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Ann Thorac Surg 2004;77:496-499
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery

^a Division of Cardiovascular Surgery, Navy Hospital, French Hospital, Swiss-Argentine Clinic, Argentine Institute of Diagnosis and Saint Elizabeth Clinic, Buenos Aires, Argentina

Accepted for publication August 1, 2003.

^* Address reprint requests to Dr Levin, Postoperatory Cardiovascular Critical Care Navy Hospital, Migueletes 1203 2do 16, Buenos Aires 1426 Argentina
e-mail: rllevin{at}intramed.net.ar

	Abstract

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BACKGROUND: The discovery of nitric oxide as mediator in cardiac postoperative vasoplegia encourages the use of inhibitory drugs such as methylene blue. This drug has been used with favorable results in isolated cases. The purpose of this article is to analyze the incidence of the postoperative vasoplegic syndrome, to consider its prognosis, and to evaluate the effect of intravenous methylene blue on mortality.

METHODS: Cardiac surgery patients were consecutively included. Vasoplegic syndrome was defined by the presence of the following five criteria: (1) hypotension, (2) low filling pressures, (3) high or normal cardiac index, (4) low peripheral resistance, and (5) vasopressor requirements. Those with vasoplegia were randomized to receive 1.5 mg/Kg of methylene blue or a placebo. A p value less than 0.05 was considered significant.

RESULTS: Six hundred thirty eight cardiac surgery patients were consecutively included in this study. Fifty-six of these patients fulfilled vasoplegia criteria (8.8%) resulting in higher mortality (10.7% or 6 of 56 patients vs 3.6% or 21 of 582 patients; p value = 0.02). Those treated with methylene blue showed morbidity and mortality reductions (0% versus 21.4% or 6 of 28 patients; p value = 0.01). The duration of the vasoplegic syndrome was shorter in those patients treated with the drug, lasting less than 6 hours in all patients. Patients in the control group showed a slower recovery, lasting more than 48 hours in 8 patients (p value = 0.0007).

CONCLUSIONS: Vasoplegic postoperative syndrome was seen in 8.8% of all patients. Outcome in patients with vasoplegia was worse with increased morbidity and mortality. The use of methylene blue reduced the high mortality in this population.

	Introduction

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The discovery of nitric oxide as mediator in systemic inflammatory response after cardiopulmonary bypass, as in other situations, encourages the use of inhibitory drugs such as methylene blue (MB) as a therapeutic option [1–9]. This drug has been used for treating vasoplegia in isolated cases with our group as the first to report a reduction in postoperative mortality [10–13]. This article seeks to achieve a multicenter analysis of the incidence of vasoplegia in the postoperative setting, to consider its prognosis, and to assess the impact of methylene blue treatment on morbidity and mortality.

	Material and methods

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Populations
Elective cardiac operations performed at the participating centers between 01/01/01 and 06/01/02 were included consecutively. Vasoplegic syndrome (VS) was defined using the following criteria: hypotension, mean arterial pressure less than 50 mm Hg, low filling pressures, central venous pressure lower than 5 mm Hg and wedge capillary pressure less than 10 mm Hg, normalor elevated cardiac index more than 2.5 L/min/m², low peripheral resistance, less than 800 dyn/s/cm^-5, and vasopressor drug requirements. Temperature was not a criterion for vasoplegia. Off-pump coronary artery bypass surgery, patients with bacterial endocarditis, aortic dissection, and urgent or emergent procedures were excluded from the study. Arrow Swan-Ganz catheters were used in all patients, considering a period of 3 hours from arrival at the recovery room to the first measurement to avoid the postoperative re-heat phenomenon. Blood culture samples were taken in vasoplegic patients at 12 and 24 hours after randomization and every 24 hours thereafter. The surgical technique was similar in all patients with normothermic surgery and blood cardioplegia, with roller pump cardiac pulmonary bypass, membrane device, and balanced anesthesia (Midazolan hydrochloride, fentanyl citrate, pancuronium bromide, and the inhalatory agent Sevofluorane). The study protocol was approved by the Institutional Review Boards, and informed consent was obtained from the patients when possible or from the patient's next of kin. The method used for randomization was the hospital admission number. Thirty-one patients from the Navy Hospital, 14 from Santa Isabel Clinic, 9 from French Hospital, and 2 from the Diagnostic Institute in Buenos Aires were included. Those presenting VS were randomized either to a placebo or to the nitric oxide inhibitory drug MB. The latter was used in a 1.5 mg/kg dose infused over a 1-hour span of time. Clinical evolution was assessed, especially perioperative mortality.

Statistics
The differences between populations with and without VS (control group) were analyzed as were those treated with MB and the placebo using the ² test and Fischer's exact test for those categorical variables and the Student's t test for continuous variables. The relationship among variables is shown as odds ratio (OR) of 95%. A p value lower than 0.05 was considered significant.

