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Methylene Blue for Vasoplegic Syndrome After Cardiac Operation: Early Administration Improves Survival
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CARDIOTHORACIC ANESTHESIOLOGY: The Annals of Thoracic Surgery CME Program is located online at http://www.annalsthoracicsurgery. org/cme/home. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal.
Methylene Blue for Vasoplegic Syndrome After Cardiac Operation: Early Administration Improves Survival J. Hunter Mehaffey, MD, Lily E. Johnston, MD, MPH, Robert B. Hawkins, MD, Eric J. Charles, MD, Leora Yarboro, MD, John A. Kern, MD, Gorav Ailawadi, MD, Irving L. Kron, MD, and Ravi K. Ghanta, MD Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia, Charlottesville, Virginia
Background. Vasoplegic syndrome, defined by hypotension despite normal or increased cardiac output, is associated with high mortality rate after cardiopulmonary bypass. Methylene blue (MB) is reported to ameliorate vasoplegic syndrome through the nitric oxide pathway. We hypothesized that early administration of MB would improve outcomes in patients with vasoplegic syndrome after cardiopulmonary bypass. Methods. All patients that underwent cardiopulmonary bypass at our institution (Jan 1, 2011 to Jun 30, 2016) were identified through our Society of Thoracic Surgery database. Pharmacy records identified patients receiving MB within 72 hours of cardiopulmonary bypass. Multivariate logistic regression identified predictors of major adverse events among patients receiving MB. Results. A total of 118 cardiopulmonary bypass patients (3.3%) received MB for vasoplegic syndrome. These patients had a higher incidence of comorbidities, and these cases were more commonly reoperative (76.1%
versus 41.2%, p < 0.0001) and complex (70.3% versus 31.8%, p < 0.0001). The only difference in preoperative medications was that MB patients had a higher rate of amiodarone use (15.3% versus 2.2%, p < 0.0001). MB patients had significantly higher rates of postoperative complications, except atrial fibrillation. Early (operating room, 40.7%) versus late (intensive care unit, 59.3%) administration of MB was associated with significantly reduced operative mortality rate (10.4% versus 28.6%, p [ 0.018) and risk-adjusted major adverse events (odd ratio 0.35, p [ 0.037). Conclusions. Operative mortality rate is high in patients receiving MB for the treatment of vasoplegia after cardiopulmonary bypass. Early administration of MB improves survival and reduces the risk-adjusted rate of major adverse events in these patients.
O
release and increased systemic vascular resistance (SVR) [9]. There have been a number of retrospective studies that examined the use of this drug in the treatment of vasoplegic syndrome with mixed results regarding efficacy [6, 10, 11]. Two prospective, randomized trials evaluated MB administration at the onset of CPB in 30 and 100 patients with risk factors for vasoplegic syndrome and demonstrated safety in the CPB population [12, 13]. Despite promising results, significant criticism has focused on the fact that neither trial selected for patients with the clinical diagnosis of vasoplegic syndrome. In addition, several animal studies evaluated MB’s mechanism of action and biochemical pathways for resolution of vasoplegia. These studies demonstrated a time-dependent decrease in NO synthase production, improved microvascular function, and decreased transendothelial inflammatory cell migration [14–17]. Currently, MB does not have any US Food and Drug Administration (FDA) approved indications, but it is most commonly used for treatment of methemoglobinemia. The purpose of this study is to determine the incidence of CPB-induced vasoplegic syndrome and to describe
ver the past 20 years, there has been an increase in the incidence of vasoplegic syndrome, which affects more than 5% of patients undergoing cardiopulmonary bypass (CPB) and is associated with a mortality rate approaching 25% [1–3]. Standard treatment options for severe refractory vasoplegic syndrome are extremely limited and include vasopressor support and systemic corticosteroids [3–5]. With the increasing incidence of vasoplegic syndrome, the use of alternative treatment options such as methylene blue (MB) has also increased. MB has demonstrated beneficial effects on the severe vasodilation associated with vasoplegic syndrome [6–8]. MB is a potent inhibitor of nitric oxide (NO) synthase in vascular endothelial cells, resulting in decreased NO
Accepted for publication Feb 16, 2017. Presented at the Poster Session of the Fifty-third Annual Meeting of The Society of Thoracic Surgeons, Houston TX, Jan 21–25, 2017. Address correspondence to Dr Mehaffey, Department of Surgery, University of Virginia School of Medicine, PO Box 800300, Charlottesville, VA 22908; email: [email protected].
Ó 2017 by The Society of Thoracic Surgeons Published by Elsevier Inc.
(Ann Thorac Surg 2017;104:36–41) Ó 2017 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2017.02.057
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MEHAFFEY ET AL METHYLENE BLUE FOR VASOPLEGIA
Statistical Methods Abbreviations and Acronyms ACE CI CPB FDA MAE MB NO STS SVR
= = = = = = = = =
angiotensin-converting enzyme cardiac index cardiopulmonary bypass Food and Drug Administration major adverse event methylene blue nitric oxide Society of Thoracic Surgeons systemic vascular resistance
contemporary practice patterns of MB use at an academic cardiac surgical center. We hypothesized that early administration of MB would reduce the risk of adverse outcome in patients with vasoplegic syndrome.
Patients and Methods Patients This study was approved the University of Virginia Institutional Review Board with waiver of informed consent (protocol 19247). All patients receiving MB within 72 hours of CPB at our institution between January 2011 and March 2016 were identified. Our Society of Thoracic Surgeons (STS) database prospectively collects preoperative characteristics, intraoperative details, and postoperative outcomes through 30 days for all patients undergoing cardiac operation at our institution. These records were linked with all episodes of MB administration recorded in our institutional pharmacy database. In addition, the Clinical Data Repository was queried which includes laboratory values, cost data, and detailed hemodynamic data for all inpatient hospitalizations. Finally, long-term survival data were collected from the Social Security Death Master File.
Post-CPB Vasoplegia University of Virginia MB Protocol Since 2011, the Division of Thoracic and Cardiovascular Surgery at our institution has used a consensus approach to the management of post-CPB vasoplegic syndrome. Diagnosis includes vasodilation characterized by low SVR with elevated cardiac index (CI) resulting in hypotension despite high doses of vasopressors on pump or postoperatively. Standard vasopressor support is used with a preference for vasopressin and norepinephrine to combat vasodilation with phenylephrine used as a second-line therapy. Given the common hyperdynamic cardiac function during vasoplegic syndrome with CIs typically greater than 4.0 L/min/m2, epinephrine is used sparingly. In addition, after clinical diagnosis of vasoplegic syndrome, patients receive stress-dose steroids, diphenhydramine, and famotidine to target the systemic inflammatory response. Our MB administration protocol for patients with refractory vasoplegic syndrome was a bolus dose of 2 mg/kg intravenous MB followed by 12hour infusion at 0.5 mg/kg/h. This protocol was in place for all patients during the study period.
