Is methylene blue of benefit in treating adult patients who develop catecholamine-resistant vasoplegic syndrome during cardiac surgery
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《血管的通路杂志》
a Cardiovascular and Endothelium Function Laboratory from the Surgical Research Division, Ribeiro Preto Faculty of Medicine – University of So Paulo, Ribeiro Preto, So Paulo, Brazil
b Department of Cardiac Anaesthesia, Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK
Supported in part by FAPESP-Fundao de Amparo a Pesquisa do Estado de So Paulo, Brasil, and FAEPA-Fundao de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clinicas da Faculdade de Medicina de Ribeiro Preto da Universidade de So Paulo.
Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether methylene blue (MB) is of benefit in treating adult patients who develop catecholamine-resistant vasoplegic syndrome (VPS) during cardiac surgery. Altogether 47 papers were found in Medline and 107 in Embase using the reported search. A further five papers were found by hand-searching reference lists. Four papers represented the best evidence on the subject and details of authors, journal, date and country of publication, patient group, relevant outcomes and weaknesses were tabulated. In addition, a further 14 papers are referenced to aid the discussion. We conclude that MB may provide an interesting and novel therapeutic option for adult patients who develop catecholamine-resistant VPS during cardiac surgery. Whilst there is currently insufficient evidence to advocate its use as first-line therapy it should be considered as a possible ‘rescue therapy’ in catecholamine-resistant VPS and some work has suggested that it may have a prophylactic role in preventing VPS. However, further large well-controlled studies are required before its routine use can be recommended.
Key Words: Methylene blue; Vasoplegic syndrome; Cardiopulmonary bypass; cGMP; Guanylate cyclase
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. The three-part question
In [adult patients undergoing cardiac surgery] is [Methylene Blue] of benefit in treating [vasoplegic syndrome].
3. Clinical scenario
You are performing urgent CABG surgery on a 56-year-old lady. She becomes profoundly hypotensive, unresponsive to traditional vasoconstrictors and catecholamines during cardiopulmonary bypass. One of your colleagues tells you that he has used methylene blue as a vasoconstrictor in such vasoplegic patients. You wonder if there is any evidence to support this observation.
4. Search strategy
Medline 1966 to May Week 5 2006 using OVID interface EMBASE 1980 to 2006 Week 23.
[exp Cardiopulmonary Bypass/OR CABG.mp. OR exp Thoracic Surgery/OR Coronary art$ bypass.mp. OR Cardiopulmonary bypass.mp. OR exp Cardiopulmonary Bypass/OR exp Cardiovascular Surgical Procedures/OR exp Thoracic Surgical Procedures/OR exp Coronary Artery Bypass/OR cardiac transplantation.mp. OR exp Heart Transplantation/] AND [methylene blue.mp. OR exp Methylene Blue/OR Methylthioninium chloride.mp.] AND [exp HYPOTENSION/OR hypotension.mp. OR vasodilatation.mp. OR exp Vasodilation/OR postoperative complications.mp. OR exp Postoperative Complications/OR vascular resistance.mp. OR exp Vascular Resistance/OR vasoplegia/OR vasoplegia.mp. OR vasoplegia syndrome/OR exp Systemic Inflammatory Response Syndrome/OR vasoplegic syndrome/OR exp Hypotension/OR vasoplegic syndrome.mp. OR exp Postoperative Complication/OR exp Vascular Disease/OR exp INFLAMMATION MEDIATORS/OR inflammation.mp. OR exp INFLAMMATION/].
5. Search outcome
Using the reported search, 47 papers were identified on Medline, 107 on Embase and five by hand-searching reference lists. Four papers provided the best evidence to answer the question and the author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study comments/weaknesses were tabulated. A further 14 papers were referenced to aid the discussion.
6. Results
In 1994, Gomes et al. identified a vasodilatory phenomenon in adult patients undergoing cardiac surgery utilizing cardiopulmonary bypass which was often refractory to high-dose catecholamines and coined the phrase ‘Vasoplegic Syndrome’ (VPS) [2,3]. A similar syndrome has subsequently been identified in patients undergoing off-pump surgery [4]. As the condition has become better understood, novel treatment modalities have been described. One such treatment is methylene blue (MB) which is thought to act by inhibiting activation of soluble guanylate cyclase thus preventing formation of cylic guanosine 3'5'monophosphate (cGMP). cGMP has been shown to trigger vasodilatation and decreased myocardial contractility. The pathophysiology of VPS together with the pharmacology, dosage, pharmacokinetics and side-effects of MB, and some of the data supporting its use, has been discussed in detail in three recent reviews [5–7] (Table 1).
