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| ORIGINAL ARTICLE |
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| Year : 2014 | Volume
: 7
| Issue : 3 | Page : 327-335 |
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Methylene blue: Role in early management of septic shock patients?
Amr E Abd-Alhameed, Ahmed MS Hamed, Ahmed S Omran
Department of Anesthesiology, Intensive Care, and Pain Management, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
| Date of Web Publication | 27-Aug-2014 |
Correspondence Address:
Ahmed MS Hamed
Department of Anesthesiology, Intensive Care, and Pain Management, Faculty of Medicine, Ain-Shams University, Cairo
Egypt
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/1687-7934.139558
Background
The incidence of sepsis has increased steadily over the last three decades. Aggressive fluid challenge and administration of catecholamines still play a vital role in the current treatment regimen of patients with septic shock. However, new methods and drugs are needed for better management.
Objective
The aim of the study was to evaluate the role of early intervention with continuous infusion of methylene blue in management of septic shock patients regarding hemodynamics, duration of septic shock, and vasopressor support.
Patients and methods
Forty patients fulfilling the criteria of septic shock were randomized into two groups: group 1 that received methylene blue bolus at a dose of 1 mg/kg followed after 2 h by infusion at 0.5 mg/kg/h for 4 h and group 2 that received normal saline.
Results
The results were favorable in the study group, which showed higher and better mean arterial blood pressure, systemic vascular resistance, and cardiac output and less need for inotropes reflected by the lower length of ICU stay.
Conclusion
It can be concluded that the early application of methylene blue (defined by the need for norepinephrine at a dose of at least 0.2 μg/kg/min required to maintain mean arterial blood pressure between 70 and 90 mmHg) at a dose of 1 mg/kg bolus followed by 0.5 mg/kg/h for 4 h showed favorable effects on hemodynamics of cardiac output, decreasing the length of hospital stay. Keywords: methylene blue, septic shock
How to cite this article:
Abd-Alhameed AE, Hamed AM, Omran AS. Methylene blue: Role in early management of septic shock patients?. Ain-Shams J Anaesthesiol 2014;7:327-35 |
How to cite this URL:
Abd-Alhameed AE, Hamed AM, Omran AS. Methylene blue: Role in early management of septic shock patients?. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2023 Dec 11];7:327-35. Available from: http://www.asja.eg.net/text.asp?2014/7/3/327/139558 |
| Introduction | |  |
The incidence of sepsis has increased steadily over the last three decades. Nearly, 15% of patients in intensive care have severe sepsis and two-third of them have septic shock. Despite our increased understanding, improved support, and more powerful antibiotic therapy, severe sepsis is consistently reported as a leading cause of death in noncardiac ICUs. Mortality remains high and severe sepsis claims far more lives than the common diseases such as acute myocardial infarction, stroke, and trauma [1].
Aggressive fluid challenge and administration of catecholamines still play a vital role in the current treatment regimen of patients with septic shock. However, development of adrenergic hyposensitivity with loss of catecholamine pressor effects, resulting in refractory hypotension, is a well-known clinical dilemma [2].
The mechanism of widespread vasodilatation involves the activation of the soluble intracellular enzyme guanylate cyclase (GC) by nitric oxide (NO), resulting in the production of cyclic guanosine monophosphate (cGMP). Initially discovered as an endothelium-derived relaxing factor in blood vessels, NO is made by the enzyme nitric oxide synthase (NOS). There are two general subtypes of NOS:
(1) Constitutive NOS (cNOS) is constantly active and is further subdivided into neuronal NOS (nNOS) and endothelial NOS (eNOS) and
(2) Inducible NOS (iNOS) is activated under the influence of endotoxin and cytokines.
It has been suggested that the inhibition of NO generation might be a treatment option for sepsis and septic shock. One way of performing this is by competitive antagonism of NOS [3].