The primary outcome was major adverse event (MAE) after administration of MB for vasoplegic syndrome. MAEs included the STS major morbidities (permanent stroke, renal failure, reoperation, deep sternal wound infection, and prolonged ventilation) as well as operative mortality (in-hospital or 30-day). Standard STS definitions were used for all variables, including new onset renal failure and prolonged ventilation (>24 hours). In addition, preoperative and intraoperative variables associated with MB treatment for vasoplegic syndrome were assessed. Early administration was defined as operating room, and patients not receiving MB until reaching the postoperative intensive care unit were classified as late administration. Univariate analysis was performed using c2 and Mann-Whitney U tests for categorical and continuous variables, respectively. Multivariable logistic regression was used to identify risk-adjusted predictors of MAEs in patients receiving MB for vasoplegic syndrome. SAS version 9.4 (SAS Institute, Cary, NC) statistical software was used for analysis with a statistical threshold for significance set at 0.05.
Results Vasoplegic Population A total of 3,608 patients underwent CPB during the study period, of whom 118 (3.3%) received MB for the treatment Table 1. Characteristics of Patients Receiving MB for Vasoplegic Syndrome Variable
MB
No MB
Number of patients 118 (3.3) Isolated coronary artery 35 (29.6) bypass or valve Ventricular assist device 40 (33.9) Prior ventricular assist 32 (27.1) device Age, years 63 [58, 71] Male sex 81 (69.2) Tobacco use 46 (39.3) Heart failure diagnosis 88 (74.6) Dialysis-dependent renal 7 (6.9) failure Diabetes mellitus 46 (39.0) Severe chronic lung disease 10 (8.6) Hypertension 77 (65.8) Ejection fraction, % 42 [20, 58] Preoperative amiodarone 18 (15.3) therapy ACE inhibitor within 48 13 (11.0) hours Prior cardiac operation 89 (76.1) Cross-clamp time, minutes 100 [79, 126] a
p Value
3490 (96.7) . 2381 (68.2) <0.0001a 130 (3.7) 28 (0.1)
<0.0001a <0.0001a
67 [57, 75] 0.031a 2334 (67.7) 0.720 785 (22.8) <0.0001a 1740 (49.9) <0.0001a 94 (2.6) 0.036a 3488 (36.5) 0.586 143 (4.1) 0.008a 2646 (76.7) 0.007a 57 [45, 63] <0.0001a 78 (2.2) <0.0001a 398 (11.4)
0.896
1435 (41.2) <0.0001a 75 [58, 96] <0.0001a
Significantly different.
Values are n (%) or median [interquartile range]. ACE ¼ angiotensin-converting enzyme;
MB ¼ methylene blue.
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Table 2. Outcomes for Patients Receiving MB for Vasoplegic Syndrome Variable Postoperative atrial fibrillation Stroke Renal failure Deep sternal wound infection Reoperation Prolonged ventilation Operative mortality Major adverse event composite a
MB 27 6 25 1 31 27 25 55
(22.9) (5.1) (21.2) (0.9) (26.3) (22.9) (21.2) (46.6)
No MB 725 71 151 2 222 232 112 516
(20.8) (2.0) (4.3) (0.1) (6.4) (6.7) (3.2) (14.8)
p Value 0.579 0.025a <0.0001a 0.003a <0.0001a <0.0001a <0.0001a <0.0001a
group had lower rates of tobacco use (29.6% versus 47.6%, p ¼ 0.047), isolated coronary artery bypass graft or valve operation (14.6% versus 42.9%, p ¼ 0.001) and early administration of MB (35.4% versus 64.6%, p ¼ 0.044) but a higher rate of prior cardiac operation (81.5% versus 71.4%, p ¼ 0.02) (Table 5). In addition, preoperative diastolic blood pressure (58 versus 68 mm Hg, p ¼ 0.024) was lower and cross-clamp time (167 versus 147 minutes, p ¼ 0.021) was longer in the MAE group. Multivariate logistic regression demonstrated early administration of MB independently reduces the risk of MAEs in patients with vasoplegic syndrome (odds ratio 0.35, p ¼ 0.037, c-statistic ¼ 0.798) (Table 6).
Significantly different.
Values are n (%). MB ¼ methylene blue.
of vasoplegic syndrome. Patients receiving MB were more likely younger (63 versus 67 years, p ¼ 0.031) and had higher rates of medical comorbidities, especially heart failure (74.6% versus 49.4%, p < 0.0001) (Table 1). Preoperative amiodarone use was higher (15.3% versus 2.2%, p < 0.0001), with no difference in angiotensin-converting enzyme (ACE) inhibitor use within 48 hours of operation (11.0% versus 11.4%, p ¼ 0.896). Patients receiving MB for vasoplegic syndrome had significantly higher rates of all STS major morbidities and operative mortality (Table 2).
MB Outcomes After MB administration, patients with vasoplegic syndrome demonstrated improvement in mean arterial pressure in addition to gradual increases in SVR and decreases in CI (Fig 1). In addition, patients demonstrated a gradual reduction in vasopressor requirements (Fig 2). When stratified by early (operating room) versus late (intensive care unit) administration of MB, patients demonstrated reduced renal failure (10.4% versus 28.6%, p ¼ 0.018) and reduced operative mortality rate (10.4% versus 28.6%, p ¼ 0.018) with early administration (Tables 3 and 4).
Major Adverse Events A total of 46.6% (55 of 118) of patients receiving MB for vasoplegic syndrome experienced a MAE. The MAE
Comment Vasoplegic syndrome after CPB is a growing problem because cardiac operation case complexity increases and continuous flow mechanical circulatory support devices are used more frequently. In the present study, 3.3% of patients at a quaternary care academic medical center received MB for the treatment of severe refractory vasoplegia. These patients had significantly worse outcomes, including higher rates of STS major morbidities and operative mortality. Specific predictors for development of vasoplegic syndrome are limited and related to case complexity and comorbidities [1, 3, 18, 19]. A standardized approach to the treatment of severe vasoplegic syndrome resulted in an operative mortality rate of 21.2% compared with rates as high as 44% previously reported [10, 20, 21]. This study demonstrated that MB administration for treatment of vasoplegic syndrome results in an improvement in mean arterial pressure, with a compensatory increase in SVR and decrease in CI, coinciding with a reduction in vasopressor requirements. In addition to confirming MB improves vasoplegia, we validate that early administration of MB in the operating room at first signs of vasoplegic syndrome provide better outcomes and improved survival. Surprisingly, the previously reported link between ACE inhibitors and vasoplegic syndrome was not identified in this study. These findings can likely be attributed to the low rate of ACE inhibitor use within 48 hours of operation (11%), due to increased vigilance ensuring
Fig 1. Hemodynamic response (mean arterial pressure, cardiac index, and systemic vascular resistance) after methylene blue administration. Graphs are means and 95% confidence intervals.
