Introduction
 Vasoplegic syndrome (VPS) is a relatively common and lethal complication following cardiopulmonary bypass (CPB) with the incidence rate of 5% to 25%. syndrome VPS can be characterized by severe and persistent hypotension, tachycardia, and normal to elevated cardiac output, diminished systemic vascular resistance (SVR), and high fluid intakes (1). Although VPS is a multifactorial condition, the exact pathophysiology is not clear; activation of vasodilators and resistance to vasopressors, all interfere in the occurrence of VPS in a form of vasodilatory shock and Low SVR (2). Patients-specific risk factors are possibly associated with the increased incidence rate of VPS, including the type and the duration of surgery, preoperative hemodynamic instability, administration of angiotensin-converting enzyme (ACE) inhibitors or beta-blockers (2). The likelihood of developing postoperative vasoplegic syndrome (PVS) is reported to be higher following, valve procedures and surgery specifically intended for the management of heart failure while compared with coronary artery bypass grafting, aortic surgery, and reoperations. Based on the literatures, PVS is associated with poor prognosis, prolonged hospital stay, higher mortality, and morbidity risk (3).
Vasoactive infusions like phenylephrine, norepinephrine, or vasopressin are known as the regular and conventional treatment strategy for intraoperative or postoperative VPS, however high dosages of these medications might cause some serious side effects including peripheral and mesenteric ischemia, mucosal injury, tissue necrosis, and metabolic acidosis (4,5).
Despite methylene blue, a well-known dye, application as a medication for methemoglobinemia, it can bind to the iron heme moiety, can inhibit enzyme guanylate and can subsequently block the accumulation of cyclic guanosine monophosphate (cGMP). Therefore, methylene blue (MB) has been proposed as an alternative therapeutic strategy for vasopressor-resistant vasoplegia (6). Nowadays, the efficacy of post-CPB administration of methylene blue on the reversal of vasoplegia is under investigation. The main scope of this systematic review is to study the effect of methylene blue on mortality rate, duration of VPS, and the occurrence of further complications in patients with VPS following cardiac surgery.

Methods
This systematic review was performed by literature search in PubMed from 1966 to 1st February 2015. Search strategy included “Methylene blue AND vasoplegic syndrome”. Only cohort studies and human randomized controlled trials (RCT), which studied the efficacy of methylene blue on the prevention of VPS following cardiac surgery, were eligible to be included in the study.

Results
Literature search on therapeutic efficacy of methylene blue resulted in a total of 54 articles, which were directly related to the VPS in cardiac surgery. Titles, abstracts, and full text of the articles were studied for relevancy. Flow chart of the included articles is provided Figure 1.
Majority of the extracted articles were case reports, which were omitted. Only four articles consisted of RCTs and cohort studies were included in this systematic review. The quality of the included RCTs is summarized in Table 1, based on oxford center for evidence based medicine chart. The results of these articles are provided in Table 2.