Recent studies have revealed that methylene blue (MB) reverses endotoxin-induced hypotension and antagonizes the hyporeactivity to vasoconstrictors by selectively acting on the inducible NO pathway [4].
| Patients and methods | | |
The study was conducted at the Ain-Shams University Hospital on 40 adult patients of both sexes, who fulfilled the criteria of septic shock and received pharmacological support for the treatment of hypotension. Patients were selected according to the American College of Chest Physicians and Society of Critical Care Medicine (ACCP/SCCM) consensus conference criteria [5] as shown in [Table 1]. | Table 1 Defi nition given by American College of Chest Physicians and Society of Critical Care Medicine Consensus Conference [5]
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Patients were eligible for the study, if they fulfilled the above criteria for severe sepsis diagnosed less than 72 h and septic shock diagnosed less than 24 h before randomization, initiating from norepinephrine dose of at least 0.2 μg/kg/min required to maintain mean arterial blood pressure (MAP) between 70 and 90 mmHg. The fluid resuscitation was considered adequate when additional infusion caused no further increase in cardiac index (CI), and pulmonary artery occlusion pressure remained between 8 and 18 mmHg. Dobutamine was infused when required to maintain CI greater than 3.5 l/min/m 2 . Patients who were pregnant, less than 18 years of age, with known sensitivity to MB, G6PD disease, valvular heart disease, present or suspected coronary heart disease, and present or suspected acute mesenteric ischemia or vasoplastic diathesis were excluded from the study.
Patients were randomly allocated into two groups (each included 20 patients): group 1 that received MB bolus at a dose of 1 mg/kg followed after 2 h by infusion at 0.5 mg/kg/h for 4 h and group 2 that received normal saline.
A five-lead ECG is applied to the back of the patient with ST-segment analyzer activated; a peripheral venous cannula of at least 18 G is applied. A 20-G arterial cannula is applied to the right radial artery after local infiltration to the site of entry by 1% lidocaine for continuous arterial pressure monitoring and SpO 2 by pulse oximetry.
All patients are instrumented by a pulmonary artery catheter (PAC) (Baxter Healthcare Corporation, Irvine, California, USA) that is inserted at the right internal jugular vein, where central venous pressure, pulmonary capillary wedge pressure, mean pulmonary arterial pressure, cardiac output, and systemic vascular resistance (SVR) are recorded; in addition, urine output was monitored throughout the ICU stay.
The following was performed to the studied groups:
Vasopressor therapy was adjusted to maintain MAP within the range of 70-90 mmHg. If MAP exceeded 90 mmHg, norepinephrine or epinephrine was tapered off in steps of 0.03 μg/kg/min and dopamine in steps of 1 μg/kg/min, respectively, every 15 min. Norepinephrine was weaned first, followed by epinephrine and dopamine, and this sequence was guided by Kirov's regimen [6]. In addition, as declared, this was guided by the measurement of SVR using the PAC, to decrease the hazards imposed on the intestinal and renal vasoconstriction and the direct toxic effects on the myocardium. If CI exceeded 3.5 l/min/m 2 , dobutamine was tapered off in steps of 1 μg/kg/min every 15 min. Packed red blood cells were given, if hemoglobin level was less than 8 g/dl.
Data collection and measurement
Hemodynamic monitoring was recorded at 0, 2, 6, and 24 h. The MAP was measured through an arterial cannula inserted at the radial artery. A pulmonary artery balloon floatation catheter (131HF7; Baxter Healthcare Corporation) was applied through the internal jugular vein for measuring central venous pressure, pulmonary artery pressure, and pulmonary artery occlusion pressure. Cardiac output was measured in triplicate by injection of 10 ml of 5% dextrose at room temperature into the proximal part of the PAC, and SVR and pulmonary vascular resistance were computed by a hemodynamic monitor. Laboratory data were collected, including alanine aminotransferase, aspartate aminotransferase, serum creatinine for 48 h, intensive care length of stay, vasopressor need, and the number of organ dysfunction at 24 h.
Statistical analyses
A total of 20 patients were required in each group to achieve an α error of 5% and a β error of 10%. Thus, 20 patients in each group were considered.
IBM SPSS statistics (version 20.0, 2011; IBM Corp., USA) was used for data analysis. Data were expressed as mean ± SD for quantitative parametric measures. The following tests were performed:
(1) Comparison between the two independent mean groups for parametric data using the Student t-test and
(2) Comparison between the two dependent groups for parametric data using the paired t-test.
