To determine role of methyleneblue in septic shock as a vasopressor sparing agent:a prospective randomized controlled study

To Determine role of methyleneblue in  septic shock as a vasopressor sparing agent

Introduction:

Shock is defined as an acute syndrome of circulatory failure leading to inadequate oxygen delivery to the cells.1 A number of different pathophysiological mechanisms may cause shock, including cardiogenic factors, obstruction, distributive factors (anaphylaxis or sepsis), and hypovolemia. In intensive care patients, the most common type of shock is septic (62%), followed by cardiogenic (16%) and hypovolemic shock (16%). Other types of obstructive and vasodilatory shock are relatively less frequent.1

Septic shock is a type of distributive shock .It is defined by persisting hypotension requiring vasopressors to maintain a mean arterial pressors of 65mmhg or higher and a serum lactate level greater than 2mmol/l despite adequate fluid resustication. It underlying pathophysiology is vasodilation and pooling of blood. Fluid resuscitation and vasopressors are the initial approaches to the management of shock. Management of distributive shock involves treating the cause and restoring organ perfusion with fluid resuscitation and vasopressors.Vasodilatory shock is seen whenever there is a cardiovascular failure. It frequently follows septic shock. Mortality in  shock exceeds 50%. Almost 6%-7% of critically ill patients in the ICU may develop  shock. The key to survival is to identify the cause and treat promptly and initiate combination vasopressor therapy early. Unfortunately, even with multiple rescue therapies, multi-organ failure is common, so patient monitoring is vital.

Treatment of distributive shock, the most frequent, is largely dependent on managing hypotension, ensuring adequate systemic and microcirculatory flow, and tissue oxygenation.3 To improve arterial pressure, and therefore organ perfusion, intravenous vasopressors are often employed. Among others, norepinephrine is recommended as first choice to obtain mean arterial pressure (MAP) at greater than 60–65 mmHg.3 This hemodynamic goal may require large doses of the drug. At high dosages, it may be responsible for added risk for adverse events such as dysrhythmias, peripheral ischemia, and increased myocardial oxygen consumption. Other potential side effects include hypercoagulability, immunomodulation, and gastrointestinal peristalsis alterations, and extravasation.3 Moreover, several patients are identified as “non-responders” to first-line norepinephrine treatment.

Because of the risks associated with catecholamine vasopressors, interest has grown in using catecholamine-sparing agents in order to achieve hemodynamic target with lower catecholamine doses. Although definitions for catecholamine-sparing agents vary, it is agreed that those medicines should reduce the norepinephrine dose by 50% or more for 4 h without any reduction from the patient’s baseline MAP. Well-known adjuvant agents used for catecholamine-sparing effects in shock include vasopressin, corticosteroids, whose effect on microcirculation has been demonstrated for about half century, and angiotensin II.4,5

Methylene blue (MB) becomes interesting because it is a drug used since the 19th   century with proven hemodynamic effects since 1976  besides presenting safety in its use, as it has minimal side effects when used in adequate doses. Methylene blue is a phenothiazine-related heterocyclic aromatic molecule (C16H18N3SCl). It is a solid, odorless, dark green powder at room temperature that yields a blue solution when it is dissolved in water. Methylene blue is used in a wide variety of settings and for many purposes; for example, as a redox indicator or as a dye/stain.It is increasingly used in management of distributive shock . Its mechanism of action is based on inhibition of nitric oxide -cyclic guanosine monophosphate pathways leading to the increased vascular motor tone in the arteriole.  Methylene blue (MB) represents an additional option useful to provide a catecholamine-sparing effect, but its use is controversial.  Two randomized controlled trials evaluated the use of MB in treating hypotension secondary to septic shock. In both studies, as well as in observational ones and case reports, MB was able to cause a statistically significant increase of MAP. MB led to significant increases in systemic vascular resistance. A recent meta-analysis shows that MB blue could significantly increase MAP in patients with refractory hypotension caused by vascular paralysis during the course of vasodilatory shock and decrease the lactate levels. Administration of MB was able to facilitate the weaning of catecholamine vasopressors as well.6-8

Aim of this study to determine role of methylene in septic shock as a vasopressor sparing agent.

