The Story of Nitric Oxide, Sepsis and Methylene Blue: A Comprehensive Pathophysiologic Review.

Methylene blue (MB) is considered to be the first synthetic medication ever used in humans. There are many indications for MB, including vasoplegic shock. Nitric oxide (NO), the central mediator of sepsis, promotes vasoplegia by enhancing the guanylate cyclase cyclic guanosine monophosphate second messenger system, the effect of which is attenuated by MB. Therefore, the use of MB represents a unique pharmacologic approach towards treating the underlying pathophysiology of vasoplegia in sepsis. There are numerous reports of the successful use of MB in refractory shock in the literature. This manuscript describes the historical aspects of the identification of NO as the endothelial derived relaxation factor and its role in the pathogenesis of vasoplegia in septic shock. An analysis of the existing evidence for the use of MB as an inhibitor of NO in vasodilatory shock is provided. The adverse effects associated with the use of MB and an approach to optimal dosing in septic shock are also addressed.

Commercial albumin solution enhances endotoxin-induced vasoplegia and inflammation.

BACKGROUND: The Gram-negative bacterium Escherichia coli, commonly involved in severe sepsis and septic shock, shed endotoxin that upon detection by the host triggers an inflammatory cascade. Efficiency of albumin solutions to restore hypovolemia during sepsis has been debated. To aid identification of subgroups of sepsis patients that may respond positively or negatively to treatment with albumin we investigated if preparations of albumin for medical use could affect endotoxin-induced inflammatory response. METHODS: Isolated human omental arteries obtained during surgery were incubated with endotoxin in the presence or absence of albumin solution. Isolated human monocytes were incubated with endotoxin in the presence or absence of five different commercially available albumin solutions. Vascular contractile response to noradrenaline and release of interleukin (IL)-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α were measured. RESULTS: Incubation with albumin together with endotoxin decreased median maximum contraction and increased release of IL-6 and IL-8 from the arteries compared to incubation with endotoxin alone. All albumin solutions except one significantly increased endotoxin-induced TNF-α release from monocytes. IL-6 and IL-10 were also increased and no concentration dependency of TNF-α release was observed above 2 mg mL-1 . Incubation with albumin alone did not affect contraction or release of cytokines while no potentially endotoxin-enhancing contaminant could be identified. CONCLUSION: We have shown that albumin solution in combination with endotoxin cause vasoplegia in human omental arteries, paralleled by an inflammatory response. This finding could explain the variable efficiency of albumin solutions for sepsis treatment.

Perivascular adipose tissue contributes to lethal sepsis-induced vasoplegia in rats.

It is well established that sepsis induces vascular hyporesponsiveness to vasoconstrictors. Perivascular adipose tissue (PVAT) displays anti-contractile action in various blood vessels. We hypothesized that sepsis would increase the anti-contractile effect of PVAT aggravating sepsis-induced vasoplegia. Male Wistar Hannover rats were subjected to lethal sepsis by cecal ligation and puncture (CLP) method. Aorta or PVAT were collected for functional or biochemical assays 6 h after CLP surgery. Functional experiments showed that sepsis increased the anti-contractile action of PVAT in both endothelium-intact and endothelium-denuded aortas. Carboxy-PTIO, L-NAME and ODQ reversed the hypocontractility mediated by PVAT in aortas from septic rats. Inhibition of nNOS and iNOS with 7-nitroindazole and 1400 W attenuated PVAT-mediated hypocontractility during sepsis. Similar results were found in the presence of indomethacin and Ro1138452, a selective prostacyclin IP receptor antagonist. However, neither tiron nor catalase affected phenylephrine-induced contraction in aortas from septic rats. Increased levels of superoxide anion (O2•-) and 6-keto-prostaglandin F1α (stable product of prostacyclin) were detected in PVAT from septic rats. In situ quantification of reactive oxygen species and nitric oxide (NO) using fluorescent dyes revealed increased levels of both in PVAT from septic rats. The novelty of our study is that PVAT contributes to sepsis-induced vasoplegia by releasing NO and prostacyclin. These findings suggested that signaling pathways in PVAT may be considered as potential novel pharmacological therapeutic targets during sepsis-induced vasoplegia.

Vitamin B12 for the treatment of vasoplegia in cardiac surgery and liver transplantation: a narrative review of cases and potential biochemical mechanisms.

