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Ann Thorac Surg 2005;79:1615-1619
© 2005 The Society of Thoracic Surgeons

Original articles: Cardiovascular

Preoperative Methylene Blue Administration in Patients at High Risk for Vasoplegic Syndrome During Cardiac Surgery

Ertugrul Özal, MDa, Erkan Kuralay, MDa,*, Vedat Yildirim, MDb, Selim Kilic, MDc, Cengiz Bolcal, MDa, Nezihi Kücükarslan, MDa, Celalettin Günay, MDa, Ufuk Demirkilic, MDa, Harun Tatar, MDa

a Department of Cardiovascular Surgery, Gülhane Military Medical Academy, Ankara, Turkey
b Department of Anesthesiology, Gülhane Military Medical Academy, Ankara, Turkey
c Department of Public Health and Epidemiology, Gülhane Military Medical Academy, Gülhane Military Medical Academy, Ankara, Turkey

Accepted for publication October 20, 2004.

* Address reprint requests to Dr Kuralay, Yazanlar Sokak No. 31/11, Asagi Ayranci, Ankara, 06540 Turkey (E-mail: ekural{at}gata.edu.tr).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
BACKGROUND: Angiotensin-converting enzyme inhibitors, calcium channel blockers, and preoperative intravenous heparin use are independent risk factors for vasoplegic syndrome after cardiac surgery. We prospectively studied whether preoperative methylene blue administration would prevent the vasoplegic syndrome in these high-risk patients.

METHODS: One hundred patients scheduled for coronary artery bypass graft surgery who were at high risk for vasoplegia because they were preoperatively using angiotensin-converting enzyme inhibitors, calcium channel blockers, and heparin were randomly assigned to either receive preoperative methylene blue (group 1, n = 50) or not receive it (group 2, controls, n = 50). Methylene blue (1% solution) was administered intravenously at a dose of 2 mg/kg for more than 30 minutes, beginning in the intensive care unit 1 hour before surgery.

RESULTS: Although similar in terms of all demographic and operative variables, the two groups differed significantly in terms of vasoplegic syndrome incidence (0% in group 1[0 of 50] vs 26% in group 2 [13 of 50]; p < 0.001). In 6 patients, the vasoplegic syndrome was refractory to norepinephrine. Four of these patients survived; the other 2 had vasoplegic syndromes that were refractory to aggressive vasopressor therapy, and they ultimately died of multiorgan failure. Stroke occurred in 1 patient. The two study groups also differed significantly in terms of average intensive care unit stay (1.2 ± 0.5 days in group 1 vs 2.1 ± 1.2 days in group 2; p < 0.001) and average hospital stay (6.1 ± 1.7 days in group 1 vs 8.4 ± 2.0 days in group 2; p < 0.001).

CONCLUSIONS: Our results suggest that preoperative methylene blue administration reduces the incidence and severity of vasoplegic syndrome in high-risk patients, thus ensuring adequate systemic vascular resistance in both operative and postoperative periods and shortening both intensive care unit and hospital stays.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
The vasoplegic syndrome (VS) that occurs early after cardiac surgery with cardiopulmonary bypass (CPB) is characterized by severe hypotension, decreased systemic vascular resistance (SVR), decreased arteriolar reactivity, and increased requirements for filling volume and vasopressive therapy, despite adequate cardiac output. The incidence of VS among all patients undergoing cardiac surgery with CPB may be as high as 10% [1]. Recent physiopathologic findings suggest that postoperative vasoplegia may be limited or prevented early by inhibiting nitric oxide. These findings were based on the knowledge of inflammatory response mediator pathways and on the knowledge of the important role played by nitric oxide in guanylate cyclase enzyme activation, cyclic guanosine monophosphate production, and smooth vascular muscle relaxation. One agent proposed for this nitric oxide inhibition is methylene blue (MB) [1–6]. Several groups have shown that single-dose postoperative administration of MB in response to VS findings can restore SVR [1–6]. Others have shown that intraoperative septic endocarditis can be successfully treated by adding MB to the pump prime during CPB or continually infusing MB postoperatively [7].