Unfortunately, whilst using MB to treat VPS in adults was first described some 10 years ago, few good quality clinical studies have been performed. The first report in the literature was in 1996 when Andrade et al. described a series of six patients undergoing cardiac surgery with or without cardiopulmonary bypass who presented with profound hypotension unresponsive to high-dose catecholamines [8]. All responded to 1.5 mg/kg MB by infusion with restoration of blood pressure and systemic vascular resistance without adverse effects on cardiac output or pulmonary vascular resistance. Since then a number of case reports have appeared describing MB use in VPS during complicated and uncomplicated cardiac surgery cases [9–16].
Only three other cohort and/or RCTs have been performed. In 2003 Leyh et al. reported the use of MB in 54 non-endocarditis cardiac surgical patients who developed VPS noting a response rate to treatment of over 90% [17]. They demonstrated that administration of MB 2 mg/kg led to significant increases in blood pressure and systemic vascular resistance in the first 12 h post-treatment. This was associated with a fall in cardiac output but changes in LAP, RAP and PAP were not significant. Levin et al. reported an incidence of VPS of 8.8% in 638 patients across four institutions in Argentina [18]. Mortality in their VPS group was three times that observed in their non-VPS patients. The 56 patients who developed VPS were subsequently randomized to receive MB 2 mg/kg or placebo with all those receiving MB seeing resolution of VPS within 2 h. In contrast, 28.6% of their placebo group still required vasopressors at 48 h. Mortality in their placebo group was 28.6% compared to zero in their MB group with significantly higher incidences of sepsis and multi-system organ failure (P=0.005) and trends towards higher incidences of renal failure, respiratory failure and myopathy (P=0.05).
Finally, in 2005 Ozal assessed the effectiveness of MB as prophylaxis for VPS comparing it to a control in 100 patients deemed at high risk of VPS [19]. They demonstrated a highly significant lower incidence of VPS in their MB-treated group with significantly lower requirements for norepinephrine during CPB. Fluid requirements on CPB, inotropes during weaning from CPB, ITU stay and total hospital stay were all significantly less in their MB-treated group. Six of their control patients developed VPS refractory to norepinephrine, two of whom died. However, the criteria used in this study to define ‘high-risk of VPS’ were wide-ranging with limited supporting evidence for some factors and it is, therefore, debatable whether their population did represent a truly high-risk group.
7. Clinical bottom line
We conclude that MB may provide an interesting and novel therapeutic option for patients who develop catecholamine-resistant VPS during cardiac surgery. However, despite three recent reviews and a number of individual case reports, there are few large cohort or RCTs assessing its usefulness for this indication, although a recent study has suggested a possible prophylactic role in patients at high risk of VPS. Therefore, whilst it has a role as ‘rescue therapy’ for VPS, there is currently insufficient evidence to advocate its use as a first-line therapy. Further larger studies have to be performed before its routine use can be recommended.
References
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact Cardiovasc Thorac Surg 2003; 2:405–409.
Gomes WJ, Carvalho AC, Palma JH, Goncalves I Jr, Buffolo E. Vasoplegic syndrome: a new dilemma. J Thorac Cardiovasc Surg 1994; 107:942–943.
Gomes WJ, Carvalho AC, Palma JH, Teles CA, Branco JN, Silas MG, Buffolo E. Vasoplegic syndrome after open heart surgery. J Thorac Cardiovasc Surg 1998; 39:619–623.
Gomes WJ, Erlichman MR, Batista-Filho ML, Knobel M, Almeida DR, Carvalho AC, Catani R, Buffolo E. Vasoplegic syndrome after off-pump coronary artery bypass surgery. Eur J Cardiothorac Surg 2003; 23:165–169.
Shanmugam G. Vasoplegic syndrome—the role of methylene blue. Eur J Cardiothorac Surg 2005; 28:705–710.
Faber P, Ronald A, Millar BW. Methylthioninium chloride: pharmacology and clinical applications with special emphasis on nitric oxide mediated vasodilatory shock during cardiopulmonary bypass. Anaesthesia 2005; 60:575–587.
Evora PRB, Viaro F. The guanylyl cyclase inhibition by MB as vasoplegic circulatory shock therapeutic target. Current Drug Targets 2006; (In press).
Andrade JCS, Batista Filho ML, Evora PRB, Tavares JR, Buffolo E, Ribeiro EE, Silva LA, Teles CA, Petrizzo A, Barata F, Vitor V, Duprat R. Methylene blue administration in the treatment of the vasoplegic syndrome after cardiac surgery. Revista Brasileira de Cirurgia Cardiovascular (Rev Bras Cir Cardiovasc) 1996; 11:107–114.
