an adjunct in specific circumstances (i.e. Septic shock and significant vasopressor requirements).
References:
- Ibarra-Estrada, M et al. Early Adjunctive Methylene Blue in Patients with Septic Shock: A Randomized Controlled Trial. Crit Care 2023. PMID: 36915146 [Access on Read by QxMD]
- Kirov MY et al. Infusion of Methylene Blue in Human Septic Shock: A Pilot, Randomized, Controlled Study. Crit Care Med 2001. PMID: 11588440
- Memis D et al. The Influence of Methylene Blue infusion on Cytokine Levels During Severe Sepsis. Anaesth Intensive Care 2002. PMID: 12500513
- Lopez A et al. Multiple-Center, Randomized, Placebo-Controlled, Double-Blind Study of the Nitric Oxide Synthase Inhibitor 546C88: Effect on Survival in Patients with Septic Shock. Crit Care 2004. PMID: 14707556
- Richards-Belle et al. Lower Versus Higher Exposure to Vasopressor Therapy in Vasodilatory Hypotension: A Systematic Review with Meta-Analysis. Crit Care Med 2023. PMID: 36398968
Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)
