Endothelial Dysfunction in Distributive Shock

Chapter 7 Endothelial Dysfunction in Distributive Shock Since the 1990s, nitric oxide (NO) has been associated with vasoplegia of septic shock resistant to high doses of catecholamines. After exposure to bacterial endotoxin or specific cytokines, the inducible nitric oxide synthase (iNOS) expression occurs in a wide variety of tissues. This enzyme produces large NO amounts over long periods, closely related to the pathophysiological changes in sepsis. In some cells, including macrophages, NO synthesized by iNOS is toxic and appears to be an essential mediator in the defense of the host. Animal and in vitro studies have shown that this NO release into other tissues can cause extreme vasodilation, damage to the cell population and heart failure [1]. NO synthesis inhibitors can reverse hypotension caused by endotoxin and cytokine, and these agents could, in theory, constitute a modern therapeutic approach to severe septic shock. Preliminary studies in humans suggest that NOS inhibition improves blood pressure and stabilizes hemodynamics, but mortality rates remain undetermined. It can be said that the use of synthesis inhibitors was associated with increased mortality compared to the control group in humans, causing multicenter studies to be interrupted. The participation of the overproduction of NO by the iNOS expression is evident, leading to a vasoplegia state that is irresponsible to high doses of catecholamines [2]. Contrary to these concepts, which are already established for septicemic shock, there is little experimental evidence that relates to increasing NO production as a pathophysiological factor in anaphylactic shock, whose secondary mediators are different. Systemic anaphylaxis is associated with the acute release of substances such as histamine, leukotrienes, and platelet activation factor, although there is experimental evidence that there is no increase in pro-inflammatory cytokines. It is not surprising that the marked iNOS expression is not found in systemic © The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 P. R. Barbosa Evora et al., Vasoplegic Endothelial Dysfunction, https://doi.org/10.1007/978-3-030-74096-2_7 45 46 7 Endothelial Dysfunction in Distributive Shock anaphylaxis. On the other hand, there is an increase in NO production due to eNOS expression, which can be associated with early vascular hyporeactivity, with acute hypotension, observed in anaphylactic shock [2]. The use of NOS inhibitors in the experimental treatment of anaphylactic shock is questionable. NOS inhibition can increase blood pressure, but with a significant decrease in cardiac output. Also, the NO produced by the bronchial epithelium plays an essential role in counterbalancing anaphylactic bronchoconstriction, and the use of NOS inhibitors could worsen this clinical condition. These concepts, taken together, seem to show that NOS inhibitors have a limited role in anaphylactic shock treatment. This makes room for another therapeutic modality that does not interfere with NOS production, but rather with its effect on vascular smooth muscle, justifying guanylate cyclase inhibition, preventing the increase of guanosine 3′5′-cyclic monophosphate (cGMP) that is responsible for vasodilation. Thus, methylene blue (MB) gains space to be tested in this type of circulatory shock [1]. Regarding neurogenic shock, studies on the participation of NO in vasoplegia are associated with it, and very few reviews are found in the specialized literature. Inhibition of Nitric Oxide Synthesis as a Therapeutic Proposal for Vasoplegia Associated with Shock When sepsis occurs, the first change in the circulatory system is the hypotension resulting from the dilation of systemic blood vessels. Although the NO and NOS relationship during sepsis is not well understood, it is believed that cytokines cause refractory hypotension and failure of the circulatory system due to LPS originating from bacteria. Subsequently, large NO volumes are produced. NOS inhibition in sepsis can lead to liver and intestinal damage, increased platelet aggregation, pulmonary vasoconstriction, and expanded and reduced cardiac output. Also, the cellular biochemistry defense against exogenous pathogens could be impaired by the NOS inhibition. NOS inhibitors can have long-lasting effects that are not always predictable, limiting their use in a clinical setting. NOS inhibition to restore hypotension is still connected with many uncertainties and evident adverse side effects. More knowledge about the NO role in septicemic shock and the participation of different NOS, which can be selectively inhibited, is needed. It should be noted that studies in humans had to be interrupted after the observation of a significant increase in mortality due to the use of NO synthesis inhibitors. The Inhibition of Guanylate Cyclase by Methylene Blue as a Therapeutic Proposal… 47 The Inhibition of Guanylate Cyclase by Methylene Blue as a Therapeutic Proposal for Vasoplegia Associated with Shock Because of all the concepts discussed, MB seems to be the most reasonable therapeutic proposal since it does not interfere with NO synthesis and because it is a medication widely used in other clinical conditions. MB action implies guanylate cyclase inhibition, preventing