The P of error at 0.05 was considered significant, whereas P of error at 0.01 and 0.001 was considered highly significant.
| Results | | |
Forty patients were included in this study and were randomized into two groups. There were no statistically significant differences between the studied groups regarding demographic data, age, sex, weight, Sepsis-Related Organ Failure Assessment (SOFA) score, number of organ dysfunction, primary illness, underlying infection, and adrenergic support as shown in [Table 2]. | Table 2 Characteristics of patients with septic shock, randomized to receive methylene blue (methylene blue
group; n = 20) or isotonic saline (control group; n = 20) in addition to conventional therapy at inclusion to the study
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Hemodynamics
Regarding the MAP, there was a marked difference in MAP between the methylene group and the control group, being higher in the methylene group than in the control group initiating after 2 h of drug infusion. There was a marked difference in initial MAP (66.8 ± 6.469 vs. 66.2 ± 6.305 mmHg) compared with MAP after 2 h (59 ± 6.8 vs. 91 ± 5.9 mmHg; P < 0.001). In addition, in the MB group there was a significant difference between the initial blood pressure and at 2, 6, and 24 h (66.2 ± 6.305 vs. 70.2 ± 5.482 vs. 91 ± 5.983 vs. 91 ± 2.052 mmHg, respectively) as shown in [Figure 1]. In addition, there were higher values being evident both intragroup and intergroup as shown in [Table 3] and [Table 4], respectively. | Table 3 Highly signifi cant difference in mean arterial blood pressure between the two groups after 2 h that lasted until 24 h
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 | Table 4 Marked difference intergroup (methylene blue) in mean arterial blood pressure being signifi cantly higher after 2 h and at 6 and 24 h, respectively
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In addition, there was marked decline in the cardiac output in the control group with respect to the MB group, where the MB group almost kept near its baseline with the marked difference shown after 2 h as shown in [Figure 2].
SVR was significantly different between the two groups, being significantly higher in the MB group, and there was significant difference between the recorded time intervals in the MB group, being higher after 2 h (P < 0.01), showing the effect of MB as noted in [Figure 3] and [Table 5] and [Table 6], respectively. | Table 5 Highly signifi cant difference between the two groups regarding systemic vascular resistance after 2 h that lasted
until 24 h
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 | Table 6 Marked difference intergroup (methylene blue) being signifi cantly higher regarding systemic vascular resistance after 2 h and at 6 and 24 h, respectively
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Other hemodynamic parameters including central venous pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, and pulmonary vascular resistance showed no marked difference between the control and MB groups.
In contrast, laboratory data concerning arterial blood gases [Table 7], mixed venous oxygen saturation (SVO 2 ) [Table 8], oxygen extraction ratio [Table 9], serum creatinine, and liver transaminases showed no statistical differences between the two groups during the studied intervals. | Table 7 Comparing the arterial blood gases between the methylene blue group and the control group
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 | Table 8 Comparing the mixed venous oxygen saturation between the methylene blue group and the control group
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 | Table 9 Comparing the oxygen extraction ratio between the methylene blue group and the control group
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Regarding the oxygen delivery index (DO 2 I), there was statistical difference between the MB group and the control group, being higher in the MB group. In addition, marked difference intragroup was noted, where there was marked decrease in the control group, whereas the MB group almost stayed near the baseline (P < 0.05) as shown in [Table 10].
Regarding the oxygen consumption index, there was no statistically significant difference between the two groups during the studied intervals, except at 24 h where the oxygen consumption index was statistically higher in the MB group as shown in [Table 11]. | Table 10 Signifi cant difference between the two groups regarding oxygen delivery index after 2 h that lasted until 24 h
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 | Table 11 Highly signifi cant difference between the two groups regarding oxygen consumption index after 24 h
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Regarding the vasopressors and inotropic drugs usage, there was significant difference; the consumption was much higher in the control group, whereas MB decreased markedly the need for norepinephrine, epinephrine, dopamine, and dobutamine, respectively, as shown in [Figure 4], [Figure 5], [Figure 6], [Figure 7].
Regarding the intensive care length of stay and the mortality rate, there was significant difference, with lower days of stay at the intensive care and much lower number of mortality in the MB-treated group ([Figure 8] and [Figure 9], respectively). | Figure 1: The marked difference in mean arterial blood pressure (MAP) in favor of the methylene blue (MB) group, being higher than in the control group 2 h after infusion of the drug.
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 | Figure 2: Follow-up chart showing COP comparison between the methylene blue (MB) and control groups.
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 | Figure 3: Follow-up chart showing systemic vascular resistance (SVR) follow-up among both the methylene blue (MB) and control groups.
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 | Figure 4: Follow-up chart showing norepinephrine (NE) requirement follow-up among both the control and methylene blue (MB) groups, comparing norepinephrine requirement between the MB and the control group
and showing the marked difference between the norepinephrine
requirement in the control group being much higher than in the MB
group (P < 0.001).