Several recent studies have established preoperative intravenous heparin, angiotensin-converting enzyme inhibitors, and calcium channel blockers as independent risk factors for postoperative VS [2–4]. According to Mekontso-Dessap and coworkers [2], the incidence of VS associated with the preoperative use of these three agents is 55.6%, 44.4%, and 47.2%, respectively.

Moreover, VS has been linked with poor clinical outcomes and worse overall prognosis. Mortality after cardiac surgery was 24% in a series reported by Levin and colleagues [3] and 25% in a small series reported by Gomes and colleagues [8] in which postoperative VS persisted for longer than 36 to 48 hours.

In light of these data, we set out to prospectively determine the incidence of VS in patients at high risk for VS. To do this, we performed a prospective randomized comparative study in which one group received a single dose of MB in the preoperative period just before anesthesia and another group did not.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Patient Population
The study population consisted of 100 otherwise healthy patients who were preoperatively using heparin, angiotensin-converting enzyme inhibitors, and calcium channel blockers and underwent elective coronary artery bypass graft surgery with CPB at the Gülhane Military Medical Academy from April 2003 to May 2004. The study protocol was approved by an institutional ethics committee, and informed consent was obtained from all patients.

Patient Randomization
Patients were randomly assigned to two groups by using a table of random digits [9]. Half of the patients received MB just before surgery (group 1, n = 50), and the other half did not (group 2, control, n = 50). Methylene blue (1% solution) was administered intravenously at a dose of 2 mg/kg for more than 30 minutes, beginning in the intensive care unit 1 hour before surgery. The preoperative (baseline) demographic characteristics of the patient population are summarized in Table 1.


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  		Table 1. Baseline Demographic Characteristics of Patient Population
 
Clinical Definitions and Exclusion Criteria
Vasoplegic syndrome was defined as severe and persistent hypotension (mean arterial pressure <50 mm Hg) occurring in the intraoperative period or in the early postoperative period within 6 hours after weaning from CPB. Signs of the syndrome were decreased SVR (<800 dynes · sec–1 · cm–5), low filling pressures, right atrial pressure < 5 mm Hg, left atrial pressure < 10 mm Hg, and normal or increased cardiac output (cardiac index > 2.5 L · min–1 · m–2).

The preoperative left ventricular ejection fraction was determined by transthoracic echocardiography or ventriculography using planimetric analysis. A left ventricular ejection fraction > 0.50 was considered normal; a left ventricular ejection fraction between 0.35 and 0.50 was considered moderately reduced.

Patients in cardiogenic shock, patients with a left ventricular ejection fraction < 0.35, and patients with postoperative low cardiac output syndrome were excluded from the study.

Hemodynamic Measurements, Anesthesia, and Cardiopulmonary Bypass
The left radial artery was routinely cannulated, and the right internal jugular vein was used as a central route. A thermodilution catheter was advanced through the right jugular vein route. Cardiac output, mean arterial pressure, and central venous pressure were measured every 5 minutes during surgery and every 30 minutes after surgery.

Systemic vascular resistance was calculated during the surgical (ie, total CPB) period as follows:


{402140X.1615.si1}

(1)
Systemic vascular resistance was calculated during the off-pump (ie, postoperative) period as follows:


{402140X.1615.si2}

(2)
Pulmonary capillary wedge pressure and mean pulmonary artery were also recorded in all patients and used to calculate pulmonary vascular resistance just before and after CPB as follows:


{402140X.1615.si3}

(3)
Cardiac index was used instead of cardiac output in calculating both SVR and pulmonary vascular resistance. Cardiac index was calculated by dividing cardiac output by body surface area.

