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| ORIGINAL ARTICLE |
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| Year : 2016 | Volume
: 9
| Issue : 3 | Page : 319-324 |
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Methylene blue versus vasopressin in sepsis-induced vasoplegia
Mostafa ElAdawy MD, DESA , Ahmed S Omran
Department of Anesthesia and ICU, Ain Shams University, Cairo, Egypt
| Date of Submission | 25-Mar-2015 |
| Date of Acceptance | 16-Sep-2015 |
| Date of Web Publication | 31-Aug-2016 |
Correspondence Address:
Mostafa ElAdawy
84 Orouba Street, Heliopolis, Cairo 11361
Egypt
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/1687-7934.189091
Background
Septic shock is one of the biggest causes of mortality in intensive care settings, and, despite all the recent advances in pharmacological and mechanical support therapies, is the second leading cause of death among ICU patients. Although vasopressors have been widely used in these situations, where keeping the hemodynamic stability is of utmost importance, a detailed study of their effects is undoubtedly needed.
Objective
Our study compared the effect of methylene blue (MB) in the vasoplegic situation associated with sepsis with that of vasopressin.
Patients and methods
We randomized 40 patients into two groups (20 patients each); patients in the first group received MB, whereas patients in the second group received vasopressin as a hemodynamic support.
Results
In the present study, mean arterial blood pressure was found to be significantly higher in the MB group compared with the vasopressin group, whereas within the MB group, it was significantly higher after 6 h compared with the baseline level. The systemic vascular resistance showed no difference between the two groups at the start but a marked difference only after 2 h, being higher for the MB group — that is, there was a significant decrease in the vasopressors and inotropes needed in the MB group. There was no significant difference between the two groups regarding the ICU length of stay, the central venous pressure, pulmonary artery pressure, and oxygen extraction ratio.
Conclusion
The use of MB in sepsis-induced refractory vasoplegic situations remains one of the salvage management strategies; however, the practice of its routine use is yet to be established and needs further investigation. Keywords: methylene blue, sepsis, vasoplegia, vasopressin
How to cite this article:
ElAdawy M, Omran AS. Methylene blue versus vasopressin in sepsis-induced vasoplegia. Ain-Shams J Anaesthesiol 2016;9:319-24 |
| Introduction | |  |
Septic shock is one of the biggest causes of mortality in the intensive care settings, and, despite all the efforts and the recent advances in pharmacological and mechanical support therapies, is the second leading cause of death among ICU patients [1].
The septic response is a component of an overall continuum that ranges from infection to multiple-organ failure and death. The severe sepsis (acute organ dysfunction secondary to infection) and septic shock (severe sepsis plus hypotension not reversed with fluid resuscitation) are major healthcare problems affecting millions of individuals around the world each year, killing one in four (and often more), and its incidence continues to increase [2],[3],[4],[5],[6].
The surviving sepsis campaign advocates the use of a 6-h resuscitation bundle. This is a group of evidence-based elements, which when delivered together is seen to be more effective; it consists of the following:
- Measure serum lactate;
- obtain blood cultures before antibiotic administration;
- Administer broad-spectrum antibiotics;
- Deliver an initial dose of 20 ml/kg crystalloid;
- Apply vasopressors to maintain a mean arterial pressure (MAP) greater than 65 mmHg; and
- Achieve a central venous pressure (CVP) equal to or greater than 8 mmHg and mixed venous oxygen saturation (SvO2) equal to or greater than 65% [7].
Exogenous vasopressin (8-arginine vasopressin) is presented as a sterile aqueous solution of synthetic vasopressin for intravenous, intramuscular, and subcutaneous administration. It is not protein-bound and has a volume of distribution of 140 ml/kg. The plasma half-life of vasopressin is 24 min. It is cleared mainly by renal elimination (65%) and metabolism (35%) [8].