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 | Figure 5: Follow-up chart showing epinephrine (EPI) follow-up among both the control and methylene blue (MB) groups, comparing epinephrine requirement between the MB and the control group, where there was
signifi cant difference between the MB group and the control group
being higher in the control group (P < 0.001).
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 | Figure 6: Follow-up chart showing dopamine (DOP) requirement follow-up among both the control and methylene blue (MB) groups, comparing dopamine requirement between the MB and the control group, showing signifi cant difference between the MB group and the control group being higher in the control group (P < 0.001).
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 | Figure 7: Follow-up chart showing dobutamine (Dobutrex) requirement follow-up among both the control and methylene blue (MB) groups, comparing dobutamine requirement between the MB and the control group, showing signifi cant difference between the MB group and the control group being higher in the control group (P < 0.001).
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 | Figure 8: Marked difference is shown regarding the intensive care length of stay being much lower in the methylene blue group.
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 | Figure 9: Comparison between control and cases with respect to frequency of living and died cases.
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| Discussion | | |
Sepsis is a common cause of mortality and morbidity in critically ill patients. Its pathogenesis includes a severe systemic inflammatory response that may be caused by a variety of microorganisms. Bacterial endotoxins stimulate different types of cells to release cytokines such as tumor necrosis factor a, interleukin-13 as well as other inflammatory mediators that activate the iNOS [7].
iNOS escalates the production of NO that leads to activation of GC of smooth muscles cells. NO increases the generation of cGMP. In hyperdynamic sepsis, excessive formation of NO and cGMP is associated with profound vasodilatation, hyporeactivity to catecholamines, and myocardial depression [7].
These changes may cause tissue hypoxia and result in multiple organ failure and increased mortality. In contrast, the minute amount of NO produced by the cNOS is responsible for regulation of basal vascular tone and other physiological effect [4].
Inhibition of excessively produced NO and cGMP may eventually prevent the detrimental hemodynamic effects associated with septic shock. MB has been found to counteract NO-induced effects by inhibiting soluble GC; in addition, recent studies have revealed that MB reverses endotoxin-induced hypotension and antagonizes the hyporeactivity to vasoconstriction [4].
The aim of this study was to determine the effect of early administration of MB (defined by the need for norepinephrine >0.2 μg/kg/min) and the effect regarding the hemodynamic effect and parameters, oxygen delivery, uptake and extraction, effect on renal and liver functions, ICU length of stay, and others.
The present study revealed the effect of MB infusion in septic patients regarding many aspects initiating with the dose of MB where a 1 mg/kg bolus was used, which is lower than that used in other investigations[8-12].
The same and even higher dose is used to treat methemoglobinemia, because the effect of the drug lasts between 2 and 3 h [13]; we initiated infusion after 2 h to minimize the risk for toxic effects and we did not continue administration of MB beyond 4 h. The initiation with a lower dose may be attributed to the fact of the definition of 'early', defined as initiating the drug, MB infusion, at a norepinephrine dose of at least 0.2 μg/kg/min guided by hemodynamics as described in the 'Patients and methods' section.
In our study, there was significant difference in MAP, being higher in the MB group versus the control group, and even the difference was present in the same MB group, being higher after 6 h than the starting level MB group (P < 0.001), which is in agreement with the studies conducted by Brown et al. [14], Anderson et al. [13], Kirov et al. [6], Grayling et al. [15], and Zygun [16].
There was also marked difference regarding the cardiac output, with marked decrease in the control group, whereas it remained near the baseline in the MB group. The difference between the initiating time and after 24 h cardiac output in the control group showed marked decrease in the control group cardiac output, whereas between the two groups, the initiating values had no difference but after only 2 h the difference started to appear with the MB group values versus the control group. These results also are concomitant with a study conducted by Kirov and colleagues; however, the early usage of MB effect initiated 2 h after infusion and not after 6 h as in Kirov and colleagues' study, which may be attributed to the early administration of the drug [6].
The SVR showed no difference at the beginning but marked difference appeared after only 2 h, being higher in the MB group versus the control group, whereas after 24 h the values were still higher. These results also coincide with the results of Anderson et al. [13] and Kirov et al. [6]; even in the control group, there was marked difference, being significantly lower at the studied intervals, whereas also in the MB group, there was a significant increase initiating 2 h after infusion, and these early effects may be attributed to the early administration of MB.