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Fig 2. Vasopressor requirements (epinephrine and norepinephrine) after methylene blue administration. Graphs are means and 95% confidence intervals.
patients hold this medication because it is a known risk factor [5, 13, 22, 23]. However, preoperative amiodarone therapy was significantly higher in the MB group than the standard population. Given the retrospective nature of this study, it is impossible to ascertain if this is an association or causation, because patients requiring preoperative amiodarone are likely higher surgical risk. In light of the increasing use of amiodarone and the growing prevalence of vasoplegic syndrome, further investigation is warranted in a prospective manner. Prior heart failure and ejection fraction were also important patient level factors associated with higher rates of MB treatment for vasoplegic syndrome, which have been previously described [3, 19]. The composite MAE was used to identify risk factors for poor outcomes after MB administration for vasoplegic syndrome. Univariate analysis demonstrated six variables Table 3. Characteristics of Early Versus Late Administration of MB for Vasoplegic Syndrome Variable
Early
Late
Number of patients 48 (40.7) 70 (59.3) Isolated coronary artery 20 (28.6) 15 (31.3) bypass or valve Ventricular assist device 23 (32.9) 17 (35.4) Age, years 64 [60, 73] 63 [56, 70] Male sex 34 (70.8) 47 (68.1) Tobacco use 16 (33.3) 30 (43.5) Heart failure 34 (70.8) 54 (77.1) End-stage renal disease 4 (8.3) 3 (4.3) Diabetes mellitus 20 (17.0) 26 (37.1) Severe chronic lung disease 2 (4.2) 8 (11.6) Hypertension 36 (75.0) 41 (59.4) Ejection fraction, % 41 [18, 58] 42 [23, 59] Preoperative amiodarone 4 (8.3) 14 (20.0) therapy ACE inhibitor within 48 3 (6.3) 10 (14.3) hours Prior cardiac operation 41 (85.4) 48 (69.6) Cross-clamp time, minutes 100 [86, 118] 102 [75, 134] a
p Value . 0.754 0.773 0.305 0.754 0.269 0.439 0.361 0.621 0.304 0.081 0.787 0.083 0.171 0.048a 0.848
associated with MAEs, including markers of case complexity, such as prior cardiac operation, cross-clamp time, and procedure performed, as well as patientspecific factors such as tobacco use and preoperative diastolic blood pressure. The timing of MB administration was also significant, with patients receiving the medication in the operating room having a reduced rate of MAEs compared with receiving it in the intensive care unit despite no major baseline differences. On multivariate regression, tobacco use was independently associated with reduced rates of MAEs, suggesting a potential reversible cause of vasoplegic syndrome through the NO pathway, which is affected by MB treatment. Tobacco use may cause endothelial cell activation, which predisposes patients to vasoplegic syndrome that is attenuated though the MB pathway [24]. In addition, isolated coronary artery bypass graft or valve operations reduced risk-adjusted odds of MAEs, highlighting case complexity as a predictor of poor outcomes. This was particularly pronounced in the population undergoing ventricular assist device placement, especially in patients with prior continuous flow ventricular assist devices, or heart transplantations, which has been well described in the published studies [25, 26]. Table 4. Outcomes of Early Versus Late Administration of MB for Vasoplegic Syndrome Variable
p Value 0.554 0.170 0.447 0.178 0.863 0.707 0.018a 0.266 0.219 0.994 0.062 0.018a
Significantly different.
Values are n (%) or median [interquartile range].
Values are n (%) or median [interquartile range].
ACE ¼ angiotensin-converting enzyme;
MB ¼ methylene blue;
MB ¼ methylene blue.
Late
Postoperative adverse event 34 (70.8) 53 (75.7) Blood transfusion 44 (91.7) 58 (82.9) Length of stay, days 12 [10, 18.5] 12 [6, 21] Postoperative atrial fibrillation 14 (29.2) 13 (18.6) Postoperative cardiac arrest 5 (10.4) 8 (11.4) Stroke 2 (4.2) 4 (5.7) Renal failure 5 (10.4) 20 (28.6) Reoperation 10 (20.8) 21 (30.0) Deep sternal wound infection 1 (2.2) 0 (0.00) Prolonged ventilation 11 (22.9) 16 (22.9) STS major morbidity 17 (35.4) 37 (52.9) 30-Day mortality 5 (10.4) 20 (28.6) a
Significantly different.
Early
STS ¼ The Society of Thoracic Surgeons.
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Table 5. Baseline Characteristics for MB Patients Experiencing a MAE Variable Cases Male sex Age, years Heart failure Hypertension Dialysis Diabetes Severe lung disease Prior cardiac operation Tobacco use Preoperative amiodarone therapy ACE inhibitor within 48 hours Preoperative diastolic blood pressure, mm Hg Initial postoperative white blood cell count, 109/L Isolated CABG/valve operation Cross-clamp time, minutes Early MB administration a
MAE
No MAE
p Value
25 (21.2) 37 (68.5) 61 [56, 70] 45 (81.8) 36 (66.7) 3 (5.45) 21 (38.2) 4 (7.4) 44 (81.5) 16 (29.6) 7 (12.7) 7 (12.7) 58 [43, 68] 17.5 [13.5, 26.0] 8 (14.6) 167 [125, 234] 17 (35.4)
93 (78.8) 44 (69.8) 64 [59, 73] 43 (68.3) 41 (65.1) 4 (6.4) 25 (39.7) 6 (9.5) 45 (71.4) 30 (47.6) 11 (17.5) 6 (9.5) 68 [52, 84] 16.2 [13.0, 21.8] 27 (42.9) 147 [118, 190] 31 (64.6)
. 0.877 0.280 0.291 0.857 0.837 0.868 0.912 0.204 0.047a 0.476 0.579 0.024a 0.582 0.001a 0.021a 0.044a
Significantly different.
Values are n (%) or median [interquartile range]. ACE ¼ angiotensin-converting enzyme;
CABG ¼ coronary artery bypass graft;
Early administration of MB resulted in reduced incidence of postoperative renal failure and operative mortality. This benefit is likely because of early attenuation of the NO-induced vasodilation cascade, which reduces the severe systemic inflammatory response [15, 20]. Multivariate regression confirmed early MB administration as an independent predictor of reduced risk-adjusted MAEs. These results highlight the importance of early recognition and treatment of vasoplegic syndrome. A standardized treatment protocol as described above is a critical step in improving outcomes in these patients with a high risk of morbidity and mortality. This study is limited by the retrospective single-center nature of the data available for analysis. However, this design allowed for increased granularity of patientspecific data, including hourly hemodynamic and Table 6. Predictors of Major Adverse Events Variable
Odds Ratio p (95% Confidence Interval) Value
Tobacco use Early MB administration Isolated CABG/valve operation Cross-clamp time Preoperative diastolic blood pressure Prior cardiac operation a
0.26 (0.087–0.771) 0.35 (0.127–0.936) 0.29 (0.095–0.855)
0.015a 0.037a 0.025a
1.01 (0.999–1.022) 1.00 (0.981–1.022)
0.077 0.904
2.89 (0.968–8.635)
0.057
MAE ¼ major adverse event;
MB ¼ methylene blue.