It has been suggested that refractory vasoplegia may reflect a dysregulation of nitric oxide synthesis and vascular smooth cell guanylate cyclase activation. Based on recent pathophysiologic findings, it appears that the soluble intracellular enzyme guanylate cyclase is activated to produce cyclic GMP presumably under the influence of several mediators including nitric oxide. Methylene blue (MB) acts by inhibiting guanylate cyclase, thus decreasing cyclic GMP and vascular smooth muscle relaxation [9].
Many trials compared the use of MB with normal saline in the treatment of refractory sepsis-induced vasoplegia [10]. The initial trials using MB as a treatment option in deep hypotension states were conducted in the early 1990s [11], but this management was not clearly practiced until the early 2000s; it is hypothesized that MB inhibits the synthesis of nitric oxide, which is a powerful vasodilator released in response to mediators such as bradykinin and histamine [12].
Most studies have reported a clinically relevant increase in systemic vascular resistance (SVR) and a decrease in norepinephrine dosage shortly after MB infusion. Several studies have also found a significant decrease in serum lactate concentrations within 24 h after MB infusion, underlining the restoration of normal peripheral blood flow [13].
To our knowledge, there are no studies comparing the beneficial effect of MB in the vasoplegic situations with the vasoconstrictor effect of another commonly used vasopressor, V, previously known as anti diruetic hormone (ADH) or arginine vasopressin.
MB can reduce renal, respiratory, arrhythmic, and septic complications, reduce mortality, and accelerate ICU and hospital discharge [14].
Safety concerns of vasopressin include thrombocytopenia and potentially altered mesenteric and renal perfusion, whereas safety concerns of MB include oximeter interference, pulmonary hypertension, neurotoxicity, arrhythmias, and potentially altered coronary, mesenteric, and renal perfusion [14],[15].
Lavigne [14] reviewed the studies conducted on both MB and vasopressin in post-CPB vasoplegia and he concluded that, although both vasopressin and MB have obvious MAP-increasing and catecholamine-sparing effects, neither shows enough convincing evidence on outcomes to make them first-line choices for vasodilatory shocks. In selected high-risk circumstances, the use of both might be considered as an additional off-label therapy [14].
| Patients and methods | | |
Approval for the study was obtained from the local medical ethics committee, and all patients, or their guardians, provided their informed consent before participating in the study.
This single-blind, randomized controlled study was conducted from 2010 to 2014 in Ain Shams University Hospitals. A total of 40 patients were enrolled in the study on fulfilling the American College of Chest Physicians and Society of Critical Care Medicine (ACCP/SCCM) consensus conference's criteria for sepsis [16], which consists of severe sepsis diagnosed within 72 h, and septic shock diagnosed within 24 h from the time of giving norepinephrine dose of greater than or equal to 0.2 μg/kg/min, which is required to maintain the MAP between 70 and 90 mmHg.
Patients enrolled in the study were allocated to two groups by assigning random numbers from random number tables (20 patients each): the MB group and the vasopressin group.
Methylene blue group
Patients in this group received MB bolus in a dose of 1 mg/kg, followed, 2 h later, by an infusion of 0.5 mg/kg/h for 4 h.
Vasopressin group
Patients in this group received vasopressin infusion in a dose of 0.02 U/kg/h for 6 h.
Exclusion criteria
Following were the exclusion criteria: pregnant females, patients sensitive to MB or vasopressin, patients with known G6PD deficiency, age less than 18 years, vasospastic diathesis (e.g. Raynaud's syndrome), coronary artery disease, or patients receiving mono amine oxidase inhibitors (MAOI).
Epinephrine and norepinephrine were adjusted to maintain the MAP within the range of 60–80 mmHg. If MAP exceeded 80 mmHg, norepinephrine or epinephrine were tapered off in steps of 0.02 μg/kg/min every 15 min. Norepinephrine was weaned first, followed by epinephrine. The fluid resuscitation was considered adequate when additional infusion caused no further increase in the cardiac index, and pulmonary artery occlusion pressure remained between 8 and 18 mmHg.