PURPOSE: Hydroxocobalamin, or vitamin B12 (V-B12), is frequently used to treat smoke inhalation and cyanide poisoning. Recent reports have also described its use to treat vasoplegia in cardiac surgery and liver transplantation. This narrative review discusses this "off-label" indication for V-B12, focusing on the potential biochemical mechanisms of its actions. SOURCE: PubMed, Cochrane, and Web of Science databases were searched for clinical reports on the use of V-B12 for vasoplegia in cardiac surgery and liver transplantation, with the biochemical mechanisms discussed being based on a survey of the related biochemistry literature. PRINCIPAL FINDINGS: Forty-four patients have been treated with V-B12 for vasoplegia in various isolated case reports and one series. Although 75% of patients have increased blood pressure in response to V-B12, there were some "non-responders". The true efficacy remains unknown because clinical trials have not been performed, and significant reporting bias likely exists. Plausible biochemical explanations exist for the potential beneficial effects of V-B12 in treating vasoplegia, including binding nitric oxide and other gasotransmitters. Additional research is required to clarify if and how these mechanisms are causally involved in effective clinical responders and non-responders. CONCLUSIONS: Although anecdotal reports utilizing V-B12 for vasoplegia are available, no higher-level evidence exists. Future work is necessary to further understand the dosing, timing, adverse events, and biochemical mechanisms of V-B12 compared with other therapies such as methylene blue.

Enzymatic changes in myosin regulatory proteins may explain vasoplegia in terminally ill patients with sepsis.

The current study was conducted with the hypothesis that failure of maintenance of the vascular tone may be central to failure of the peripheral circulation and spiralling down of blood pressure in sepsis. Namely, we examined the balance between expression of myosin light chain (MLC) phosphatase and kinase, enzymes that regulate MLCs dephosphorylation and phosphorylation with a direct effect on pharmacomechanical coupling for smooth muscle relaxation and contraction respectively. Mechanical recordings and enzyme immunoassays of vascular smooth muscle lysates were used as the major methods to examine arterial biopsy samples from terminally ill sepsis patients. The results of the present study provide evidence that genomic alteration of expression of key regulatory proteins in vascular smooth muscles may be responsible for the relentless downhill course in sepsis. Down-regulation of myosin light chain kinase (MLCK) and up-regulation of MLCK may explain the loss of tone and failure to mount contractile response in vivo during circulation. The mechanical studies demonstrated the inability of the arteries to develop tone when stimulated by phenylephrine in vitro. The results of our study provide indirect hint that control of inflammation is a major therapeutic approach in sepsis, and may facilitate to ameliorate the progressive cardiovascular collapse.

Vasoplegia in septic shock (review).

Vasoplegia is considered as a key factor responsible for the death of patients with septic shock, due to persistent and irreversible hypotension. The latter associated with vascular hyporeactivity to vasoconstrictors is a significant independent prognostic factor of mortality in severe sepsis. Loss of control of the vascular tone occurs through the complex, multifactorial mechanism and implicates deeply disrupted balance between vasoconstrictors and vasodilators. The aim of this review is to discuss in detail the recent suggested alternative mechanisms of vasoplegia in severe sepsis: Overproduction of nitric oxide (NO) by activation of inducible form of nitric oxide synthase (iNOS); up-regulation of prostacyclin (PG12); vasopressin deficiency; significantly elevated levels of circulating endothelin; increased concentrations of vasodilator peptides such as adrenomedulin (AM) and calcitonin gene-related peptide (CGRP); oxidative stress inducing endothelial dysfunction and vascular hyporeactivity to vasoconstrictors; inactivation of catecholamines by oxidation; over-activation of ATP-sensitive potassium channels (KATP channels) during septic shock and their involvement in vascular dysfunction. The review also discusses some therapeutic approaches based on pathogenetic mechanisms of severe sepsis and their efficacy in treatment of patients with septic shock. The loss of vascular tone control occurs through the complex, multifactorial mechanism and implicates deeply disrupted balance between vasoconstrictors and vasodilators in the pathogenesis of septic shock. Overproduction of nitric oxide (NO) by the inducible form of nitric oxide synthase (iNOS); up-regulation of prostacyclin (PG12); vasopressin deficiency; elevated levels of circulating endothelin; increased concentrations of vasodilator peptides such as adrenomedulin (AM) and calcitonin gene-related peptide (CGRP); oxidative stress inducing endothelial dysfunction and vascular hyporeactivity to vasoconstrictors; inactivation of catecholamines by oxidation; over-activation of ATP-sensitive potassium channels (KATP channels) and their involvement in vascular dysfunction - all these factors combined together lead to steady refractory shock with the lethal outcome in patients.

[Pathophysiological mechanisms and treatment of septic shock-induced vasoplegia]. / Physiopathologie et traitement de la vasoplégie au cours du sepsis.

The hemodynamics of septic shock is characterized by a primary reduction of vascular tone, which defines vasoplegia. Septic vasoplegia is due to reduced endogenous production of vasopressin, as well as to the overproduction of vasodilating molecules (nitric oxide, prostacyclin, peroxynitrite and kynurenine) and the opening of ATP-sensitive potassium channels. Treatment is supportive and includes primarily alpha-adrenergic catecholamines. Vasopressin may also be useful, although its place is still controversial. Further agents can improve the vascular responsiveness to catecholamines, most notably low doses hydrocortisone, and, to a lesser extent, activated protein C. Further, innovative therapies, based on recent understanding of pathophysiological mechanisms, might become useful agents to treat septic vasoplegia in the future.