	Results

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During the study period, 638 cardiac operations were included, fulfilling 56 patients the vasoplegic postoperative criteria proposed (8.8%). Table 1 shows the general and surgical characteristics of the population. The overall mortality was of 27 patients (4.2%), 6 of these patients were in the VS population (10.7%) versus 21 patients in the nonvasoplegic group (3.6%; p value = 0.02; odds ratio = 0.31; CI = 0.11 to 0.91). Vasoplegic patients were randomized to MB (1.5 mg/Kg intravenously in 1 hour) for 28 patients and 28 patients were given the placebo (Table 2 shows the hemodynamic data before randomization). There were no deaths in those treated with MB; the 6 deceased patients were in the placebo group (21.4%). Another interesting finding was the diverse length of course of the vasoplegia. Although those treated with MB resolved in 2 hours in all patients, those patients treated only with vasopressors (8 of 28) showed an evolution lasting more than 48 hours (28.6%) (Figs 1, 2) being the 6 deceased patients among the latter group (0% or 0 of 28 patients vs 21.4% or 6 of 28 patients; p value = 0.01). Blood culture samples were negative in both groups during the first 96 hours. Nevertheless, after this lapse of time, 7 patients in the placebo group positivized their cultures. Six of these patients died from sepsis and multi-organ failure. Table 3 shows reductions in postoperative morbidity in those treated with MB.

View larger version (19K): [in this window] [in a new window]   Fig 1. Evolution of vasoplegic patients. (MB = methylene blue; VS = vasoplegic syndrome.)

View larger version (47K): [in this window] [in a new window]   Fig 2. Number of vasoplegic patients with vasopressor requirements. (MB = methylene blue.)

	Comment

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The clinical outcome has been linked to a worse overall prognosis. Our previous series showed higher mortality (24% or 7of 29 patients and 16% or 7 of 22 patients) in coincidence with other authors. Gomes and colleauges [17] reported 4 deaths in 16 patients (25% mortality) in their second series; whereas the study by Argenziano and colleauges [15] shows a 27% mortality. In all cases, mortality of those with vasoplegia supersedes those who did not have the syndrome develop [13–17].

Conventional treatment has been based in hemodynamic support using vasopressor drugs such as Phenilephrine (used in our first series), norepinephrine, or dopamine [6, 14, 16–19].

Recent physiopathologic findings based on the knowledge of activation and release of inflammatory response mediators, and the capital role of nitric oxide (activating the guanylate-cyclase enzyme, with cGMP production and relaxation of the smooth vascular muscle) have led to early intervention, avoiding or limiting the inflammatory response by the action of inhibitory drugs over nitric oxide, proposing vasopressin and methylene blue as alternative choices (Fig 3) [3–4, 7–10].

View larger version (46K): [in this window] [in a new window]   Fig 3. Therapeutic options in postoperative vasoplegia. (NO = nitric oxide.)

We and other authors have used MB in selected cases. Yiu and colleagues [11] reported a patient with postoperative VS who did not respond to norepinephrine, achieving fast reversion through the use of MB (2 mg/Kg). Evora and colleagues [3] resolved 6 patients with VS in postoperative cardiac surgery using MB (1.5 mg/Kg doses). Pagni and Austin [21] reported 1 patient after aortic valve replacement treated with MB (2 mg/Kg) [13–14, 11–12]. Another patient described by Kofidis and colleagues [22] in a postcardiac transplant with complete reversion of the syndrome after the use of MB (2 mg/Kg). Our randomization shows the similarity between both populations in regard to general and surgical characteristics, showing mortality reduction with the use of intravenous MB. The drug defined fast resolution of vasoplegia with no adverse effects, with the exception of green or blue coloring of the urine. The short length of vasoplegia in those treated with MB is based on the inhibition or limitation of the inflammatory response by nitric oxide blockade, which has been considered of prognostic value in the postoperative inflammatory and vasoplegia response. Gomes and colleagues [17] refers to the duration of VS more than 36 to 48 hours as a marker of worse outcome, with increased development of multi-organic failure and death, similar to Gando and colleagues [23], who established specific cut-off points, finding more multi-organic failure and deaths if the length exceeded 48 hours.

Our findings of worse evolution, more sepsis, and higher mortality in patients who had VS that persisted should reinforce those concepts, nitric oxide blockade being responsible for the lower mortality. Following this study line will enable us to establish the real value of this therapeutic choice [17, 23].

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Carlos D. Del Mazo Fernando J. Boullon Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Levin, R. L. Articles by Boullon, F. J. Search for Related Content PubMed PubMed Citation Articles by Levin, R. L. Articles by Boullon, F. J. Related Collections Cardiac - other