Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue

Weingartner, Roger; Oliveira, Elizabeth dos Santos Boos de; Sant'Anna, Urbano Leonel; Oliveira, Rodrigo Pereira de; Azambuja, L. A.; Friedman, Gilberto

doi:10.1590/s0100-879x1999001200009

Cited by 51 publications

(55 citation statements)

References 48 publications

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“…The dosing used for refractory septic shock has included a single bolus, repeated bolus based on response, low-dose infusion, and infusions followed by a bolus. It is clear based on other studies that the use of high doses of methylene blue, typically doses greater than 7 mg/kg, is associated with adverse effects such as paradoxical induction of methemoglobinemia, acute hemolytic anemia, and detrimental effects on pulmonary function [86,87].…”

Section: The No-cgmp Pathway In Anaphylaxis and The Role Of Methylenementioning

confidence: 99%

Methylene Blue for Distributive Shock: A Potential New Use of an Old Antidote

2013

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Methylene blue is used primarily in the treatment of patients with methemoglobinemia. Most recently, methylene blue has been used as a treatment for refractory distributive shock from a variety of causes such as sepsis and anaphylaxis. Many studies suggest that the nitric oxidecyclic guanosine monophosphate (NO-cGMP) pathway plays a significant role in the pathophysiology of distributive shock. There are some experimental and clinical experiences with the use of methylene blue as a selective inhibitor of the NO-cGMP pathway. Methylene blue may play a role in the treatment of distributive shock when standard treatment fails.

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Section: The No-cgmp Pathway In Anaphylaxis and The Role Of Methylenementioning

confidence: 99%

Methylene Blue for Distributive Shock: A Potential New Use of an Old Antidote

2013

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“…In this case, we report the need for a prolonged infusion of MB over a period of 120 hr in a patient with intractable septic shock. Previous research has demonstrated that MB may be efficacious in septic shock when given by intravenous bolus or short-term (B6 h) infusions, 3,4,9,11,[16][17][18] although a case report of a longer-term infusion of 44 hr has been described. 12 Despite standard treatment for septic shock with early goal-directed therapy, conventional vasopressors, including norepinephrine, epinephrine, and vasopressin, our patient responded only to the administration of MB.…”

Section: Discussionmentioning

confidence: 99%

“…3,4,16,23 In patients with septic shock, bolus doses of MB have been associated with increases in pulmonary vascular resistance, 5 and caution has been advised in patients with acute respiratory distress syndrome. 18 Additionally, while little is known about the appropriate dose of MB, a recent study demonstrated that bolus doses of 7 mgÁkg -1 may compromise splanchnic perfusion, while maintaining dosedependent hemodynamic properties. 24 In addition, the safety of MB for patients undergoing CRRT has not been adequately studied.…”

Section: Discussionmentioning

confidence: 99%

Prolonged methylene blue infusion in refractory septic shock: a case report

Dumbarton

Minor

Yeung

et al. 2011

Can J Anesth/J Can Anesth

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Purpose Methylene blue (MB) has been advocated for the treatment of refractory hemodynamic instability in patients with septic shock. However, the use of MB infusions in septic shock is not considered standard treatment, and the available literature describes infusions of short duration, typically less than six hours. Clinical features We report a case of septic shock in a 67-yr-old male who required maximal vasopressor support with norepinephrine, epinephrine, and vasopressin. Despite standard protocols for the treatment of septic shock, the patient's hemodynamic status was refractory 80 hr post admission. However, initiation of a MB infusion resulted in the rapid restoration of hemodynamic stability and a subsequent decrease in vasopressor requirements.Multiple attempts to discontinue the MB infusion resulted in immediate and repeated increases in vasopressor requirements, necessitating a continuous infusion with a slow taper of MB for 120 hr. Ultimately, the patient survived the illness and was discharged home. We observed no adverse events that could be attributed to the use of MB. Conclusion In our patient, the use of MB resulted in hemodynamic stability unattained with standard vasopressor support. Further research is warranted on the use of MB in patients with septic shock. RésuméObjectif Le bleu de me´thyle`ne (BM) a e´te´propose´par certains chercheurs comme traitement de l'instabiliteh e´modynamique re´fractaire chez les patients en choc septique. La perfusion de BM n'est toutefois pas conside´re´e comme un traitement standard du choc septique, et la litte´rature publie´e de´crit des perfusions de courte dure´e, en ge´ne´ral de moins de six heures. É léments cliniques Nous rapportons un cas de choc septique chez un homme de 67 ans qui a eu besoin d'un soutien vasopresseur maximal avec de la nore´pine´phrine, de l'e´pine´phrine et de la vasopressine. Malgre´l'application des protocoles normalise´s pour le traitement du choc septique, l'e´tat he´modynamique du patient demeurait re´fractaire 80 h apre`s son admission. L'amorce d'une perfusion de BM a toutefois permis de re´tablir rapidement la stabilite´he´modynamique du patient et a entraıˆne´une re´duction subse´quente de ses besoins en vasopresseurs. Les nombreuses tentatives d'interruption de la perfusion de BM ont entraıˆne´des augmentations imme´diates et re´pe´te´es des besoins en vasopresseurs, c'est pourquoi une perfusion continue a`un de´bit plus bas de BM durant 120 h a e´te´mise en place. Le patient a finalement surve´cu a`la maladie et reçu son conge´de l'hôpital. Nous