AIMS AND OBJECTIVES

·        To determine role of methyleneblue in  septic shock as a vasopressor sparing agent

  Objective

Primary objective

To determine the vasopressor sparing effect of methylene blue in septic shock patients.

Secondary objective

a)28 days mortality

b) Serum lactate level

c) length of stays in ICU

     MATERIAL AND METHODS

Study settings:

The study will be conducted in Department of Anaesthesiology,  King George’s Medical University, Lucknow.

Study duration: One and half year

Study design: Prospective Randomized controlled study

  Sample size

On the basis of previous study, the mean difference of time to vasopressor discontinuation in  methylene blue group (69) and control group (94) was 25 and the variance (σ2) was 49.63 (Ibarra-Estrada et al., 2023). The sample size (n) = 2 (Zα/2 + Z [1-β])2 × σ2/( μ1−μ2)2,assuming 0.05 level significance (Zα/2 =1.96), and 80% power (Z [1-β])=0.84) was 61.80. In this study we will enroll 62 patients in each group of the study.

  2 (Zα/2 + Z [1-β])2 × σ2

n

(μ1−μ2)2

 2 (1.96 + 1.28)2 ×49.632

n=

(94-69)2

 n=61.80

 Ibarra-Estrada M, Kattan E, Aguilera-González P, Sandoval-Plascencia L, Rico-Jauregui U, Gómez-Partida CA, Ortiz-Macías IX, López-Pulgarín JA, Chávez-Peña Q, Mijangos-Méndez JC, Aguirre-Avalos G, Hernández G. Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial. Crit Care. 2023 Mar 13;27(1):110.

Inclusion criteria:

·        All adult patient aged between 20- 50 year of aged admitted in ICU with septic shock will be included in the study after obtaining written informed consent.

Exclusion criteria:

·        Not giving consent

·       

 24 h since initiation of norepinephrine,

·        pregnancy,

·        high probability of death within 48 h

·        APACHE  Score >25

·        concurrent hemorrhagic and cardiogenic Shock

·        obstructive or hypovolemic shock,

·        pending damage control surgery,

·        major burn injury,

·        patient expire within 24 hr

·        allergy to methylene blue,

  Study Protocol:

Ethical approval and informed consent will be taken.  After signing informed consent, patients will be randomly assigned to receive methylene blue using a predetermined randomization sequence prepared in sealed opaque envelopes. The sequence will be generated by computer with a 1:1 allocation ratio, using permuted blocks with a size of 4. Critical care physicians will be responsible for assignment of intervention. Patients  will be blinded to the treatment received.

All enrolled patients who full fill the inclusion criteria will randomly allocated with two groups:

1)    Patients assigned to MB group will receive an intravenous (IV) infusion of 100 mg of MB in 50 ml of 0.9% sodium chloride solution over 6 h once daily for a total of 3 doses over 3 days.

2)     Patients assigned to control group will receive the same dose of 50 ml of 0.9% Sodium chloride without methylene blue .

In patients of both groups, adjunctive vasopressin will be initiated at a dose of 0.03 IU/min if norepinephrine dose reached ≥ 0.25 mcg/kg/min; . Hydrocortisone at 200 mg/day dose by continuous infusion will also be given in both the groups, and it is withheld within 6-h after discontinuation of all vasopressors without taper.

Recorded information at randomization will include demographic variable, ventilatory and laboratory data, including diagnosis of acute respiratory distress syndrome defined according to Berlin Criteria.

APACHE score will be calculated on days of admission and SOFA score daily till follow up patients.

Serial procalcitonin monitoring every alternate day will be used to guide resolution of sepsis.

All patients will be followed up until time to decrease vasopressors requirement as primary objective.

Secondary objective will include 28 days mortality ,Serum lactate level and length of stay in ICU

We will stop methylene blue if Shock resolve, Decrease vasopressor requirement and patient discharge.