Dagenais F, Mathieu P. Rescue therapy with methylene blue in systemic inflammatory response syndrome after cardiac surgery. Can J Cardiol 2003; 19:167–169.
Grayling M, Deakin CD. Methylene blue during cardiopulmonary bypass to treat refractory hypotension in septic endocarditis. J Thorac Cardiovasc Surg 2003; 125:426–427.
Kofidis T, Struber M, Wilhelmi M, Anssar M, Simon A, Harringer W, Haverich A. Reversal of severe vasoplegia with single-dose methylene blue after heart transplantation. J Thorac Cardiovasc Surg 2001; 122:823–824.
Pagni S, Austin EH. Use of intravenous methylene blue for the treatment of refractory hypotension after cardiopulmonary bypass. J Thorac Cardiovasc Surg 2000; 119:1297–1298.
Yiu P, Robin J, Pattison CW. Reversal of refractory hypotension with single-dose methylene blue after coronary artery bypass surgery. J Thorac Cardiovasc Surg 1999; 118:195–196.
Evora PRB, Rodrigues AJ. Methylene blue revised. J Thorac Cardiovasc Surg 2006; 131:250–251.
Sparicio D, Landoni G, Pappalardo F, Crivellari M, Cerchierini E, Marino G, Zangrillo A. Methylene blue for lithium-induced refractory hypotension in off-pump coronary artery bypass graft: report of two cases. J Thorac Cardiovasc Surg 2004; 127:592–593.
Riha H, Rihova L, Pind'ak M, Brezina A, Pirk J. Methylene blue in the therapy of vasoplegic syndrome after cardiac surgery procedure. [Czech] Casopis Lekaru Ceskych 2006; 145:322–324.
Leyh RG, Kofidis T, Struber M, Fischer S, Knobloch K, Wachsmann B, Hagl C, Simon AR, Haverich A. Methylene blue: the drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass. J Thorac Cardiovasc Surg 2003; 125:1426–1431.
Levin RL, Degrange MA, Bruno GF, Del Mazo CD, Taborda DJ, Griotti JJ, Boullon FJ. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg 2004; 77:496–499.
Ozal E, Kuralay E, Yildirim V, Kilic S, Bolcal C, Kucukarslan N, Gunay C, Demirkilic U, Tatar H. Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg 2005; 79:1615–1619.(Eduardo Guilherme Leite, )
b Department of Cardiac Anaesthesia, Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK
Supported in part by FAPESP-Fundao de Amparo a Pesquisa do Estado de So Paulo, Brasil, and FAEPA-Fundao de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clinicas da Faculdade de Medicina de Ribeiro Preto da Universidade de So Paulo.
Abstract
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether methylene blue (MB) is of benefit in treating adult patients who develop catecholamine-resistant vasoplegic syndrome (VPS) during cardiac surgery. Altogether 47 papers were found in Medline and 107 in Embase using the reported search. A further five papers were found by hand-searching reference lists. Four papers represented the best evidence on the subject and details of authors, journal, date and country of publication, patient group, relevant outcomes and weaknesses were tabulated. In addition, a further 14 papers are referenced to aid the discussion. We conclude that MB may provide an interesting and novel therapeutic option for adult patients who develop catecholamine-resistant VPS during cardiac surgery. Whilst there is currently insufficient evidence to advocate its use as first-line therapy it should be considered as a possible ‘rescue therapy’ in catecholamine-resistant VPS and some work has suggested that it may have a prophylactic role in preventing VPS. However, further large well-controlled studies are required before its routine use can be recommended.
Key Words: Methylene blue; Vasoplegic syndrome; Cardiopulmonary bypass; cGMP; Guanylate cyclase
1. Introduction
A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
2. The three-part question
In [adult patients undergoing cardiac surgery] is [Methylene Blue] of benefit in treating [vasoplegic syndrome].
3. Clinical scenario
You are performing urgent CABG surgery on a 56-year-old lady. She becomes profoundly hypotensive, unresponsive to traditional vasoconstrictors and catecholamines during cardiopulmonary bypass. One of your colleagues tells you that he has used methylene blue as a vasoconstrictor in such vasoplegic patients. You wonder if there is any evidence to support this observation.
4. Search strategy
Medline 1966 to May Week 5 2006 using OVID interface EMBASE 1980 to 2006 Week 23.