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“…Methylene blue has been used in several studies in human sepsis (Schneider et al, 1992;Daemen-Gubbels et al, 1995;Gachot et al, 1995;Preiser et al, 1995;Andresen et al, 1998;Weingartner et al, 1999;Donati et al, 2002). MB was effective in increasing MAP of septic rats only when injected 48 h after the CLP procedure.…”

Section: Discussionmentioning

confidence: 99%

“…Several uncontrolled studies in patients with septic shock requiring adrenergic support have shown that sGC inhibited by MB restores the mean arterial pressure and improves the myocardial contractility (Schneider et al, 1992;Daemen-Gubbels et al, 1995;Preiser et al, 1995;Andresen et al, 1998). On the other hand, sGC inhibition was found to be deleterious to gas exchange in the lung and myocardial contractility (Gachot et al, 1995;Weingartner et al, 1999). These findings prompted some researchers to question the use of MB in human sepsis (Schneider, 1995), whereas other groups found that the beneficial effects are worth the risk (Donati and Preiser, 2006).…”

mentioning

confidence: 99%

Late, but Not Early, Inhibition of Soluble Guanylate Cyclase Decreases Mortality in a Rat Sepsis Model

Fernandes¹,

Sordi²,

Pacheco³

et al. 2008

J Pharmacol Exp Ther

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Overproduction of nitric oxide and activation of soluble guanylate cyclase (sGC) are important in sepsis-induced hypotension and hyporesponsiveness to vasoconstrictors. A time course of the expression and activity of sGC in a sepsis model [cecal ligation and puncture (CLP)] was evaluated in rats. Soluble GC ␣-1 and ␤-1 subunit mRNA levels increased in the lungs, but not in the aorta. However, in both tissues, the protein levels increased 24 h after sepsis and remained high for up to 48 h. Sodium nitroprusside-stimulated cGMP accumulation was higher 48 h after CLP in the lung and aorta. NOS-2 protein expression peaked 24 h after CLP, decreasing thereafter. The impact of inhibiting the expression of sGC early (8 h) or late (20 h) on vascular reactivity and the indexes of organ damage and mortality were also studied. Late administration of methylene blue (MB) or ODQ (1H-[1,2,4]-oxadiazole[4,3-a]quinoxalin-1-one) restored the blood pressure and vascular responsiveness to vasoconstrictors to normal levels but was ineffective in early sepsis. Late MB injection reduced the plasma levels of urea, creatinine, and lactate. MB improved the survival if administered late, but it increased the mortality when administrated early after sepsis onset. The increased sGC expression/ activity may be relevant for the late hypotension and hyporesponsiveness to vasoconstrictors in sepsis. In accordance, MB increased survival if administered in late sepsis, but not in early sepsis. Therefore, differential responsiveness to sGC during the course of sepsis may determine the success or failure of treatment with sGC inhibitors.Severe sepsis and septic shock are major causes of mortality in intensive care units (Vincent et al., 2006). The number of patients with severe sepsis and septic shock is increasing because of increased life expectancy and the rise in the number of immunocompromised patients, among other reasons (Bonde et al., 2006).Large amounts of nitric oxide (NO) are produced by NO synthase (NOS) 2 (inducible NOS) isoform in response to an injury in the vascular endothelium (Chin-Wei et al., 2008), vascular smooth muscle (Rees et al., 1990), and myocardium (Niu et al., 2008). Increased NO production contributes to some of the key features of septic shock, such as severe hypotension, vascular hyporesponsiveness toward vasoconstrictors, and myocardial dysfunction. NOS inhibition studies in sepsis are mostly based on in vitro or animal studies (for review, see Assreuy, 2006). To date, all the NOS inhibitors that have been tested in the clinical setting are nonselective for the three NOS isoforms, which causes undesired side effects, such as excessive vasoconstriction, which was the most likely reason for a phase III study with a NOS inhibitor in human sepsis to be interrupted (López et al., 2004).Soluble guanylate cyclase (sGC) is a key element in NO signaling. This enzyme is usually a heterodimer of ␣ and ␤ subunits, and it is activated by NO binding to its heme This work was supported by

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Blockade of the action of nitric oxide in human septic shock increases systemic vascular resistance and has detrimental effects on pulmonary function after a short infusion of methylene blue

Cited by 51 publications

References 48 publications

Methylene Blue for Distributive Shock: A Potential New Use of an Old Antidote

Methylene Blue for Distributive Shock: A Potential New Use of an Old Antidote

Prolonged methylene blue infusion in refractory septic shock: a case report

Late, but Not Early, Inhibition of Soluble Guanylate Cyclase Decreases Mortality in a Rat Sepsis Model

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