Statistical Analysis

The SPSS (Version 23.0) program will be used for statistical analysis. Descriptive statistics will be presented as mean, standard deviation, median, minimum, maximum, frequency and ratios. Categorical data will be analysed using the chi-square test, and continuous data will be analysed using the student t-test. Spearman’s rank correlation coefficient will be used to determine the association between variables. Significance will be evaluated at a p-value <0.05. Outcomes will be analyzed on an intention-to-treat basis.

Review of Literature

Jang DH, et al (2013) conducted a study that 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 oxide–cyclic 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.

Puntillo F  et al (2020) studied that the Shock is a serious acute circulatory failure leading to inadequate oxygen delivery to the cells. Its treatment is mainly based on circulating fluid optimization, and vasopressors to provide an adequate mean arterial pressure and microcirculatory flow. Norepinephrine is the drug of choice, but high dosages may be responsible for several side effects, including increased myocardial oxygen consumption, dysrhythmias, and peripheral and organ ischemia. Moreover, some patients are “non-responders” to first-line norepinephrine treatment. Hence, other drugs have been proposed to reach and maintain the hemodynamic target. In general, they are described as catecholamine-sparing agents. Among others, the most used are vasopressin, corticosteroids, and angiotensin II. Methylene blue (MB) represents a further option, even though its use is still a topic of controversy. This review article tries to summarize what is known and unknown about the actions of MB in patients in shock. It reduces excessive production of nitric oxide via blockade of guanylate cyclase in shock states. At present, it appears the MB provides positive results in septic shock, if administered early. Further randomized controlled trials are warranted regarding its use to provide more precise indications to physicians involved in the treatment of such patients.

Pořízka M,  et al (2021) conducted a study that Refractory distributive shock is associated with excessive mortality in critically ill patients. Non-adrenergic vasopressors, including methylene blue, are often considered as an adjuvant therapy to the usual, catecholamine-based vasopressor treatment. In this narrative review we summarize the current scientific evidence on the use of methylene blue in the treatment of refractory distributive shock in different clinical situations.

Ibarra-Estrada, M et al (2023)  conducted a study that single-center randomized controlled trial, assigned patients with septic shock according to Sepsis-3 criteria to MB or placebo. Primary outcome was time to vasopressor discontinuation at 28 days. Secondary outcomes included vasopressor-free days at 28 days, days on mechanical ventilator, length of stay in ICU and hospital, and mortality at 28 days. Among 91 randomized patients, forty-five were assigned to MB and 46 to placebo. The MB group had a shorter time to vasopressor discontinuation (69 h [IQR 59–83] vs 94 h [IQR 74–141]; 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. In patients with septic shock, MB initiated within 24 h reduced time to vasopressor discontinuation and increased vasopressor-free days at 28 days. It also reduced length of stay in ICU and hospital without adverse effects. Our study supports further research regarding MB in larger randomized clinical trials.

Luis-Silva F  et al (2023) conducted a study that to demonstrate the benefit of MB in early phase of septic shock. Total 6 cases of patients with septic shock with up to 72 hours of evolution. We used MB after fluid replacement, use of norepinephrine and vasopressin. Patients received a loading dose of MB and maintenance for 48 hours. All patients presented a reduction in the dose of vasopressors and lactate levels soon after the administration of the loading dose of MB, an effect that was maintained with the maintenance dose for 48 hours. Interleukin 6 and interleukin 8 were elevated at the beginning of the septic condition, with a progressive and marked reduction after the beginning of MB infusion, demonstrating a role of MB in reducing the inflammatory activity. This case series suggests that MB used early in the treatment of septic shock may be useful in reducing vasopressor dose and lactate levels. Further studies are still required to further validate these findings.

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Ibarra-Estrada, M., Kattan, E., Aguilera-González, P. et al. Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial. Crit Care 27, 110 (2023). https://doi.org/10.1186/s13054-023-04397-7

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