vasopressor dosages. In addition, vasoplegic syndrome is an often mentioned but poorly described disease process in published reports, characterized by low SVR and high CI with no widely accepted cutoffs. As such, we used administration of MB as a marker of severe refractory vasoplegic syndrome, which limits the availability of a true control group. We were unable to identify any patients at our institution having vasoplegic syndrome who did not receive MB. However, given practice patterns and current vasoplegic syndrome protocols, all patients in the past 5 years with severe vasoplegic syndrome received MB and were captured for analysis. For this reason, we did not seek to identify predictors of vasoplegic syndrome after CBP as others have done. Instead, we focused on predictors of favorable response to MB to identify patients most likely to benefit from receiving this non–FDAapproved drug. Finally, timing of MB administration was at the discretion of the attending surgeon, and patients receiving the therapy in the operating room represent a more aggressive treatment. In conclusion, early administration of MB improves survival and reduces the risk of MAEs in patients with CPB-induced vasoplegic syndrome. These patients have a high mortality rate that may be improved with standardized protocols that encourage MB initiation at the first signs of vasoplegic syndrome. Currently, MB is not FDA approved and is administered off-label to treat this life-threatening condition. These results support the need for a prospective study and further investigation into the use of MB for vasoplegic syndrome.
Significantly different.
C-statistic ¼ 0.798. CABG ¼ coronary artery bypass graft;
MB ¼ methylene blue.
Methylene blue is not FDA approved for the treatment of vasoplegic syndrome in patients after cardiopulmonary bypass. The National Heart, Lung, and Blood Institute of the National
Institutes of Health under Award Number T32HL007849 supported research reported in this publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
References 1. Byrne JG, Leacche M, Paul S, et al. Risk factors and outcomes for ’vasoplegia syndrome’ following cardiac transplantation. Eur J Cardiothorac Surg 2004;25:327–32. 2. Cremer J, Martin M, Redl H, et al. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg 1996;61:1714–20. 3. Fischer GW, Levin MA. Vasoplegia during cardiac surgery: current concepts and management. Semin Thorac Cardiovasc Surg 2010;22:140–4. 4. Levin MA, Lin HM, Castillo JG, Adams DH, Reich DL, Fischer GW. Early on-cardiopulmonary bypass hypotension and other factors associated with vasoplegic syndrome. Circulation 2009;120:1664–71. 5. Mekontso-Dessap A, Houel R, Soustelle C, Kirsch M, Thebert D, Loisance DY. Risk factors for postcardiopulmonary bypass vasoplegia in patients with preserved left ventricular function. Ann Thorac Surg 2001;71: 1428–32. 6. Evora PR, Jose Rodrigues A, Celotto AC. “Methylene blue should be relegated to rescue use and not as first-line therapy” cannot become a paradigm. J Cardiothorac Vasc Anesth 2014;28:e11–2. 7. Evora PR, Levin RL. Methylene blue as drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass. J Thorac Cardiovasc Surg 2004;127:895–6; author reply 896. 8. Evora PR, Ribeiro PJ, Vicente WV, et al. Methylene blue for vasoplegic syndrome treatment in heart surgery: fifteen years of questions, answers, doubts and certainties. Rev Bras Cir Cardiovasc 2009;24:279–88. 9. Omar S, Zedan A, Nugent K. Cardiac vasoplegia syndrome: pathophysiology, risk factors and treatment. Am J Med Sci 2015;349:80–8. 10. Weiner MM, Lin HM, Danforth D, Rao S, Hosseinian L, Fischer GW. Methylene blue is associated with poor outcomes in vasoplegic shock. J Cardiothorac Vasc Anesth 2013;27:1233–8. 11. Riha H, Augoustides JG. Pro: methylene blue as a rescue therapy for vasoplegia after cardiac surgery. J Cardiothorac Vasc Anesth 2011;25:736–8. 12. Ozal E, Kuralay E, Yildirim V, et al. Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg 2005;79: 1615–9.
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13. Maslow AD, Stearns G, Butala P, Schwartz CS, Gough J, Singh AK. The hemodynamic effects of methylene blue when administered at the onset of cardiopulmonary bypass. Anesth Analg 2006;103:2–8; table of contents. 14. Nantais J, Dumbarton TC, Farah N, et al. Impact of methylene blue in addition to norepinephrine on the intestinal microcirculation in experimental septic shock. Clin Hemorheol Microcirc 2014;58:97–105. 15. Werner I, Guo F, Bogert NV, et al. Methylene blue modulates transendothelial migration of peripheral blood cells. PLoS One 2013;8:e82214. 16. Menardi AC, Viaro F, Vicente WV, Rodrigues AJ, Evora PR. Hemodynamic and vascular endothelium function studies in healthy pigs after intravenous bolus infusion of methylene blue. Arq Bras Cardiol 2006;87: 525–32. 17. Siriwardena DK, Tagori H, Thiemermann C. Nitric oxide synthase inhibitors. Methods Mol Med 2000;36:115–31. 18. Alfirevic A, Xu M, Johnston D, Figueroa P, Koch CG. Transfusion increases the risk for vasoplegia after cardiac operations. Ann Thorac Surg 2011;92:812–9. 19. Kortekaas KA, Lindeman JH, Versteegh MI, Stijnen T, Dion RA, Klautz RJ. Preexisting heart failure is an underestimated risk factor in cardiac surgery. Neth Heart J 2012;20: 202–7. 20. Dagenais F, Mathieu P. Rescue therapy with methylene blue in systemic inflammatory response syndrome after cardiac surgery. Can J Cardiol 2003;19:167–9. 21. Leite EG, Ronald A, Rodrigues AJ, Evora PRB. Is methylene blue of benefit in treating adult patients who develop catecholamine-resistant vasoplegic syndrome during cardiac surgery? Interact Cardiovasc Thorac Surg 2006;5: 774–8. 22. Colson PH, Bernard C, Struck J, Morgenthaler NG, Albat B, Guillon G. Post cardiac surgery vasoplegia is associated with high preoperative copeptin plasma concentration. Crit Care 2011;15:R255. 23. Raja SG, Fida N. Should angiotensin converting enzyme inhibitors/angiotensin II receptor antagonists be omitted before cardiac surgery to avoid postoperative vasodilation? Interact Cardiovasc Thorac Surg 2008;7:470–5. 24. Kortekaas KA, Lindeman JH, Reinders ME, et al. Pre-existing endothelial cell activation predicts vasoplegia after mitral valve surgery. Interact Cardiovasc Thorac Surg 2013;17: 523–30. 25. Kofidis T, Struber M, Wilhelmi M, et al. Reversal of severe vasoplegia with single-dose methylene blue after heart transplantation. J Thorac Cardiovasc Surg 2001;122: 823–4. 26. Michel S, Weis F, Sodian R, et al. Use of methylene blue in the treatment of refractory vasodilatory shock after cardiac assist device implantation: report of four consecutive cases. J Clin Med Res 2012;4:212–5.
