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Three Part Question

In [adult patients undergoing cardiac surgery] is [Methylene Blue] of benefit in treating [vasoplegic syndrome].

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.

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/].

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

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Andrade et al, 1996, Brazil	6 patients who developed vasoplegic syndrome (VPS) during cardiac surgery with/without cardiopulmonary bypass Criteria for VPS- tachycardia, oliguria, satisfactory peripheral perfusion and systemic hypotension refractory to high-dose catecholamine All monitored with PA catheters Methylene Blue (MB) 1.5 mg/kg given over 1 hr	Cohort (level 2b)	Response to MB	Prompt restoration of blood pressure and SVR post MB administration	Small cohort study Limited outcome data
			Systemic vascular resistance (SVR) pre and post MB treatment	Mean pre MB vs post MB. SVR = 868 vs 1693 dyne/s/cm to the power of 5
			Cardiac output (CO) and pulmonary vascular resistance (PVR) pre and post MB treatment	No adverse effect on CO or PVR
Leyh et al, 2003, Germany	54 patients with norepinephrine-resistant VPS post CPB out of 1111 patients undergoing cardiac surgery in 12 months Norepinephrine-resistant VPS: cardiac output 4 l/min SVR<600 dyne/s/cm5 Norepinephrine 0.5 µg/kg/min 2 mg/kg MB administered over 20 min in addition to Norepinephrine Standard anaesthetic/ITU management	Cohort (level 2b)	Haemodynamic parameters at time ), +1 h, +6 h, & +12 h: MAP, mPAP, RAP, LAP	All outcome measurements 0 h vs +1 h vs +6 h vs +12 h: MAP 68±9 mmHg vs. 72±12 vs. 71±9 vs. 73±10 (P=0.02 at all post MB points vs. 0 h)	41/54 (76%) male Wide range of surgical procedures Patients with endocarditis excluded from cohort Observational study without control group Numbers do not add up i.e. 51 responders +4 non-responders = 55 patients
			Cardiac output	CO 7.6±3.1 l/min vs. 6.5±2.8 vs. 6.1±2.4 vs. 5.8±1.9 (P<0.001 at all post MB points vs. 0 h)
			SVR	SVR 547±108 dynes/s/cm5 vs. 766±194 vs. 796±153 vs.876±184 (P<0.001 at all post MB points vs 0 h) Changes in PAP, RAP and LAP not significant. 4/54 (7.4%) patients had no response to MB
			Mortality	3/54 (5.6%) died incl 2/4 'non-responders'
Levin et al, 2004, Argentina	Cohort of 638 consecutive cardiac surgery patients in 5-month period VPS patients randomised to MB (1.5 mg/kg over 1 h) or placebo VPS defined as: MAP<50 mmHg CVP<5 mmHg; PCWP<10 mmHg CI=2.5 l/min/m2 SVR<800 dyne/s/cm5 vasopressor requirement Standard anaesthetic/Surgical technique	Cohort (level 2b) progressing to PRCT (level 1b)	Cohort outcome: Incidence of VPS	56/638 (8.8%) patients developed VPS	Small numbers progressing to RCT Patients from 4 centres 2, 9, 14 and 31 recruited to RCT Randomisation technique based on hospital number-may not be truly random Excluded inf OPCAB, endocarditis Ao dissection, urgent or emergency
			Cohort outcome: Comparisons of outcomes in VPS and non-VPS cohorts	Mortality 6/56 (10.7%) VPS vs. 21/582 (3.6%) non-VPS patients (P=0.02; OR 0.31; CI 0.11–0.91)
			RCT: VPS mortality rate MB vs placebo	Mortality MB+VPS vs. Placebo+VPS =0/28 (0%) vs. 6/28 (21.4%) P=0.01
			RCT: Duration of VPS/vasopressor requirement	Duration of VPS shorter in MB+VPS patients vs. Placebo +VPS patients –<2 h all patients vs. 8/28 48 h (P=0.0007) 0/28 (0%) MB+VPS vs. 8/28 (28.6%) Placebo +VPS (incl 6 ultimate deaths) still requiring vasopressors at 48 h (P=0.002) (P=0.00 at time points 3, 6, 12, & 24 h post- treatment MB+VPS vs. Placebo+VPS)
			Other complications	MB+VPS vs. Placebo+VPS Renal failure, Resp failure or Myopathy 0/28 (0%) vs. 4/28 (14.3%) P=0.05 – SVT 2/28 (7.1%) vs. 8/28 (28.6%) P=0.03 – Sepsis & MSOF both 0/28 vs.7/28 (25%) P=0.005
Ozal et al, 2005, Turkey	100 patients at high risk of VPS scheduled for CABG surgery randomized to preoperative MB or control Excluded if LVEF<35%, in cardiogenic shock or low cardiac output postop VPS defined as MAP<50 mmHg intraop/within 6 h of end of CPB CVP<5 mmHg; PCWP<10 mmHg CI=2.5 l/min/m2 SVR<800 dyne/s/cm5 Norepinephrine requirement 0.5 µg/kg/min MB patients – 2 mg/kg over 30 min 1 h preop Routine surgical/anaesthetic management	PRCT (level 1b)	Incidence of VPS	0/50 (0%) MB vs. 13/50 (26%) Control patients developed symptoms of VPS (P<0.001)	Patients deemed 'at risk' of VPS wide ranging (preop ACE inhibitors, calcium channel blockers and Heparin) with variable supportive evidence particularly as regards calcium channel blockers therefore may not have targeted a truly 'high risk' cohort for study MB administered unsuccessfully as 'rescue therapy' to the 2 control patients who developed VPS and MSOF
			Progress of VPS	6/50 Control patients had VPS refractory to Norepinephrine (P<0.001) 4/6 resolved within 8 h 2/6 died of MSOF
			Systemic vascular resistance (SVR) during CPB	SVR on CPB significantly higher in MB vs.control patients (P<0.001)
			Norepinephrine requirement	Norepinephrine requirement to maintain MAP 45 mmHg on CPB 2/50 (4%) MB vs 41/50 (82%) Control 0/13 (0%) MB vs. 13/50 (26%) required Norepinephrine infusion 0.5 µg/kg/ min (P<0.001)
			Fluid requirements during CPB	Lower requirement for fluids in MB patients vs. Control on CPB Crystalloid (1577±329 vs. 1749±414 ml; P=0.024) Colloid (373±59 vs. 404±76 ml; P=0.027) Red Cells (2.2±0.7 vs. 3.3±1.5 Units; P<0.001)
			Inotrope requirement	Post-CPB Inotropes required in 7/50 (14%) MB vs. 24/50 (48%) Control (P<0.001)
			Length of ITU & Hospital stay	Length of stay MB vs. control patients (days) ITU 1.2±0.5 vs.2.1±1.2 days (P<0.001). Hospital 6.1±1.7 vs. 8.4±2.0 (P<0.001)