[exp Cardiopulmonary Bypass/OR CABG.mp. OR exp Thoracic Surgery/OR Coronary art$ bypass.mp. OR Cardiopulmonary bypass.mp. OR exp Cardiopulmonary Bypass/OR exp Cardiovascular Surgical Procedures/OR exp Thoracic Surgical Procedures/OR exp Coronary Artery Bypass/OR cardiac transplantation.mp. OR exp Heart Transplantation/] AND [methylene blue.mp. OR exp Methylene Blue/OR Methylthioninium chloride.mp.] AND [exp HYPOTENSION/OR hypotension.mp. OR vasodilatation.mp. OR exp Vasodilation/OR postoperative complications.mp. OR exp Postoperative Complications/OR vascular resistance.mp. OR exp Vascular Resistance/OR vasoplegia/OR vasoplegia.mp. OR vasoplegia syndrome/OR exp Systemic Inflammatory Response Syndrome/OR vasoplegic syndrome/OR exp Hypotension/OR vasoplegic syndrome.mp. OR exp Postoperative Complication/OR exp Vascular Disease/OR exp INFLAMMATION MEDIATORS/OR inflammation.mp. OR exp INFLAMMATION/].
5. Search outcome
Using the reported search, 47 papers were identified on Medline, 107 on Embase and five by hand-searching reference lists. Four papers provided the best evidence to answer the question and the author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study comments/weaknesses were tabulated. A further 14 papers were referenced to aid the discussion.
6. Results
In 1994, Gomes et al. identified a vasodilatory phenomenon in adult patients undergoing cardiac surgery utilizing cardiopulmonary bypass which was often refractory to high-dose catecholamines and coined the phrase ‘Vasoplegic Syndrome’ (VPS) [2,3]. A similar syndrome has subsequently been identified in patients undergoing off-pump surgery [4]. As the condition has become better understood, novel treatment modalities have been described. One such treatment is methylene blue (MB) which is thought to act by inhibiting activation of soluble guanylate cyclase thus preventing formation of cylic guanosine 3'5'monophosphate (cGMP). cGMP has been shown to trigger vasodilatation and decreased myocardial contractility. The pathophysiology of VPS together with the pharmacology, dosage, pharmacokinetics and side-effects of MB, and some of the data supporting its use, has been discussed in detail in three recent reviews [5–7] (Table 1).
Unfortunately, whilst using MB to treat VPS in adults was first described some 10 years ago, few good quality clinical studies have been performed. The first report in the literature was in 1996 when Andrade et al. described a series of six patients undergoing cardiac surgery with or without cardiopulmonary bypass who presented with profound hypotension unresponsive to high-dose catecholamines [8]. All responded to 1.5 mg/kg MB by infusion with restoration of blood pressure and systemic vascular resistance without adverse effects on cardiac output or pulmonary vascular resistance. Since then a number of case reports have appeared describing MB use in VPS during complicated and uncomplicated cardiac surgery cases [9–16].
Only three other cohort and/or RCTs have been performed. In 2003 Leyh et al. reported the use of MB in 54 non-endocarditis cardiac surgical patients who developed VPS noting a response rate to treatment of over 90% [17]. They demonstrated that administration of MB 2 mg/kg led to significant increases in blood pressure and systemic vascular resistance in the first 12 h post-treatment. This was associated with a fall in cardiac output but changes in LAP, RAP and PAP were not significant. Levin et al. reported an incidence of VPS of 8.8% in 638 patients across four institutions in Argentina [18]. Mortality in their VPS group was three times that observed in their non-VPS patients. The 56 patients who developed VPS were subsequently randomized to receive MB 2 mg/kg or placebo with all those receiving MB seeing resolution of VPS within 2 h. In contrast, 28.6% of their placebo group still required vasopressors at 48 h. Mortality in their placebo group was 28.6% compared to zero in their MB group with significantly higher incidences of sepsis and multi-system organ failure (P=0.005) and trends towards higher incidences of renal failure, respiratory failure and myopathy (P=0.05).
Finally, in 2005 Ozal assessed the effectiveness of MB as prophylaxis for VPS comparing it to a control in 100 patients deemed at high risk of VPS [19]. They demonstrated a highly significant lower incidence of VPS in their MB-treated group with significantly lower requirements for norepinephrine during CPB. Fluid requirements on CPB, inotropes during weaning from CPB, ITU stay and total hospital stay were all significantly less in their MB-treated group. Six of their control patients developed VPS refractory to norepinephrine, two of whom died. However, the criteria used in this study to define ‘high-risk of VPS’ were wide-ranging with limited supporting evidence for some factors and it is, therefore, debatable whether their population did represent a truly high-risk group.
