This study will include patients requiring high dose of norepinephrine (NA) to maintain blood pressure after fluid resuscitation. The patients will be randomized into two groups, the study protocol is early combined application of methylene blue. The primary outcome is Sequential Organ Failure Assessment (SOFA) score 72 hours after admission. Second outcome includes duration of shock, length of intensive care unit (ICU) hospitalization and so on. To explore the underlying mechanism, the changes of sublingual microcirculation before and after vasopressor combination will be collected, also is the global longitudinal strain of left ventricle.

Background: Decreased vascular tone is one of the main mechanisms leading to septic shock. The guidelines recommend NA as the first-line vasopressor. The benefits of early combination with other vasopressors are not yet known.

Methods:

1. Patients: Septic shock patients in need of high dose of NA (≥0.5ug/kg.min maintaining more than 2 hours) to maintain blood pressure after fluid resuscitation.
2. Intervention: The patients will be randomized into two groups. The study group will receive 2mg/kg methylene blue infusion with 15 minutes, 2 hours laters followed by 0.5mg/kg/h for 4 hours. The control group received conventional treatments, the attending physicians decide the protocol of vasopressors. The data including patients' characters, duration of shock and hospitalization, duration of mechanical ventilation, cumulative dose of vasopressors will be collected. Before and 6h after meeting the inclusion standard, sublingual microcirculation and automated function imaging of myocardium will be performed.
3. Outcome: The primary outcome is SOFA score 72 hours after admission. Second outcome includes duration of shock, length of ICU hospitalization and so on. the changes of sublingual microcirculation will be collected, also is the global longitudinal strain of left ventricle.

Inclusion Criteria:

• Septic shock, receive 0.5 ug/kg/min NA to maintain blood pressure for more than 2 hours after fluid resuscitation.

Exclusion Criteria:

• Pregnant women
• Without internal jugular vein or subclavian vein catheterization
• Child-Pugh grade C with liver cirrhosis
• Severe chronic obstructive pulmonary disease (severe acidosis caused by type II respiratory failure, PaCO2 ≥60mmHg and PH<7.2 )
• End-stage of malignant tumors
• Glucose-6-phosphate dehydrogenase (G6PD enzyme) deficiency
• Positive end-respiratory pressure (PEEP) >10mmHg, the oxygenation index <150mmHg under mechanical ventilation
• Definitive pulmonary hypertension or chronic pulmonary heart disease.
• Oral use of 5-hydroxytryptamine in recent 3 months

The study protocol, objective data could be shared when required.

Within 1 year after completion of the study.

Just for academic requirement.