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CARDIOTHORACIC ANESTHESIOLOGY: The Annals of Thoracic Surgery CME Program is located online at http://www.annalsthoracicsurgery. org/cme/home. To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal.
Methylene Blue for Vasoplegic Syndrome After Cardiac Operation: Early Administration Improves Survival J. Hunter Mehaffey, MD, Lily E. Johnston, MD, MPH, Robert B. Hawkins, MD, Eric J. Charles, MD, Leora Yarboro, MD, John A. Kern, MD, Gorav Ailawadi, MD, Irving L. Kron, MD, and Ravi K. Ghanta, MD Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia, Charlottesville, Virginia
Background. Vasoplegic syndrome, defined by hypotension despite normal or increased cardiac output, is associated with high mortality rate after cardiopulmonary bypass. Methylene blue (MB) is reported to ameliorate vasoplegic syndrome through the nitric oxide pathway. We hypothesized that early administration of MB would improve outcomes in patients with vasoplegic syndrome after cardiopulmonary bypass. Methods. All patients that underwent cardiopulmonary bypass at our institution (Jan 1, 2011 to Jun 30, 2016) were identified through our Society of Thoracic Surgery database. Pharmacy records identified patients receiving MB within 72 hours of cardiopulmonary bypass. Multivariate logistic regression identified predictors of major adverse events among patients receiving MB. Results. A total of 118 cardiopulmonary bypass patients (3.3%) received MB for vasoplegic syndrome. These patients had a higher incidence of comorbidities, and these cases were more commonly reoperative (76.1%
versus 41.2%, p < 0.0001) and complex (70.3% versus 31.8%, p < 0.0001). The only difference in preoperative medications was that MB patients had a higher rate of amiodarone use (15.3% versus 2.2%, p < 0.0001). MB patients had significantly higher rates of postoperative complications, except atrial fibrillation. Early (operating room, 40.7%) versus late (intensive care unit, 59.3%) administration of MB was associated with significantly reduced operative mortality rate (10.4% versus 28.6%, p [ 0.018) and risk-adjusted major adverse events (odd ratio 0.35, p [ 0.037). Conclusions. Operative mortality rate is high in patients receiving MB for the treatment of vasoplegia after cardiopulmonary bypass. Early administration of MB improves survival and reduces the risk-adjusted rate of major adverse events in these patients.
O
release and increased systemic vascular resistance (SVR) [9]. There have been a number of retrospective studies that examined the use of this drug in the treatment of vasoplegic syndrome with mixed results regarding efficacy [6, 10, 11]. Two prospective, randomized trials evaluated MB administration at the onset of CPB in 30 and 100 patients with risk factors for vasoplegic syndrome and demonstrated safety in the CPB population [12, 13]. Despite promising results, significant criticism has focused on the fact that neither trial selected for patients with the clinical diagnosis of vasoplegic syndrome. In addition, several animal studies evaluated MB’s mechanism of action and biochemical pathways for resolution of vasoplegia. These studies demonstrated a time-dependent decrease in NO synthase production, improved microvascular function, and decreased transendothelial inflammatory cell migration [14–17]. Currently, MB does not have any US Food and Drug Administration (FDA) approved indications, but it is most commonly used for treatment of methemoglobinemia. The purpose of this study is to determine the incidence of CPB-induced vasoplegic syndrome and to describe
ver the past 20 years, there has been an increase in the incidence of vasoplegic syndrome, which affects more than 5% of patients undergoing cardiopulmonary bypass (CPB) and is associated with a mortality rate approaching 25% [1–3]. Standard treatment options for severe refractory vasoplegic syndrome are extremely limited and include vasopressor support and systemic corticosteroids [3–5]. With the increasing incidence of vasoplegic syndrome, the use of alternative treatment options such as methylene blue (MB) has also increased. MB has demonstrated beneficial effects on the severe vasodilation associated with vasoplegic syndrome [6–8]. MB is a potent inhibitor of nitric oxide (NO) synthase in vascular endothelial cells, resulting in decreased NO
Accepted for publication Feb 16, 2017. Presented at the Poster Session of the Fifty-third Annual Meeting of The Society of Thoracic Surgeons, Houston TX, Jan 21–25, 2017. Address correspondence to Dr Mehaffey, Department of Surgery, University of Virginia School of Medicine, PO Box 800300, Charlottesville, VA 22908; email: [email protected].
Ó 2017 by The Society of Thoracic Surgeons Published by Elsevier Inc.
(Ann Thorac Surg 2017;104:36–41) Ó 2017 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2017.02.057
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MEHAFFEY ET AL METHYLENE BLUE FOR VASOPLEGIA
Statistical Methods Abbreviations and Acronyms ACE CI CPB FDA MAE MB NO STS SVR
= = = = = = = = =
angiotensin-converting enzyme cardiac index cardiopulmonary bypass Food and Drug Administration major adverse event methylene blue nitric oxide Society of Thoracic Surgeons systemic vascular resistance
contemporary practice patterns of MB use at an academic cardiac surgical center. We hypothesized that early administration of MB would reduce the risk of adverse outcome in patients with vasoplegic syndrome.
Patients and Methods Patients This study was approved the University of Virginia Institutional Review Board with waiver of informed consent (protocol 19247). All patients receiving MB within 72 hours of CPB at our institution between January 2011 and March 2016 were identified. Our Society of Thoracic Surgeons (STS) database prospectively collects preoperative characteristics, intraoperative details, and postoperative outcomes through 30 days for all patients undergoing cardiac operation at our institution. These records were linked with all episodes of MB administration recorded in our institutional pharmacy database. In addition, the Clinical Data Repository was queried which includes laboratory values, cost data, and detailed hemodynamic data for all inpatient hospitalizations. Finally, long-term survival data were collected from the Social Security Death Master File.
Post-CPB Vasoplegia University of Virginia MB Protocol Since 2011, the Division of Thoracic and Cardiovascular Surgery at our institution has used a consensus approach to the management of post-CPB vasoplegic syndrome. Diagnosis includes vasodilation characterized by low SVR with elevated cardiac index (CI) resulting in hypotension despite high doses of vasopressors on pump or postoperatively. Standard vasopressor support is used with a preference for vasopressin and norepinephrine to combat vasodilation with phenylephrine used as a second-line therapy. Given the common hyperdynamic cardiac function during vasoplegic syndrome with CIs typically greater than 4.0 L/min/m2, epinephrine is used sparingly. In addition, after clinical diagnosis of vasoplegic syndrome, patients receive stress-dose steroids, diphenhydramine, and famotidine to target the systemic inflammatory response. Our MB administration protocol for patients with refractory vasoplegic syndrome was a bolus dose of 2 mg/kg intravenous MB followed by 12hour infusion at 0.5 mg/kg/h. This protocol was in place for all patients during the study period.