7. Clinical bottom line
We conclude that MB may provide an interesting and novel therapeutic option for patients who develop catecholamine-resistant VPS during cardiac surgery. However, despite three recent reviews and a number of individual case reports, there are few large cohort or RCTs assessing its usefulness for this indication, although a recent study has suggested a possible prophylactic role in patients at high risk of VPS. Therefore, whilst it has a role as ‘rescue therapy’ for VPS, there is currently insufficient evidence to advocate its use as a first-line therapy. Further larger studies have to be performed before its routine use can be recommended.
References
Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact Cardiovasc Thorac Surg 2003; 2:405–409.
Gomes WJ, Carvalho AC, Palma JH, Goncalves I Jr, Buffolo E. Vasoplegic syndrome: a new dilemma. J Thorac Cardiovasc Surg 1994; 107:942–943.
Gomes WJ, Carvalho AC, Palma JH, Teles CA, Branco JN, Silas MG, Buffolo E. Vasoplegic syndrome after open heart surgery. J Thorac Cardiovasc Surg 1998; 39:619–623.
Gomes WJ, Erlichman MR, Batista-Filho ML, Knobel M, Almeida DR, Carvalho AC, Catani R, Buffolo E. Vasoplegic syndrome after off-pump coronary artery bypass surgery. Eur J Cardiothorac Surg 2003; 23:165–169.
Shanmugam G. Vasoplegic syndrome—the role of methylene blue. Eur J Cardiothorac Surg 2005; 28:705–710.
Faber P, Ronald A, Millar BW. Methylthioninium chloride: pharmacology and clinical applications with special emphasis on nitric oxide mediated vasodilatory shock during cardiopulmonary bypass. Anaesthesia 2005; 60:575–587.
Evora PRB, Viaro F. The guanylyl cyclase inhibition by MB as vasoplegic circulatory shock therapeutic target. Current Drug Targets 2006; (In press).
Andrade JCS, Batista Filho ML, Evora PRB, Tavares JR, Buffolo E, Ribeiro EE, Silva LA, Teles CA, Petrizzo A, Barata F, Vitor V, Duprat R. Methylene blue administration in the treatment of the vasoplegic syndrome after cardiac surgery. Revista Brasileira de Cirurgia Cardiovascular (Rev Bras Cir Cardiovasc) 1996; 11:107–114.
Dagenais F, Mathieu P. Rescue therapy with methylene blue in systemic inflammatory response syndrome after cardiac surgery. Can J Cardiol 2003; 19:167–169.
Grayling M, Deakin CD. Methylene blue during cardiopulmonary bypass to treat refractory hypotension in septic endocarditis. J Thorac Cardiovasc Surg 2003; 125:426–427.
Kofidis T, Struber M, Wilhelmi M, Anssar M, Simon A, Harringer W, Haverich A. Reversal of severe vasoplegia with single-dose methylene blue after heart transplantation. J Thorac Cardiovasc Surg 2001; 122:823–824.
Pagni S, Austin EH. Use of intravenous methylene blue for the treatment of refractory hypotension after cardiopulmonary bypass. J Thorac Cardiovasc Surg 2000; 119:1297–1298.
Yiu P, Robin J, Pattison CW. Reversal of refractory hypotension with single-dose methylene blue after coronary artery bypass surgery. J Thorac Cardiovasc Surg 1999; 118:195–196.
Evora PRB, Rodrigues AJ. Methylene blue revised. J Thorac Cardiovasc Surg 2006; 131:250–251.
Sparicio D, Landoni G, Pappalardo F, Crivellari M, Cerchierini E, Marino G, Zangrillo A. Methylene blue for lithium-induced refractory hypotension in off-pump coronary artery bypass graft: report of two cases. J Thorac Cardiovasc Surg 2004; 127:592–593.
Riha H, Rihova L, Pind'ak M, Brezina A, Pirk J. Methylene blue in the therapy of vasoplegic syndrome after cardiac surgery procedure. [Czech] Casopis Lekaru Ceskych 2006; 145:322–324.
Leyh RG, Kofidis T, Struber M, Fischer S, Knobloch K, Wachsmann B, Hagl C, Simon AR, Haverich A. Methylene blue: the drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass. J Thorac Cardiovasc Surg 2003; 125:1426–1431.
Levin RL, Degrange MA, Bruno GF, Del Mazo CD, Taborda DJ, Griotti JJ, Boullon FJ. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg 2004; 77:496–499.
Ozal E, Kuralay E, Yildirim V, Kilic S, Bolcal C, Kucukarslan N, Gunay C, Demirkilic U, Tatar H. Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg 2005; 79:1615–1619.(Eduardo Guilherme Leite, )