Septic shock is a life-threatening condition that occurs when an infection triggers a systemic inflammatory response that leads to organ dysfunction and hypotension. It is associated with high mortality and morbidity, especially when patients do not respond adequately to fluid resuscitation and vasopressors. Vasopressors are drugs that constrict blood vessels and increase blood pressure, improving tissue perfusion and oxygen delivery. However, they also have side effects such as arrhythmias, digital ischemia, and immunosuppression.
Nitric Oxide Role in Septic Shock
One of the mechanisms involved in septic shock is the overproduction of nitric oxide (NO), a potent vasodilator that reduces vascular tone and impairs cardiac contractility. NO is synthesized by three isoforms of nitric oxide synthase (NOS): neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). iNOS is the main source of NO in sepsis, and its expression is stimulated by inflammatory cytokines. Therefore, inhibiting iNOS could be a potential strategy to reverse the vasodilatory state of septic shock [1].
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Inducible nitric oxide synthase (iNOS) activation during sepsis leads to increased NO levels that affect renal hemodynamics and cause tubular injury through reactive nitrogen species. Selective inhibition of renal iNOS may have significant implications for treating sepsis-induced AKI. Animal studies have shown that selective iNOS inhibition improves renal function and survival, which merits further investigation in clinical trials. This review discusses selective iNOS inhibition as a potential novel treatment for sepsis-induced AKI [2].
The Evidence on the Use of Methylene Blue in Septic Shock
Methylene blue (MB) is a dye that has been used for various medical purposes since the 19th century. It has several pharmacological properties, including acting as a selective inhibitor of iNOS, thus reducing NO production and increasing vascular tone. MB has been used successfully in patients with post-cardiopulmonary bypass associated vasoplegia, a condition similar to septic shock in terms of hemodynamic instability and NO excess [3]. However, the evidence of the use of MB in septic shock patients is limited to case reports, observational studies, and small randomized trials.
A prospective, randomized, controlled, open-label pilot study evaluated the effects of continuous methylene blue (MB) infusion on hemodynamics and organ functions in 20 patients with septic shock. Patients were randomized to receive either MB or isotonic saline alongside conventional treatment. MB infusion prevented stroke volume and left-ventricular stroke work indexes from falling and increased mean arterial pressure. It also reduced the requirement for norepinephrine, epinephrine, and dopamine, maintained oxygen delivery, and lowered body temperature and plasma nitrates/nitrites concentrations. No significant adverse effects on organ function variables were observed. They concluded that MB infusion counteracts myocardial depression and reduces concurrent adrenergic support in human septic shock, warranting further investigation [4].
A recent randomized controlled trial by Ibarra-Estrada et al. [5] evaluated the effect of early adjunctive MB on time to vasopressor discontinuation in patients with septic shock. They enrolled 91 patients who met the Sepsis-3 criteria for septic shock and randomized them to receive either MB or placebo within 24 hours of diagnosis. Patients assigned to MB group received an intravenous (IV) infusion of 100 mg of MB in 500 ml of 0.9% sodium chloride solution over 6 h once daily for a total of 3 doses.
The results showed that the MB group had a shorter time to vasopressor discontinuation (69 h vs 94 h; p < 0.001), one more day of vasopressor-free days at day 28 (p = 0.008), a shorter ICU length of stay by 1.5 days (p = 0.039) and shorter hospital length of stay by 2.7 days (p = 0.027) compared to patients in the control group. Days on mechanical ventilator and mortality were similar. There were no serious adverse effects related to MB administration.
This study is one of the first to assess the role of MB as an adjuvant therapy rather than a rescue therapy in septic shock patients. It has several strengths, such as being randomized, blinded, placebo-controlled, and having a clinically relevant primary outcome. However, some limitations should be acknowledged. The study was conducted in a single center with a relatively small sample size, which may limit its generalizability and statistical power. The study did not report the doses of vasopressors used or the severity of illness scores of the patients and did not adjust for potential confounders. The study was also open-label, which may introduce bias in the assessment of outcomes and adverse events. Moreover, the study did not measure any biomarkers or surrogate endpoints of NO metabolism, inflammation or organ function, which could have provided mechanistic insights and clinical correlations.
The findings of this study are encouraging but need to be confirmed by larger and more rigorous trials before MB can be recommended as a routine therapy for septic shock patients. The optimal timing, dosing, duration, and safety profile of MB also need to be determined.
CONCLUSION
Septic shock, a life-threatening condition caused by infection-triggered systemic inflammatory responses, is associated with high mortality and morbidity rates, particularly when patients inadequately respond to fluid resuscitation and vasopressors. Nitric oxide (NO) overproduction is a mechanism involved in septic shock, and inhibiting inducible nitric oxide synthase (iNOS) has been considered as a potential treatment strategy. Methylene blue (MB), a selective iNOS inhibitor, has shown promise in case reports, observational studies, and small randomized trials. A pilot study found that MB infusion counteracts myocardial depression and reduces concurrent adrenergic support in human septic shock, while a recent randomized controlled trial demonstrated that early adjunctive MB reduced time to vasopressor discontinuation, increased vasopressor-free days, and shortened ICU and hospital stays without adverse effects. Despite these encouraging findings, larger and more rigorous trials are needed to confirm MB's efficacy in septic shock patients, as well as to determine the optimal timing, dosing, duration, and safety profile of MB treatment.
REFERENCES:
1. Gamcrlidze MM, Intskirveli NA, Vardosanidze KD, Chikhladze KhE, Goliadze LSh, Ratiani LR. Vasoplegia in septic shock (review). Georgian Med News. 2015 Feb;(239):56-62. PMID: 25802451.
2. Heemskerk S, Masereeuw R, Russel FG, Pickkers P. Selective iNOS inhibition for the treatment of sepsis-induced acute kidney injury. Nat Rev Nephrol. 2009 Nov;5(11):629-40. doi: 10.1038/nrneph.2009.155. Epub 2009 Sep 29. PMID: 19786992.
3. Mazzeffi M, Hammer B, Chen E, Caridi-Scheible M, Ramsay J, Paciullo C. Methylene blue for postcardiopulmonary bypass vasoplegic syndrome: A cohort study. Ann Card Anaesth. 2017 Apr-Jun;20(2):178-181. doi: 10.4103/aca.ACA_237_16. PMID: 28393777; PMCID: PMC5408522.
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