The primary outcome was major adverse event (MAE) after administration of MB for vasoplegic syndrome. MAEs included the STS major morbidities (permanent stroke, renal failure, reoperation, deep sternal wound infection, and prolonged ventilation) as well as operative mortality (in-hospital or 30-day). Standard STS definitions were used for all variables, including new onset renal failure and prolonged ventilation (>24 hours). In addition, preoperative and intraoperative variables associated with MB treatment for vasoplegic syndrome were assessed. Early administration was defined as operating room, and patients not receiving MB until reaching the postoperative intensive care unit were classified as late administration. Univariate analysis was performed using c2 and Mann-Whitney U tests for categorical and continuous variables, respectively. Multivariable logistic regression was used to identify risk-adjusted predictors of MAEs in patients receiving MB for vasoplegic syndrome. SAS version 9.4 (SAS Institute, Cary, NC) statistical software was used for analysis with a statistical threshold for significance set at 0.05.
Results Vasoplegic Population A total of 3,608 patients underwent CPB during the study period, of whom 118 (3.3%) received MB for the treatment Table 1. Characteristics of Patients Receiving MB for Vasoplegic Syndrome Variable
MB
No MB
Number of patients 118 (3.3) Isolated coronary artery 35 (29.6) bypass or valve Ventricular assist device 40 (33.9) Prior ventricular assist 32 (27.1) device Age, years 63 [58, 71] Male sex 81 (69.2) Tobacco use 46 (39.3) Heart failure diagnosis 88 (74.6) Dialysis-dependent renal 7 (6.9) failure Diabetes mellitus 46 (39.0) Severe chronic lung disease 10 (8.6) Hypertension 77 (65.8) Ejection fraction, % 42 [20, 58] Preoperative amiodarone 18 (15.3) therapy ACE inhibitor within 48 13 (11.0) hours Prior cardiac operation 89 (76.1) Cross-clamp time, minutes 100 [79, 126] a
p Value
3490 (96.7) . 2381 (68.2) <0.0001a 130 (3.7) 28 (0.1)
<0.0001a <0.0001a
67 [57, 75] 0.031a 2334 (67.7) 0.720 785 (22.8) <0.0001a 1740 (49.9) <0.0001a 94 (2.6) 0.036a 3488 (36.5) 0.586 143 (4.1) 0.008a 2646 (76.7) 0.007a 57 [45, 63] <0.0001a 78 (2.2) <0.0001a 398 (11.4)
0.896
1435 (41.2) <0.0001a 75 [58, 96] <0.0001a
Significantly different.
Values are n (%) or median [interquartile range]. ACE ¼ angiotensin-converting enzyme;
MB ¼ methylene blue.
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Table 2. Outcomes for Patients Receiving MB for Vasoplegic Syndrome Variable Postoperative atrial fibrillation Stroke Renal failure Deep sternal wound infection Reoperation Prolonged ventilation Operative mortality Major adverse event composite a
MB 27 6 25 1 31 27 25 55
(22.9) (5.1) (21.2) (0.9) (26.3) (22.9) (21.2) (46.6)
No MB 725 71 151 2 222 232 112 516
(20.8) (2.0) (4.3) (0.1) (6.4) (6.7) (3.2) (14.8)
p Value 0.579 0.025a <0.0001a 0.003a <0.0001a <0.0001a <0.0001a <0.0001a
group had lower rates of tobacco use (29.6% versus 47.6%, p ¼ 0.047), isolated coronary artery bypass graft or valve operation (14.6% versus 42.9%, p ¼ 0.001) and early administration of MB (35.4% versus 64.6%, p ¼ 0.044) but a higher rate of prior cardiac operation (81.5% versus 71.4%, p ¼ 0.02) (Table 5). In addition, preoperative diastolic blood pressure (58 versus 68 mm Hg, p ¼ 0.024) was lower and cross-clamp time (167 versus 147 minutes, p ¼ 0.021) was longer in the MAE group. Multivariate logistic regression demonstrated early administration of MB independently reduces the risk of MAEs in patients with vasoplegic syndrome (odds ratio 0.35, p ¼ 0.037, c-statistic ¼ 0.798) (Table 6).
Significantly different.
Values are n (%). MB ¼ methylene blue.
of vasoplegic syndrome. Patients receiving MB were more likely younger (63 versus 67 years, p ¼ 0.031) and had higher rates of medical comorbidities, especially heart failure (74.6% versus 49.4%, p < 0.0001) (Table 1). Preoperative amiodarone use was higher (15.3% versus 2.2%, p < 0.0001), with no difference in angiotensin-converting enzyme (ACE) inhibitor use within 48 hours of operation (11.0% versus 11.4%, p ¼ 0.896). Patients receiving MB for vasoplegic syndrome had significantly higher rates of all STS major morbidities and operative mortality (Table 2).
MB Outcomes After MB administration, patients with vasoplegic syndrome demonstrated improvement in mean arterial pressure in addition to gradual increases in SVR and decreases in CI (Fig 1). In addition, patients demonstrated a gradual reduction in vasopressor requirements (Fig 2). When stratified by early (operating room) versus late (intensive care unit) administration of MB, patients demonstrated reduced renal failure (10.4% versus 28.6%, p ¼ 0.018) and reduced operative mortality rate (10.4% versus 28.6%, p ¼ 0.018) with early administration (Tables 3 and 4).
Major Adverse Events A total of 46.6% (55 of 118) of patients receiving MB for vasoplegic syndrome experienced a MAE. The MAE
Comment Vasoplegic syndrome after CPB is a growing problem because cardiac operation case complexity increases and continuous flow mechanical circulatory support devices are used more frequently. In the present study, 3.3% of patients at a quaternary care academic medical center received MB for the treatment of severe refractory vasoplegia. These patients had significantly worse outcomes, including higher rates of STS major morbidities and operative mortality. Specific predictors for development of vasoplegic syndrome are limited and related to case complexity and comorbidities [1, 3, 18, 19]. A standardized approach to the treatment of severe vasoplegic syndrome resulted in an operative mortality rate of 21.2% compared with rates as high as 44% previously reported [10, 20, 21]. This study demonstrated that MB administration for treatment of vasoplegic syndrome results in an improvement in mean arterial pressure, with a compensatory increase in SVR and decrease in CI, coinciding with a reduction in vasopressor requirements. In addition to confirming MB improves vasoplegia, we validate that early administration of MB in the operating room at first signs of vasoplegic syndrome provide better outcomes and improved survival. Surprisingly, the previously reported link between ACE inhibitors and vasoplegic syndrome was not identified in this study. These findings can likely be attributed to the low rate of ACE inhibitor use within 48 hours of operation (11%), due to increased vigilance ensuring
Fig 1. Hemodynamic response (mean arterial pressure, cardiac index, and systemic vascular resistance) after methylene blue administration. Graphs are means and 95% confidence intervals.