The anesthesia protocol (intravenous administration of midazolam hydrochloride, propofol, pancuronium bromide, and fentanyl) was identical in all patients. Cardiopulmonary bypass was conducted under moderate systemic hypothermia (28°C to 32°C) by means of nonpulsatile, filtered arterial flow and gravity-driven venous drainage. A hollow-fiber membrane oxygenator was used. Myocardial protection was achieved by using both antegrade and retrograde cardioplegia. St. Thomas II crystalloid solution was used for induction, and cold blood cardioplegia was infused every 20 minutes. Norepinephrine was added to the pump reservoir if the mean arterial pressure fell below 45 mm Hg during the total CPB period. Norepinephrine was also administered to obtain adequate mean arterial pressure and SVR. Norepinephrine-refractory systemic vasoplegia was defined as a mean arterial pressure < 50 mm Hg, cardiac index > 2.5 L • min–1 · m–2, and low SVR (< 800 dynes · sec–1 · cm–5) during intravenous norepinephrine infusion (≥ 0.5 µg · kg–1 · min–1). All coronary artery bypass graft surgeries were performed using the same surgical technique. All of the patients were moderately cooled (28°C), and all distal anastomoses were created in a single cross-clamp period.

Statistical Analysis
All statistical analyses were performed using the SPSS 10.0 Statistical program for Windows (SPSS Inc, Chicago, IL). Continuous variables were expressed as the mean ± standard deviation. Differences between groups were tested for significance using the Student's t test or the Mann-Whitney U test. Categorical variables were expressed as percentages and analyzed using the {chi}2 test or Fisher's exact test. Differences were considered significant when p < 0.05 was determined by the two-tailed test.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Systemic vascular resistance during the surgical (ie, total CPB) period was significantly higher in group 1 than in group 2 (p < 0.001) (Fig 1), and norepinephrine was required by significantly fewer patients in group 1 (n = 2) than in group 2 (n = 41; p < 0.001). All patients in both groups were successfully weaned from CPB. Inotropic support was required by significantly fewer patients in group 1 (n = 7) than in group 2 (n = 24; p < 0.001). Both study groups had similar CPB and aortic cross-clamp times (p = 0.123 and p = 0.484, respectively) and received similar doses of cardioplegia. However, group 1 required significantly less crystalloid (1,577 ± 329 vs 1,749 ± 414; p = 0.024), colloid (373 ± 59 vs 404 ± 76; p = 0.027), and red blood cell (RBC) transfusion (2.2 ± 0.7 U vs 3.3 ± 1.5 U; p < 0.001) than did group 2.



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  		Fig 1. Systemic vascular resistance changes during cardiopulmonary bypass in both groups. Overall p = 0.001; {blacktriangleup} = group 1; {blacksquare} = group 2.

 
Clinical and hemodynamic signs of VS were seen significantly more often in group 2 (0 of 50 in group 1 vs 13 of 50 in group 2). In 6 patients, VS was refractory to norepinephrine (p < 0.001). In 4 of these patients, VS resolved in the first 8 hours of the postoperative period; in the other 2 patients, VS did not resolve, which led to multiorgan failure and death. Although MB was administered to these 2 patients, it had no beneficial effect because it was administered only after multiorgan failure had already developed. Stroke occurred in 1 patient.

The mean intensive care unit stay was significantly longer in group 1 than in group 2 (1.2 ± 0.5 days vs 2.1 ± 1.2 in group 2; p < 0.001). The same was true of the mean hospital stay (6.1 ± 1.7 days in group 1 vs 8.4 ± 2 days in group 2; p < 0.001). Liver serum glutamate pyruvate transaminase enzyme levels were slightly higher in group 1 in the first 2 postoperative days. The mean pulmonary vascular resistance index was similar in the two groups (472 ± 28 vs 465 ± 23; p = 0.157).

Intraoperative and postoperative variables and statistical comparisons are summarized in Table 2.


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  		Table 2. Intraoperative and Postoperative Variables
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
The preoperative use of angiotensin-converting enzyme inhibitors, heparin, and calcium channel blockers has been associated with hypotension both during and after CPB [1–3, 10]. Many studies have shown angiotensin-converting enzyme inhibitors to be a mechanism underlying VS. In fact, the renin-angiotensin system plays an important role in vascular tone changes that occur postoperatively [11–13]. Angiotensin-converting enzyme inhibitors decrease angiotensin II levels and increase the plasma levels of the vasodilator bradykinin. The increase in plasma bradykinin is due to the fact that CPB completely excludes the lungs, the major site of bradykinin catabolism [14].