One RCT was about the efficacy of preoperative administration of MB, and one RCT on its postoperative application (7,8). One observational study also studied the efficacy of MB on patients undergoing cardiac surgery with no control group. Another observational study compared the efficacy of MB with control group (9,10).
Mortality rate was reported in both RCTs relevant to our study. One RCT reported a reduction of mortality in VPS group treated with MB compared with VPS group treated with conventional treatment. Preoperative administration of MB reported no death following cardiac surgery compared with those without MB prophylaxis. The most recent observational study showed higher mortality rate in VPS patients administered MB compared to control group.
Regarding the duration of VPS, Levin et al. reported the clearance of VPS in < 2 hrs inr patients treated with MB, and > 48 hrs in patients treated with conventional medications (7).
Based on the included RCTs, VPS was characterized based on various indices including hypotension, mean arterial pressure 2.5 L/min/m2, peripheral resistance 200 ng/kg/min of norepinephrine plus >2 units/hour of vasopressin (10).
Discussion
Vasoplegic syndrome is a type of low systemic vascular resistance syndrome which activates an inflammatory response and leads to postoperative complications following cardiac surgery. According to the previous studies, incidence of VPS will change the clinical outcomes and results in poor overall prognosis. To prevent the possible side effect of conventional treatments of VPS such as arrhythmias or ischemia, efficacy of new medications is under investigation. MB has been proposed as an inhibitory drug over nitric oxide (NO, activates guanylate-cyclase enzyme, induces cGMP production, and leads to the relaxation of smooth vascular muscle) (11,12). According to the Leyh et al., over 90% of patients with norepinephrine-resistant VPS responded to the treatment with postoperative MB (9). Based on one RCT, MB prophylaxis in patients at higher risk of VPS has significant power to avoid the incidence of intraoperative and postoperative VPS in preoperative MB-treated patients (8).
Mortality rate
According to the RCT performed by Levin et al., mortality rate will be significantly reduced following intravenous (IV) application of MB in the treatment of postcardiac surgery VPS. In the observational study of Leyh et al., performing without any control group, the mortality rate was reported to be in 4 out of 54 patients and only two patients did not response to MB (9). Ozal et al. reported no mortality in patients with higher risk of VPS who applied preoperative MB compared with control group. In two cases of the control group, MB was applied after the occurrence of VPS and multiorgan failure, which could not treat the VPS or inhibit the death of patients. (8). In contrast to the mentioned studies, Weiner et al. research was the first study that revealed higher mortality and morbidity following MB administration as a result of vasoplegic shock in patients under cardiac surgery (10); this study is a nonrandomized observational study and is hardly sufficient to disapprove the prognostic value of MB. They have also suggested that an increased mortality rate might be due to the beneficial physiological effects of NO, which were inhibited by applying MB.

Duration of the PVS
Duration is an important factor which is associated with poor prognosis. Therefore, aggressive treatment of postoperative refractory vasoplegia is essential to inhibit the consequences. PVS was considerably lower (48 hrs) and no adverse effect has been reported due to infusion of MB (7). The lower duration of PVS during the application of MB is due to the NO blockade and the consequent inhibition or limitation of the inflammatory response; this event has high prognostic value during postoperative inflammatory response. Continuance of the PVS for more than 48 hrs, is associated with worse prognosis, and increases the likelihood of further morbidities or even death (13). Levin et al. reported higher incidence of renal and respiratory failures, sepsis, myopathy, and supraventricular arrhythmia in those with PVS more than 48 hrs, and no incidence of mentioned diseases in PVS patients treated with MB application and nitric oxide blockade in 2 hrs (7).

Hospital stay
Only one RCT evaluated the efficacy of administrating MB on hospital stay which revealed a longer hospital stay following preoperative application of MB in patients at higher risk of VPS compared with those that applied MB after the surgery and incidence of VPS (8).

Adverse effect
Experimental studies and some previous studies which are not included in these study, proposed several adverse effects of administrating MB in the treatment of norepinephrine-refractory vasoplegia, such as cardiac arrhythmias, coronary vasoconstriction, reduced cardiac output, renal blood flow and mesenteric blood flow, and elevated pulmonary vascular pressure and resistance (14-16). According to the RCT of Levin et al., green or blue coloration of urine is the only reported symptoms following MB administration in PVS group. This was also observed by preoperative administration of MB in patients at higher risk of PVS; the green color of urine was disappeared spontaneously after 3 days (8). In the observational study of Leyh et al., no adverse effect was observed in patients following administration of MB (9). It seems that possible side effects are dose dependent and might occur following the administration MB at dosage greater than 2 mg/kg.

Conclusion
Based on our knowledge, only 2 RCTS has studied the efficacy of MB on the prevention of VPS following cardiac surgery. MB prophylaxis can be effective in inhibiting the incidence of VPS, shortening the hospital stay, maintaining adequate SVR following cardiac surgery in high risk patients. Eventually, further studies are needed to certainly illustrate the efficacy of MB on the treatment of VPS.

Acknowledgement
We would like to thank Clinical Research Development Unit of Ghaem Hospital for their assistant in this manuscript.

Conflict of Interest
The authors declare no conflict of interest.