El Adawi

Methylene blue versus vasopressin in sepsis-induced vasoplegia

El Adawi. Ain-Shams J Anaesthesiol 2016;9:319-24. doi:10.4103/1687-7934.189091

Clinical Question

  • In adult patients with severe sepsis, does methylene blue compared to vasopressin reduce noradrenaline requirement and increase blood pressure?


  • Single centre
  • Randomised controlled trial
  • “Single blinded” but doesn’t state who or how
  • Screening and recruitment method not specified
  • Random number tables used for allocation therefore poor concealment
  • Powered at 90% with significance defined at 0.05 if 40 patients recruited
    • Primary outcome not define
    • Source of pilot or background date not provided


  • Single academic tertiary Intensive Care Unit in Egypt
  • 2010 to 2014


  • Inclusion: Within 72 hours of severe sepsis or within 24 hours of septic shock
    • As defined by ACCP/SCCM consensus criteria on sepsis
    • Requiring Noradrenaline 0.2 µg/kg/min to maintain MAP 70-90 mmHg
  • Exclusion: Pregnancy, sensitivity to study drugs, G6PD deficiency, under 18 years old, vasospastic diathesis (e.g. Raynaud’s), coronary disease, MAOI administration
  • 40 patients enrolled; none lost to follow-up
  • Baseline characteristics (Methylene Blue group vs Vasopressin group)
    • Age: 55 vs 59 years
    • SOFA score: 10 vs 10


  • Methylene Blue
    • Bolus 1 mg/kg
    • Infusion 2 hours later of 0.5 mg/kg/h for 4 hours


  • Vasopressin
    • Infusion of 0.02 U/kg/h for 6 hours

Management common to both groups

  • Adrenaline and Noradrenaline titrated to achieve MAP 60-80 mmHg
    • Adjusted in steps of 0.02 µg/kg/min every 15 minutes if MAP > 80 mmHg
    • Noradrenaline weaned before Adrenaline
  • Fluid resuscitation titrated to cardiac index and pulmonary artery occlusion pressure
  • Piperacillin+Tazobactam was first line antibiotic
  • Lung protective invasive ventilation if PaO2< 6.6 kPa (50 mmHg)
  • Enteric feeding
  • DVT and ulcer prophylaxis


  • Primary outcome: not specified
    • MAP was higher in the Methylene Blue group (numbers appear wrongly reported in manuscript’s results section but figure and discussion section are in agreement)
      • At 6 hours: 75 ± 5.9 mmHg vs 68 ± 6.8 mmHg
        • Mean difference 7.0 mmHg (95% CI 2.9 to 11.1; P = 0.001)
      • At 24 hours: 74 ± 6.9 mmHg vs 68 ± 6.9 mmHg
        • Mean difference 6.0 mmHg (95% CI 1.5 to 10.4; P = 0.009)
    • Dose of noradrenaline became significantly lower in the Methylene Blue group compared to the Vasopressin group at 6 hours
    • Dose of adrenaline became significantly lower in the Methylene Blue group compared to the Vasopressin group at 2 hours
    • Oxygen extraction ratio was significantly lower in the Methylene Blue group compared to the Vasopressin group at 6 hours
    • No significant difference in length of ICU stay

Authors’ Conclusions

  • In sepsis-induced refractory vasoplegia methylene blue may be more effective than vasopressin but further studies are required


  • Given the findings of VANISH, asking research questions like this is clinically important
  • Appropriate to examine this clinical question by a randomised, controlled trial design
  • Appropriate statistical tests for the data types presented


  • Single centre (and published in that single centre’s own medical journal)
  • Selection bias likely given only 40 patients recruited over 4 years
  • Without adequate randomisation sequence concealment, the potential impact on selection bias is huge
    • That is, researchers may have selected certain patients for the trial knowing that they will enter one group or the other
  • If ‘single blinded’ means the patient didn’t know but the clinician did, then allocation bias is possible (Cochrane Centre call this performance bias)
    • That is, clinicians may have given non standard care to favour one group over the other
  • Unclear primary outcome
    • Although they have stated a power calculation, it is meaningless if we are not told what is the primary outcome
  • Outcomes are not patient-centred
  • Errors in the manuscript

The Bottom Line

  • Although an exciting and relevant clinical question, the methodological flaws in this study potentially introduce far too many biases for the conclusion to be accepted
  • Further patient-centred trials are required before I will be reaching for the methylene blue

External Links


Summary author: Duncan Chambler
Summary date: 8 February 2017
Peer-review editor: Adrian Wong

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