The higher values of SVR, being higher in the MB group versus the control group, and also values intergroup, where the SVR in the MB group was higher initiating 2 h after the first dose, showed the role played by MB as an inhibitor of the inducible NO pathway.
As compared with healthy volunteers, the patients in the MB group had a four-fold increase in circulating NO. A similar increase has been reported in a recent investigation on human septic shock, demonstrating a negative correlation between plasma NO and SVR index [17].
In addition, the significant decrease in the cardiac output in the control group versus the almost stable cardiac output in the MB group may be due to the increased sensitivity of the cardiovascular system to catecholamines, resulting from inhibition of excessively produced NO/cGMP [12, 13, 16, 17]. Thus, the combination of improved cardiac output, SVR, and MAP coupled with the significant decrease for the need for inotropes and vasopressors show the impact of NO pathway inhibition in improving the sensitivity to catecholamines.
The above values were translated as a marked decrease in the vasopressors and inotropes needed in the MB group, in addition to a decrease in the length of intensive care stay.
The norepinephrine consumption was significantly increased in the control group at 2 and 6 h, which is in agreement with the studies conducted by Brown et al. [14], Kirov et al. [6], and Zygun [16].
Regarding epinephrine, there was marked difference initiating 2 h after the administration of the MB, being significantly higher in the control group, and continued until 24 h later; this is in agreement with the studies conducted by Brown et al. [13], Kirov et al. [14], and Zygun [16].
Dopamine requirement was still significantly less in the MB group at the beginning of supporting the circulation, ending with still significant difference between the two groups after 24 h being higher in the control group. In addition, there was marked difference in the control group where values comparing the initiation of therapy with 2, 6, and 24 h later were significantly increasing. These results are concomitant with studies conducted by Brown et al. [14] and Kirov et al. [6] and explain the utility of early administration of MB, its action, and effect on the inflammatory process.
Dobutamine was infused when required to maintain CI greater than 3.5 l/min/m 2 . The need for dobutamine was much higher in the control group denoting the myocardial depressant effects of inflammatory process with the associated cytokines; hence, dobutamine was needed when the CI was decreased, declaring the role of sepsis and the inflammatory process on the heart. It has been clear that the need for dobutamine is significantly higher in the control group and after 24 h. In addition, the requirement for dobutamine has been significantly increased in the control group; these data are still in agreement with the study by Kirov et al. [6]
Regarding the DO 2 I, there was difference between the MB group and the control group being significantly higher in the methylene group; this may be attributed to the improved cardiac output and decreased hazardous effect by the inducible NO. In addition, marked difference was noted among intragroup of the control side, as there was marked decrease in the DO 2 I, whereas the MB group almost stayed near the baseline.
In the MB group, stable CO in the presence of unchanged oxygenation kept DO 2 I above 700 ml/min/m 2 . Such a level of DO 2 I is assumed to be beneficial for survival in sepsis [18]. This effect of MB may explain the trend to resolution of shock for a larger proportion of patients, and unlike other trials it showed improved survival rate and shorter length of ICU stay, which may be attributed to the 'early' MB administration.
There was marked difference regarding the ICU length of stay, as it was significantly lower in the methylene group. In addition, the survived patient's percentage was significantly higher in the methylene group in comparison with the control group.
There were no significant statistical differences regarding the central venous pressure, pulmonary artery pressure, pulmonary artery occlusion pressure, and there was no statistical difference regarding arterial blood gases and oxygen extraction ratio. Increased oxygen consumption index that increased after 24 h in the MB group may represent improved mitochondrial function and respiratory enzymatic process or decreased arterial venous shunting giving more time to tissue to improve their uptake coupled with improved cardiac output.
There were also no significant statistical differences regarding the liver function tests (alanine aminotransferase or aspartate aminotransferase), and there was no effect on renal function represented by serum creatinine. This is in agreement with previous clinical studies conducted by Schneider et al. [10] and Preiser et al. [8]
| Conclusion | | |
Continuously infused MB as an adjuvant treatment to patients with septic shock counteracts myocardial depression, maintains oxygen transport, and reduces adrenergic support compared with conventional treatment alone. The decision whether this drug should be routinely used in all patients or when to use it and whether it should be the drug of first choice for the septic-induced hypotension needs further investigation.
| Acknowledgements | | |
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11]
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