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MEHAFFEY ET AL METHYLENE BLUE FOR VASOPLEGIA
Fig 2. Vasopressor requirements (epinephrine and norepinephrine) after methylene blue administration. Graphs are means and 95% confidence intervals.
patients hold this medication because it is a known risk factor [5, 13, 22, 23]. However, preoperative amiodarone therapy was significantly higher in the MB group than the standard population. Given the retrospective nature of this study, it is impossible to ascertain if this is an association or causation, because patients requiring preoperative amiodarone are likely higher surgical risk. In light of the increasing use of amiodarone and the growing prevalence of vasoplegic syndrome, further investigation is warranted in a prospective manner. Prior heart failure and ejection fraction were also important patient level factors associated with higher rates of MB treatment for vasoplegic syndrome, which have been previously described [3, 19]. The composite MAE was used to identify risk factors for poor outcomes after MB administration for vasoplegic syndrome. Univariate analysis demonstrated six variables Table 3. Characteristics of Early Versus Late Administration of MB for Vasoplegic Syndrome Variable
Early
Late
Number of patients 48 (40.7) 70 (59.3) Isolated coronary artery 20 (28.6) 15 (31.3) bypass or valve Ventricular assist device 23 (32.9) 17 (35.4) Age, years 64 [60, 73] 63 [56, 70] Male sex 34 (70.8) 47 (68.1) Tobacco use 16 (33.3) 30 (43.5) Heart failure 34 (70.8) 54 (77.1) End-stage renal disease 4 (8.3) 3 (4.3) Diabetes mellitus 20 (17.0) 26 (37.1) Severe chronic lung disease 2 (4.2) 8 (11.6) Hypertension 36 (75.0) 41 (59.4) Ejection fraction, % 41 [18, 58] 42 [23, 59] Preoperative amiodarone 4 (8.3) 14 (20.0) therapy ACE inhibitor within 48 3 (6.3) 10 (14.3) hours Prior cardiac operation 41 (85.4) 48 (69.6) Cross-clamp time, minutes 100 [86, 118] 102 [75, 134] a
p Value . 0.754 0.773 0.305 0.754 0.269 0.439 0.361 0.621 0.304 0.081 0.787 0.083 0.171 0.048a 0.848
associated with MAEs, including markers of case complexity, such as prior cardiac operation, cross-clamp time, and procedure performed, as well as patientspecific factors such as tobacco use and preoperative diastolic blood pressure. The timing of MB administration was also significant, with patients receiving the medication in the operating room having a reduced rate of MAEs compared with receiving it in the intensive care unit despite no major baseline differences. On multivariate regression, tobacco use was independently associated with reduced rates of MAEs, suggesting a potential reversible cause of vasoplegic syndrome through the NO pathway, which is affected by MB treatment. Tobacco use may cause endothelial cell activation, which predisposes patients to vasoplegic syndrome that is attenuated though the MB pathway [24]. In addition, isolated coronary artery bypass graft or valve operations reduced risk-adjusted odds of MAEs, highlighting case complexity as a predictor of poor outcomes. This was particularly pronounced in the population undergoing ventricular assist device placement, especially in patients with prior continuous flow ventricular assist devices, or heart transplantations, which has been well described in the published studies [25, 26]. Table 4. Outcomes of Early Versus Late Administration of MB for Vasoplegic Syndrome Variable
p Value 0.554 0.170 0.447 0.178 0.863 0.707 0.018a 0.266 0.219 0.994 0.062 0.018a
Significantly different.
Values are n (%) or median [interquartile range].
Values are n (%) or median [interquartile range].
ACE ¼ angiotensin-converting enzyme;
MB ¼ methylene blue;
MB ¼ methylene blue.
Late
Postoperative adverse event 34 (70.8) 53 (75.7) Blood transfusion 44 (91.7) 58 (82.9) Length of stay, days 12 [10, 18.5] 12 [6, 21] Postoperative atrial fibrillation 14 (29.2) 13 (18.6) Postoperative cardiac arrest 5 (10.4) 8 (11.4) Stroke 2 (4.2) 4 (5.7) Renal failure 5 (10.4) 20 (28.6) Reoperation 10 (20.8) 21 (30.0) Deep sternal wound infection 1 (2.2) 0 (0.00) Prolonged ventilation 11 (22.9) 16 (22.9) STS major morbidity 17 (35.4) 37 (52.9) 30-Day mortality 5 (10.4) 20 (28.6) a
Significantly different.
Early
STS ¼ The Society of Thoracic Surgeons.
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Table 5. Baseline Characteristics for MB Patients Experiencing a MAE Variable Cases Male sex Age, years Heart failure Hypertension Dialysis Diabetes Severe lung disease Prior cardiac operation Tobacco use Preoperative amiodarone therapy ACE inhibitor within 48 hours Preoperative diastolic blood pressure, mm Hg Initial postoperative white blood cell count, 109/L Isolated CABG/valve operation Cross-clamp time, minutes Early MB administration a
MAE
No MAE
p Value
25 (21.2) 37 (68.5) 61 [56, 70] 45 (81.8) 36 (66.7) 3 (5.45) 21 (38.2) 4 (7.4) 44 (81.5) 16 (29.6) 7 (12.7) 7 (12.7) 58 [43, 68] 17.5 [13.5, 26.0] 8 (14.6) 167 [125, 234] 17 (35.4)
93 (78.8) 44 (69.8) 64 [59, 73] 43 (68.3) 41 (65.1) 4 (6.4) 25 (39.7) 6 (9.5) 45 (71.4) 30 (47.6) 11 (17.5) 6 (9.5) 68 [52, 84] 16.2 [13.0, 21.8] 27 (42.9) 147 [118, 190] 31 (64.6)
. 0.877 0.280 0.291 0.857 0.837 0.868 0.912 0.204 0.047a 0.476 0.579 0.024a 0.582 0.001a 0.021a 0.044a
Significantly different.
Values are n (%) or median [interquartile range]. ACE ¼ angiotensin-converting enzyme;
CABG ¼ coronary artery bypass graft;
Early administration of MB resulted in reduced incidence of postoperative renal failure and operative mortality. This benefit is likely because of early attenuation of the NO-induced vasodilation cascade, which reduces the severe systemic inflammatory response [15, 20]. Multivariate regression confirmed early MB administration as an independent predictor of reduced risk-adjusted MAEs. These results highlight the importance of early recognition and treatment of vasoplegic syndrome. A standardized treatment protocol as described above is a critical step in improving outcomes in these patients with a high risk of morbidity and mortality. This study is limited by the retrospective single-center nature of the data available for analysis. However, this design allowed for increased granularity of patientspecific data, including hourly hemodynamic and Table 6. Predictors of Major Adverse Events Variable
Odds Ratio p (95% Confidence Interval) Value
Tobacco use Early MB administration Isolated CABG/valve operation Cross-clamp time Preoperative diastolic blood pressure Prior cardiac operation a
0.26 (0.087–0.771) 0.35 (0.127–0.936) 0.29 (0.095–0.855)
0.015a 0.037a 0.025a
1.01 (0.999–1.022) 1.00 (0.981–1.022)
0.077 0.904
2.89 (0.968–8.635)
0.057
MAE ¼ major adverse event;
MB ¼ methylene blue.