the cGMP elevation and, consequently, avoiding NO-mediated endothelium relaxation (Fig. 7.1) [1]. The use of MB in patients with septic shock, in the infusion of 1–2 mg.Kg−1, is already established, providing an increase in blood pressure by inhibiting the NO action in vascular smooth muscle. The NO release has been implicated in the cardiovascular septicemic shock changes. Since guanylate cyclase is the endothelium-dependent relaxation enzyme, MB is a potent inhibitor of this enzyme and an essential option for the sepsis vasoplegia treatment. A study in humans showed that MB increased the mean arterial pressure (MAP) and stroke volume in septicemic and shocked patients. The other parameters, obtained through the hemodynamic research at the bedside, did not show significant changes, and in some of the studied patients, the effect was not sustained, and, for this reason, a new dose was administered in an intravenous bolus (“Scavenger”) Dexametasone Hemoglobin Blood Aminoguanidine Endothelial cell iNOS NO L-Arginine eNOS L-NMMA L-NAME cGMP L-NOARG Smooth muscle Methylene blue (guanylate cyclase inhibition) Fig. 7.1 Nitric oxide blockers, highlighting that hemoglobin and methylene blue are independent blockers of synthesis from L-arginine. NO nitric oxide, cGMP guanosine 3′5′-cyclic monophosphate, eNOS endothelial nitric oxide synthase, iNOS inducible nitric oxide synthase, L-NMMA NG-monomethyl-L-arginine, L-NAME NG-nitro-L-arginine methyl ester, L-NOARG NG-nitro-L-arginine 48 7 Endothelial Dysfunction in Distributive Shock of 2 mg.Kg−1 of the MB, observing the same initial effects. No adverse side effects were observed regarding the failure to sustain that the initial impact led to the adoption of MB’s continuous infusion after the initial intravenous bolus. In a bibliographic search, as wide as possible, the use of MB in the clinic to treat anaphylactic shock is found only in the works of Evora et al. [2]. The excellent results obtained in 13 clinical cases suggest the fundamental role of NO in the anaphylactic shock pathophysiology, raising MB to a condition of choice, or even priority, in its therapy. The accumulation of clinical experience may confirm these impressions. The MB dosages used (3.0 mg.Kg−1) were adopted based on the knowledge acquired in the sepsis vasoplegia treatment and the methemoglobinemia treatment. This dose is safe since the lethal dose of MB, determined experimentally in goats, is 40 mg.Kg−1 [2]. Vasopressin-Dependent Mechanisms Landry et al. (1997) have shown that vasopressin levels in septic shock are abnormally low [3]. This fact supports the hypothesis that in sepsis there may be a decrease in vasopressin stocks or a baroreflex dysfunction, causing insufficient vasopressin secretion. These authors also reported sepsis situations with refractory hypotension, which was recovered by the injection of vasopressin, which led to a decrease in catecholamine requirements. Considering the similarities of the inflammatory response in sepsis and vasoplegia after cardiopulmonary bypass (CPB), Argenziano et al. (1997) published a retrospective analysis of 40 cases of distributive shock after cardiac surgery, treated with vasopressin [4]. These same authors included their experience with this drug, heart transplantation, and patients undergoing mechanical circulatory assistance. In these patients, there was no hypertensive rebound, peripheral, or mesenteric ischemia, along with an improvement in blood pressure levels and a decrease in catecholamine needs. The efficiency and safety of this new and promising pressure agent need further observation. Therapeutic Principles for the Treatment of Vasoplegic Endothelial Dysfunction Associated with Cardiocirculatory Shock The first, and most important, concept concerns the restrictions on the use of nonspecific inhibitors of NO synthesis (L-NMMA, LAME, etc.). Some points can be highlighted: Possible Paradigm Shift 49 Corticosteroids are used to inhibit the inflammatory reaction and block the iNOS action. Norepinephrine is used, as it is an amine that does not promote an increase in heart rate and may even decrease it. MB is used (2 mg.Kg−1 of weight in intravenous “bolus” or half of the dose in “bolus,” followed by the continuous infusion of additional dosages). Injectable metoprolol is used (5 mg) to reverse the downregulation situation of beta receptors, which is a consequence of tachycardia and the use of amines. Because of this phenomenon, fewer beta receptors are available for effective action of beta-adrenergic drugs, with tachyphylaxis occurring. It is imperative to avoid excess volume replacement, and the main objective is to reverse vasoplegia with vasoconstrictors and MB. As hypotension is refractory to the use of amines, the use of MB has been lifesaving. Using vasopressin arginine is quite attractive, but there is still no clinical experience with this drug, although we have performed some experimental trials. The NO action depends on the activation of the cGMP system. But, in addition to this mechanism of significant importance, we have also turned our attention to the adenosine 3′5′-cyclic monophosphate (cAMP) system, which is why we are using, almost as a routine, injectable beta-blockers (metoprolol), when the patient is very tachycardic. Another logical