Mekontso-Dessap and coworkers [2] showed intravenous heparin use to be an independent risk factor for VS. Although they did not describe the exact mechanism of action involved, their results did suggest that heparin use may be a statistically confounding risk factor associated with emergent surgical treatment of conditions such as unstable angina or myocardial infarction. They further postulated that such conditions are often responsible for a marked stress response leading to increased amounts of plasma catecholamines levels that can be depleted by CPB, which can in turn lead to diminished vascular tone and reactivity [2]. In patients with coagulation disorders, VS can cause oozing and diffuse bleeding that requires treatment with blood cell transfusions [8]. In our study, the need for crystalloid (p = 0.024), colloid (p = 0.027), and packed red blood cells (p < 0.001) was greater in group 2.

Vasoplegic syndrome is associated with poor clinical outcome and worse overall prognosis. It increases both intensive care unit and hospital stay and causes mortality (mostly due to multiorgan failure) that ranges from 24% to 27% according to several reports [3, 8, 15]. The conventional treatment for VS is hemodynamic support with vasopressor drugs such as phenylephrine, norepinephrine, or dopamine. However, as already mentioned previously, recent physiopathologic findings have led to early interventions that limit or avoid the inflammatory response by inhibiting nitric oxide with agents such as vasopressin and MB [1–8]. Apart from this physiopathologic-based argument, there is virtue in avoiding vasopressors in the early postoperative period because this would prevent potential adverse effects such as arrhythmias or ischemia, an especially important consideration in coronary artery disease patients. Moreover, as Argenziano [15] has documented, vasoplegic patients may already be refractory to vasopressor drugs. Meanwhile there have been several reports of MB-induced reversal of postoperative VS [5, 16, 17], including a patient who did not respond to norepinephrine [16] and a patient who had undergone aortic valve surgery [17].

One common thread in these studies has been the application of MB as the first-line therapy for postoperative VS. Only Grayling and Deakin [7] have intraoperatively administered MB, when they added it to the pump prime as treatment for septic endocarditis that arose during a valve operation. They also continuously infused MB in both the intraoperative and postoperative periods [7]. Yet, to date, there has been no study of preoperative MB administration reported in the literature. In our study, the primary goal was to prevent the development of VS during the intraoperative and postoperative periods in high-risk patients by administering MB preoperatively. This approach prevented VS completely in patients treated with MB (group 1) and limited its incidence to 26% (13 of 50) in group 2 (p < 0.001), even though in all patients the VS was refractory to norepinephrine. Thus, despite the small size of our patient population, we have succeeded in showing that this approach does work and does significantly limit the development of VS.

We also found that preoperative MB administration stabilized SVR during total CPB. In our study, this was evidenced by a significantly reduced norepinephrine requirement in patients who received MB (group 1). In fact, despite the administration of norepinephrine boluses in group 2, the mean SVR was still higher in group 1 (1180 ± 56 dynes · sec–1 · cm–5 vs 785 ± 45 dynes · sec–1 · cm–5 (p = 0.001) (Fig 1). Moreover, patients in group 1 required shorter intensive care unit and hospital stays (p < 0.001).

It should be noted that MB may have adverse side effects when used to treat norepinephrine-refractory vasoplegia. These effects include cardiac arrhythmias; coronary vasoconstriction; decreased cardiac output, renal blood flow, and mesenteric blood flow; increased pulmonary vascular pressure and pulmonary vascular resistance; and gas exchange deterioration. However, most of these adverse side effects are dose dependent and do not occur when the dose of MB does not exceed 2 mg/kg. In the present study, we used a 1% solution of MB at a dose of 2 mg/kg and encountered no adverse effects. Both study groups had statistically similar pulmonary vascular resistance indexes; and although liver serum glutamate pyruvate transaminase enzyme levels were slightly higher in group 1, they gradually returned to normal levels by the second postoperative day. Methylene blue is also well known to turn the urine greenish-blue, a sign that we observed with all patients in group 1. However, this colorization was self-limiting and disappeared spontaneously after 3 days. Mild skin discoloration was also observed in most patients, but it was self-limiting. We noted no permanent skin damage caused by MB at the dose we used.