Comment(s)

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). A similar syndrome has subsequently been identified in patients undergoing off-pump surgery(Gomes 2003). 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 (Shanmugam, Faber, Evora). 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. 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 (Dagenais, Grayling, Kofidis, Pagni, Yiu, Evora, Sparicio, Riha). 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%. 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 . 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. 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.

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

1. Gomes WJ, Carvalho AC, Palma JH, Goncalves I Jr, Buffolo E. Vasoplegic syndrome: a new dilemma. J Thorac Cardiovasc Surg 1994; 107:942–943.
2. 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.
3. 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.
4. Shanmugam G. Vasoplegic syndrome—the role of methylene blue. Eur J Cardiothorac Surg 2005; 28:705–710.
5. 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.
6. Evora PRB, Viaro F. The guanylyl cyclase inhibition by MB as vasoplegic circulatory shock therapeutic targets. Current Drug Targets 2006; (In press).
7. 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.
8. Dagenais F, Mathieu P. Rescue therapy with methylene blue in systemic inflammatory response syndrome after cardiac surgery. Can J Cardiol 2003; 19:167–169,
9. Grayling M, Deakin CD. Methylene blue during cardiopulmonary bypass to treat refractory hypotension in septic endocarditis. J Thorac Cardiovasc Surg 2003; 125:426–427.
10. 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.
11. 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.
12. 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.
13. Evora PRB, Rodrigues AJ. Methylene blue revised. J Thorac Cardiovasc Surg 2006; 131:250–251.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.