- Invasive MAP, central venous pressure, pulmonary artery pressure, cardiac output, and systemic vascular resistance were measured and recorded at 0, 2, 6, and 24 h from the start of the infusions.
- Mixed SvO2, lactate, and oxygen extraction ratio (O2ER) were also calculated by using commonly used formulas.
- Intensive care length of stay and vasopressor requirements were also recorded.
1st choice of Antimicrobials was Piperacillin+ Tazobactam and changed afterwards according to culture and sensitivity results and sensitivity from blood, sputum or bronchoalveolar lavage samples, and then adjusted accordingly. Patients who were not able to maintain their airways or had PO2 less than 50 mmHg and/or PCO2 greater than 50 mmHg were ventilated on a BiPap mode on a Drager ventilator (Drager Evita 2; Drager, Lubeck, Germany) with lung protective strategy. All patients were given prophylaxis against stress ulcer and deep venous thrombosis (DVT) and all of them were enterally fed.
Statistical methods
A total of 20 patients were required in each group to achieve an α error of 5% and β error of 10%. IBM SPSS statistics (V. 20.0, 2011; IBM Corp., New York City, New York, USA) was used for data analysis. Data were expressed as mean ± SD for quantitative parametric variables.
The following tests were performed:
Comparison between the two independent mean groups for parametric data was carried out using the Student t-test.
Comparison between the two dependent groups for parametric data was carried out using the paired t-test.
The P of error at 0.05 was considered significant, whereas at 0.01 it was considered highly significant.
Categorical data were tested by using the χ2-test and were presented as number of patients.
| Results | | |
There were no statistically significant differences between the studied groups regarding demographic data, age, sex, Sequential Organ Failure Assessment (SOFA) score, or organ dysfunction [Table 1]. | Table 1 Characteristics of patients randomized to receive methylene blue (methylene blue group; n = 20) or vasopressin (vasopressin group; n = 20)
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Our results showed a MAP of 68 ± 6.8 at 6 h in the MB group compared with 75 ± 5.9 mmHg in the vasopressin group (P < 0.001), and a MAP of 68 ± 6.9 at 24 h in the MB group compared with 74 ± 6.9 in the vasopressin group (P < 0.001).
There were no differences between the two groups regarding the systemic vascular resistance at the start but a marked difference appeared after only 2 h, being higher for the MB group compared with the V group (710 ± 82 vs. 660 ± 58.8 dynes/s/cm5; P < 0.001), and after 24 h the values were still higher for the MB group (840 ± 75.394 in the MB group vs. 704 ± 66.996 dynes/s/cm5 in the vasopressin group; P < 0.00) ([Figure 1], [Figure 2], [Figure 3] and [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]). | Figure 1 Comparing mean arterial pressure (MAP) between the methylene blue group (blue line) and the vasopressin (V) group (red line). Data are presented as means. Significant difference was noted at 6 and 24 h.
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 | Figure 2 Comparing the cardiac output (COP) between the methylene blue group (blue line) and the vasopressin group (red line). Data are presented as mean. No statistically significant difference was found between the two groups at anytime.
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 | Figure 3 Comparing the systemic vascular resistance between the methylene blue (blue line) group and the vasopressin group (red line). Data are presented as mean. Significant difference was found at 2, 6, and 24 h.
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 | Table 2 Comparing the central venous pressure between the methylene blue group and the vasopressin group
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 | Table 3 Comparing the pulmonary artery pressure between the methylene blue group and the vasopressin group
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 | Table 4 Comparing the pulmonary vascular resistance between the methylene blue group and the vasopressin group
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 | Table 5 Comparing the mixed venous oxygen saturation between the methylene blue group and the vasopressin group
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 | Table 6 Comparing the oxygen extraction ratio between the methylene blue group and the vasopressin group
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In our study, while there was no difference between the studied intervals in the vasopressin group, in the MB group there was a marked difference starting 6 h after the infusion as the SVR increased to 830 ± 110.501 compared with 620 ± 83.3 dynes/s/cm5 at the baseline with P value less than 0.001.