In conclusion, our results suggest that preoperative MB administration reduces the incidence of VS in high-risk patients undergoing cardiac surgery, thus ensuring adequate SVR during and after surgery and shortening intensive care unit and hospital stays.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Cremer J, Martin M, Redl H, et al. Systemic inflammatory response syndrome after cardiac operations Ann Thoracic Surg 1996;61:1714-1720.[Abstract/Free Full Text]
  2. Mekontso-Dessap A, Houel R, Soustelle C, Kirsch M, Thebert D, Loisance DY. Risk factors for post-cardiopulmonary bypass vasoplegia in patients with preserved left ventricular function Ann Thorac Surg 2001;71:1428-1432.[Abstract/Free Full Text]
  3. Levin RL, Degrange MA, Bruno GF, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery Ann Thorac Surg 2004;77:496-499.[Abstract/Free Full Text]
  4. Leyh RG, Kofidis T, Strüber M, et al. Methylene blue: the drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass J Thorac Cardiovasc Surg 2003;125:1426-1431.[Abstract/Free Full Text]
  5. Evora PRB, Riberio PJF, Andrade JCS. Methylene blue administration in SIRS after cardiac operations Ann Thorac Surg 1997;63:12-13.[Abstract/Free Full Text]
  6. Andrade JCS, Batista Filho ML, Evora PRB, et al. Methylene blue administration in the treatment of the vasoplegic syndrome after cardiac surgery Rev Bras Circ Cardiovasc 1996;11:107-114.
  7. Grayling M, Deakin CD. Methylene blue during cardiopulmonary bypass to treat refractory hypotension in septic endocarditis J Thorac Cardiovasc Surg 2003;125:426-427.[Free Full Text]
  8. Gomes WJ, Carvalho AC, Palma JH, et al. Vasoplegic syndrome after heart surgery J Cardiovasc Surg (Torino) 1998;39:619-623.[Medline]
  9. Tull D, Albawn GS. Appendix 1Survey research: a decisional approach. New York: Intext Press; 1973225.
  10. Thaker U, Geary V, Chalmers P, Sheikh F. Low systemic vascular resistance during cardiac surgery: case reports, brief review, and management with angiotensin II J Cardiothorac Anesth 1990;4:360-363.[Medline]
  11. De Leeuw PW, van der Starre PJ, Harinck-de Weerdt JE, de Bos R, Tchang PT, Birkenhager WH. Humoral changes during and following coronary bypass surgery: relationship to postoperative blood pressure J Hypertens Suppl 1983;1:52-54.[Medline]
  12. Taylor KM, Bain WH, Russel M, Brannan JJ, Morton IJ. Peripheral vascular resistance and angiotensin II levels during pulsatile and non-pulsatile cardiopulmonary bypass Thorax 1979;34:594-598.[Abstract/Free Full Text]
  13. Hayase S, Shimizu T, Nakajima M. Role of sympathoadrenal and renin-angiotensin system in hemodynamic state after coronary artery bypass grafting Nagoya J Med Sci 1987;49:1-15.[Medline]
  14. Cugno M, Nussberger J, Biglioli P, Giovagnoni MG, Gardinali M, Agostoni A. Cardipulmonary bypass increases plasma bradykinin concentrations Immunopharmacology 1999;43:145-147.[Medline]
  15. Argenziano M, Chen JM, Choudhri AF, et al. Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of novel pressor agent J Thorac Surg 1998;39:1714-1720.
  16. Yiu P, Robin J, Pattison W. Reversal of refractory hypotension with single dose methylene blue after coronary artery bypass surgery J Thorac Cardiovasc Surg 1999;118:195-196.[Free Full Text]
  17. Pagni S, Austin E. Use of intravenous methylene blue for the treatment of refractory hypotension after cardiopulmonary bypass J Thorac Cardiovasc Surg 2000;119:1297-1298.[Free Full Text]




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Ufuk Demirkilic
Harun Tatar
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