The present study used MB to reduce NO-mediated vasoplegia, which can minimize the use of vasopressors, in addition to being a low-cost medication, without side effects and being easily accessible in health units [12, 34].
We started MB in the first 72 hours of septic shock and observed a reduction in the dose of NOR immediately after the start of the infusion compared to that in the control group, where this reduction occurred only after 24 hours. Similar findings were described in a randomized clinical trial that demonstrated that early use of MB reduced the duration of vasopressor use compared to that in the control group, and most importantly, no serious adverse effects were detected. The authors further suggest that MB should not be used as rescue therapy but rather as adjuvant therapy in the early stages of septic shock. [12, 34]. Due to its safety profile, greater availability and lower cost than other catecholamine-sparing agents [35], MB could emerge as a viable therapy within a multimodal strategy to maintain MAP and improve tissue perfusion. Furthermore, MB contributes to reducing the use of high-dose vasopressors [21, 23, 24, 29–31, 36–39], which was also found in our study.
When evaluating weaning from VAS, we observed early withdrawal in the MB group within 24 hours, while in the control group, VAS withdrawal was observed within 48 hours.
The study of Preiser et al.[25] investigated the intravenous administration of MB at a single dose of 2 mg/kg in patients with septic shock and demonstrated an increase in MAP and IRVS, but these hemodynamic improvements were not sustained, suggesting that longer MB administration deserves further investigation. In our study, we performed a continuous infusion of MB for 48 hours and observed a decrease in the use of vasopressors within 2 hours that was maintained during the period of MB infusion. Perhaps this time is still short since many patients in the present study still needed the use of vasopressors, so the shock had not yet been fully resolved. Furthermore, there was a greater need for vasopressors after MB suspension. We speculate that in septic shock, a longer time is needed for complete hemodynamic restoration since the effectiveness of the antimicrobial agent is important and is linked to access to the culture results.
A randomized clinical trial in patients with septic shock showed that the administration of MB within 24 hours reduced the duration of vasopressor suspension but did not evaluate possible hemodynamic changes, inflammatory mediators, nitrites or nit dosages [9].
In the present study, we observed that the dosage of nitrate (a NO metabolite) in the MB group was greater than that in the control group during the first 48 hours (T4). This can be explained by the fact that MB, by blocking guanylate cyclase, increases NO, but it remains inactive because it depends on this enzyme. This high dosage of nitrate in the MB group may have been beneficial since NO deficiency can lead to endothelial dysfunction, increased insulin resistance and impairment of the immune system [40].
Another important aspect of MB is its antioxidant properties, which eliminate reactive oxygen species (ROS) independently of cGMP, helping to protect cells against oxidative damage or even helping to improve mitochondrial function [17].
However, few robust studies have evaluated the dosage of cytokines in patients who use MB for septic shock. Memis et al. [31] evaluated the dosage of TNF-α, IL-1, IL-2, IL-6 and CXCL8 and found no changes in serum levels during 6 hours of MB use. We speculate that these results differ from our study, as prolonged use of MB could trigger more sustained effects on inflammatory and anti-inflammatory responses.
In the present study, we also observed an increase in CXCL8 in the MB group at T2 to T3, which may have contributed to improved targeting of granulocytes, benefiting the acute phase of septic shock [41]. In the control group, there was a progressive reduction from T1 to T5; however, there was an increase from T4 to T6, at which point we already expected a reduction due to the control of the inflammatory and infectious process.
In the control group, the TNF-α concentration progressively increased, mainly after T3, and remained elevated until T6, which may indicate an excessive response to the infection, even 72 hours after the start of treatment. In the MB group, there was stabilization between T1 and T2, with a decrease in T3 and a much less pronounced increase in T4, with a subsequent decrease until T5, which increased again after withdrawal of the maintenance dose of MB in T6. Although patients in the MB group had more severe illnesses according to prognostic indices, we noticed that in the MB group, there was a lower increase in the level of this proinflammatory cytokine. TNF-α plays an important role in septic shock, signaling the path that defense cells must follow, activating the immune system and increasing the antigen-specific response; however, excessive TNF-α activation is harmful, leading to cell death [36].
IL-10, an anti-inflammatory cytokine, was expressed at lower levels from T1 to T4 in the control group than in the MB group, with increases in T5 and T6 in the MB group compared to the control group. This elevation observed in the MB group may play a role in maintaining homeostasis between inflammatory and anti-inflammatory mediators.
In this study, we also analyzed the integrative networks of vasopressor drugs and hemodynamic and immunological variables in the MB and control groups. The data analysis demonstrated that while NOR and VAS scores were directly correlated with NO in the control group, they were directly correlated with IL-10 in the MB group. These findings demonstrate that the mechanisms underlying the effect of MB on hemodynamic characteristics in septic shock may rely not only on blocking the action of NO but also on other events mediated by IL-10, which may be one of the possibilities for hemodynamic improvement, independent of action and serum nitrate levels.
In addition to the vasoconstrictor effect, norepinephrine and vasopressin can also act by decreasing the production of nitric oxide [42, 43]. Thus, in the control group, in which MB was not used, vasopressors showed a direct and strong correlation with nitrate. However, when we used MBs, there was no correlation between the use of vasopressors and nitrate. As mentioned above, when guanylate cyclase is blocked, NO levels remain elevated but are inactive. Furthermore, guanylate cyclase, when inactivated, prevents the conversion of GTP into cGMP, which, in addition to reducing vasodilation, also facilitates the action of noradrenaline via cAMP since the cGMP pathway, when little activated, releases cAMP [44]. Furthermore, in the MB group, vasopressors showed a strong and direct correlation with IL-10, which also affects nitrate reduction [45, 46].
Finally, we also observed that patients in the MB group had more severe disease according to the SOFA, SAPS3 and APACHE II scores. However, patients in the MB group used fewer days of vasopressors and had a mortality rate of 47.37% versus 60.87% in the control group. This lower mortality may be related to a balance between inflammatory and anti-inflammatory mediators, which is associated with the theory that describes an improvement in mitochondrial function and the production of adenosine triphosphate (ATP) in cells, helping to reverse cardiovascular dysfunction associated with septic shock [17].
Some limitations must be recognized. First, this was a single-center study; second, it was an unblinded study, as highlighted in the methodology section.