The dose of norepinephrine required to maintain an MAP above 65 mmHg became significantly lower in the MB group compared with the vasopressin group only after 6 h from the start of infusion (0.1 ± 0.1 vs. 0.26 ± 0.15 μg/kg/min; P < 0.001).
Regarding the dose of epinephrine required to maintain the MAP values as above, there was a marked difference after 2 h, being higher in the vasopressin group: 0.16 ± 0.05 compared with 0.11 ± 0.04 μg/kg/min in the MB group (P < 0.001). This beneficial effect lasted for 24 h as it remained high in the vasopressin group: 0.26 ± 0.11 compared with 0.12 ± 0.01 μg/kg/min in the MB group (P < 0.001).
O2ER was found significantly different, being lower in the MB group starting from 6 h and lasting until 24 h.
There was no significant difference regarding the ICU length of stay between the two groups.
There was no significant difference regarding the central venous pressure and the pulmonary artery pressure ([Figure 4], [Figure 5], [Figure 6]. | Figure 4 Follow-up chart showing NE requirement; follow-up among both vasopressin (red lines) and methylene blue (blue lines). Data are presented as means. Significant difference was found at 6 and 24 h.
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 | Figure 5 Chart showing epinephrine (EPI) requirement among both vasopressin group (red lines) and methylene blue group (blue lines). Data are presented as means. Significant difference was found at 2, 6, and 24 h.
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 | Figure 6 Comparison between the vasopressin (V) and methylene blue (MB) groups as regards ICU stay. Data are presented as mean number of days in the ICU. There was no significant difference. *Significant with P < 0.05.
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| Discussion | | |
In our study, MAP was significantly higher in the MB group compared with the vasopressin group; moreover, within the MB group, it was significantly higher after 6 h compared with its baseline value. Other studies that compared the effect of MB with normal saline showed similar beneficial effects of MB [13],[17],[18],[19],[20].
There was no significant difference regarding the cardiac output, which decreased in the two groups.
There was no difference between the two groups regarding the systemic vascular resistance at the start but a marked difference appeared after only 2 h, being higher for the MB group compared with the vasopressin group, and after 24 h the values were still higher in the MB group compared with the vasopressin group.
Similarly, in their respective studies, Andresen et al. [18] and Kirov et al. [19] found an increase in the SVR as a beneficial effect of the administration of MB.
While there was no difference between the studied intervals in the vasopressin group, in the MB group there was a marked difference starting 6 h after the infusion as the SVR increased significantly compared with the baseline values.
The above values are interpreted as a significant decrease in the vasopressors and inotropes needed in the MB group as the dose of norepinephrine required to maintain an MAP above 65 mmHg became significantly lower in the MB group compared with the vasopressin group only after 6 h from the start of infusion.
Regarding the dose of epinephrine required to maintain MAP values as above, there was a marked difference starting after 2 h, being higher in the vasopressin group compared with the MB group, and this beneficial effect lasted for 24 h as it remained high in the vasopressin group compared with the MB group. These findings are consistent with those of a study by Abd-Alhameed et al. [21], who found decreased norepinephrine and epinephrine requirements in the MB group compared with the normal saline group.
O2ER was found to be significantly different, being lower in the MB group starting from 6 h and lasting for 24 h.
There was no significant difference regarding the ICU length of stay between the two groups, as well as no significant difference regarding the central venous pressure and the pulmonary artery pressure.
| Conclusion | | |
The use of MB in sepsis-induced refractory vasoplegic situation has shown promising results as one of the salvage management strategies; however, the practice of its routine use is yet to be established and needs further investigation and larger-scale studies, and whether it should be used as an alternative to, or in conjunction with, other vasopressors remains a topic to be further explored.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]
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