approach would be to inhibit NO synthesis with the use of specific inhibitors such as L-NAME and L-NMMA. However, this approach is open to criticism, involves ethical problems related to the use of new therapies, and blocks not only iNOS but also the physiological form of this enzyme (cNOS). The use of specific iNOS inhibition, for example, with aminoguanidine, remains in the logical and speculative territories. Possible Paradigm Shift The combination of three concepts should be useful for better results against the high mortality rates in critically ill patients. These three concepts are (1) “widespectrum vasopressors,” (2) vasopressor economy strategies, and (3) protection against microcirculation. We believe that a combination of these three concepts will be useful to obtain better results against the high mortality rates in critically ill patients. Some observations should be mentioned based on these concepts [5–8]. (4) “Broad-spectrum vasopressors” – this approach suggests that shock treatment should be started with the association of vasopressors with a different mechanism of action. Norepinephrine is used worldwide as a first-line vasopressor, but most often, it is routinely associated with catecholamines that target the same adrenergic receptors. However, it would be more logical to associate with a non-adrenergic vasopressor (vasopressin, angiotensin II). In other words, there is no sense in the association of noradrenaline with epinephrine. It should be emphasized that this view considers only receptor-dependent effects. 50 7 Endothelial Dysfunction in Distributive Shock “Reserve strategies to support catecholamine vasopressors” have the same objective of protecting the microcirculation. Since fluids and amines are indisputable to maintain sufficient cardiovascular pressures for organ perfusion, inevitably, microcirculatory damage occurs over time. Therefore, it is mandatory to seek adjuvant therapeutic options to reduce the need for vasoactive support without compromising blood pressure [5, 6]. “Microcirculatory protection” is the oldest concept, assuming that even with blood pressure under control with increasing concentrations of amines, the failure in the microvasculature is inexorable. Therefore, special attention focused individually on microcirculation is correctly understood [9]. Cardiogenic shock may be associated with an inflammatory reaction. This possibility has motivated us experimentally and clinically in the use of MB in the last 25 years. Since the main targets of vasopressors are membrane receptors, wouldn’t it be more logical to associate them with drugs that interfere with messengers beyond membranes? Concluding Remarks • After exposure to bacterial endotoxin or specific cytokines, the expression of inducible nitric oxide synthase (iNOS) occurs in a wide variety of tissues. This enzyme produces large NO amounts over long periods, closely related to the pathophysiological changes in sepsis. • The participation of overproduction of nitric oxide (NO) by the expression of iNOS is evident, leading to a vasoplegia state irresponsible to high catecholamine doses. • More knowledge about the NO role in septic shock and the participation of different synthases of nitric oxide, which can be selectively inhibited, is necessary. It should be noted that studies in humans had to be interrupted by the observation of a remarkable increase in mortality due to the use of NO synthesis inhibitors. • Since guanylate cyclase is the endothelium-dependent relaxation enzyme, MB is a potent inhibitor of this enzyme and an essential option for the vasoplegia in sepsis treatment. References 1. Petros A, Lamb G, Leone A, Moncada S, Bennett D, Vallance P. Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovasc Res. 1994;28(1):34–9. 2. Evora PR, Simon MR. Role of nitric oxide production in anaphylaxis and its relevance for the treatment of anaphylactic hypotension with methylene blue. Ann Allergy Asthma Immunol. 2007;99(4):306–13. 3. Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D'Alessandro D, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95(5):1122–5. References 51 4. Argenziano M, Choudhri AF, Oz MC, Rose EA, Smith CR, Landry DW. A prospective randomized trial of arginine vasopressin in the treatment of vasodilatory shock after left ventricular assist device placement. Circulation. 1997;96(9 Suppl):II-286–90. 5. Evora PRB. Broad spectrum vasopressors support sparing strategies in vasodilatory shock beyond the vascular receptors. Chest. 2020;157(2):471–2. 6. Evora PRB, Braile DM. “Vasopressor support sparing strategies”: a concept to be incorporated as a paradigm in the treatment of vasodilatory shock. Braz J Cardiovasc Surg. 2019;34(1):I–II. 7. Squara P, Hollenberg S, Payen D. Reconsidering vasopressors for cardiogenic shock: everything should be made as simple as possible, but not simpler. Chest. 2019;156(2):392–401. 8. Chawla LS, Ostermann M, Forni L, Tidmarsh GF. Broad spectrum vasopressors: a new approach to the initial management of septic shock? Crit Care. 2019;23(1):124. 9. Nantais J, Dumbarton TC, Farah N, Maxan A, Zhou J, Minor S, et al. Impact of methylene blue in addition to norepinephrine on the intestinal microcirculation in experimental septic shock. Clin Hemorheol Microcirc. 2014;58(1):97–105.