vasopressor dosages. In addition, vasoplegic syndrome is an often mentioned but poorly described disease process in published reports, characterized by low SVR and high CI with no widely accepted cutoffs. As such, we used administration of MB as a marker of severe refractory vasoplegic syndrome, which limits the availability of a true control group. We were unable to identify any patients at our institution having vasoplegic syndrome who did not receive MB. However, given practice patterns and current vasoplegic syndrome protocols, all patients in the past 5 years with severe vasoplegic syndrome received MB and were captured for analysis. For this reason, we did not seek to identify predictors of vasoplegic syndrome after CBP as others have done. Instead, we focused on predictors of favorable response to MB to identify patients most likely to benefit from receiving this non–FDAapproved drug. Finally, timing of MB administration was at the discretion of the attending surgeon, and patients receiving the therapy in the operating room represent a more aggressive treatment. In conclusion, early administration of MB improves survival and reduces the risk of MAEs in patients with CPB-induced vasoplegic syndrome. These patients have a high mortality rate that may be improved with standardized protocols that encourage MB initiation at the first signs of vasoplegic syndrome. Currently, MB is not FDA approved and is administered off-label to treat this life-threatening condition. These results support the need for a prospective study and further investigation into the use of MB for vasoplegic syndrome.
Significantly different.
C-statistic ¼ 0.798. CABG ¼ coronary artery bypass graft;
MB ¼ methylene blue.
Methylene blue is not FDA approved for the treatment of vasoplegic syndrome in patients after cardiopulmonary bypass. The National Heart, Lung, and Blood Institute of the National
Institutes of Health under Award Number T32HL007849 supported research reported in this publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
References 1. Byrne JG, Leacche M, Paul S, et al. Risk factors and outcomes for ’vasoplegia syndrome’ following cardiac transplantation. Eur J Cardiothorac Surg 2004;25:327–32. 2. Cremer J, Martin M, Redl H, et al. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg 1996;61:1714–20. 3. Fischer GW, Levin MA. Vasoplegia during cardiac surgery: current concepts and management. Semin Thorac Cardiovasc Surg 2010;22:140–4. 4. Levin MA, Lin HM, Castillo JG, Adams DH, Reich DL, Fischer GW. Early on-cardiopulmonary bypass hypotension and other factors associated with vasoplegic syndrome. Circulation 2009;120:1664–71. 5. Mekontso-Dessap A, Houel R, Soustelle C, Kirsch M, Thebert D, Loisance DY. Risk factors for postcardiopulmonary bypass vasoplegia in patients with preserved left ventricular function. Ann Thorac Surg 2001;71: 1428–32. 6. Evora PR, Jose Rodrigues A, Celotto AC. “Methylene blue should be relegated to rescue use and not as first-line therapy” cannot become a paradigm. J Cardiothorac Vasc Anesth 2014;28:e11–2. 7. Evora PR, Levin RL. Methylene blue as drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass. J Thorac Cardiovasc Surg 2004;127:895–6; author reply 896. 8. Evora PR, Ribeiro PJ, Vicente WV, et al. Methylene blue for vasoplegic syndrome treatment in heart surgery: fifteen years of questions, answers, doubts and certainties. Rev Bras Cir Cardiovasc 2009;24:279–88. 9. Omar S, Zedan A, Nugent K. Cardiac vasoplegia syndrome: pathophysiology, risk factors and treatment. Am J Med Sci 2015;349:80–8. 10. Weiner MM, Lin HM, Danforth D, Rao S, Hosseinian L, Fischer GW. Methylene blue is associated with poor outcomes in vasoplegic shock. J Cardiothorac Vasc Anesth 2013;27:1233–8. 11. Riha H, Augoustides JG. Pro: methylene blue as a rescue therapy for vasoplegia after cardiac surgery. J Cardiothorac Vasc Anesth 2011;25:736–8. 12. Ozal E, Kuralay E, Yildirim V, et al. Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg 2005;79: 1615–9.
MEHAFFEY ET AL METHYLENE BLUE FOR VASOPLEGIA
41
13. Maslow AD, Stearns G, Butala P, Schwartz CS, Gough J, Singh AK. The hemodynamic effects of methylene blue when administered at the onset of cardiopulmonary bypass. Anesth Analg 2006;103:2–8; table of contents. 14. Nantais J, Dumbarton TC, Farah N, et al. Impact of methylene blue in addition to norepinephrine on the intestinal microcirculation in experimental septic shock. Clin Hemorheol Microcirc 2014;58:97–105. 15. Werner I, Guo F, Bogert NV, et al. Methylene blue modulates transendothelial migration of peripheral blood cells. PLoS One 2013;8:e82214. 16. Menardi AC, Viaro F, Vicente WV, Rodrigues AJ, Evora PR. Hemodynamic and vascular endothelium function studies in healthy pigs after intravenous bolus infusion of methylene blue. Arq Bras Cardiol 2006;87: 525–32. 17. Siriwardena DK, Tagori H, Thiemermann C. Nitric oxide synthase inhibitors. Methods Mol Med 2000;36:115–31. 18. Alfirevic A, Xu M, Johnston D, Figueroa P, Koch CG. Transfusion increases the risk for vasoplegia after cardiac operations. Ann Thorac Surg 2011;92:812–9. 19. Kortekaas KA, Lindeman JH, Versteegh MI, Stijnen T, Dion RA, Klautz RJ. Preexisting heart failure is an underestimated risk factor in cardiac surgery. Neth Heart J 2012;20: 202–7. 20. Dagenais F, Mathieu P. Rescue therapy with methylene blue in systemic inflammatory response syndrome after cardiac surgery. Can J Cardiol 2003;19:167–9. 21. Leite EG, Ronald A, Rodrigues AJ, Evora PRB. Is methylene blue of benefit in treating adult patients who develop catecholamine-resistant vasoplegic syndrome during cardiac surgery? Interact Cardiovasc Thorac Surg 2006;5: 774–8. 22. Colson PH, Bernard C, Struck J, Morgenthaler NG, Albat B, Guillon G. Post cardiac surgery vasoplegia is associated with high preoperative copeptin plasma concentration. Crit Care 2011;15:R255. 23. Raja SG, Fida N. Should angiotensin converting enzyme inhibitors/angiotensin II receptor antagonists be omitted before cardiac surgery to avoid postoperative vasodilation? Interact Cardiovasc Thorac Surg 2008;7:470–5. 24. Kortekaas KA, Lindeman JH, Reinders ME, et al. Pre-existing endothelial cell activation predicts vasoplegia after mitral valve surgery. Interact Cardiovasc Thorac Surg 2013;17: 523–30. 25. Kofidis T, Struber M, Wilhelmi M, et al. Reversal of severe vasoplegia with single-dose methylene blue after heart transplantation. J Thorac Cardiovasc Surg 2001;122: 823–4. 26. Michel S, Weis F, Sodian R, et al. Use of methylene blue in the treatment of refractory vasodilatory shock after cardiac assist device implantation: report of four consecutive cases. J Clin Med Res 2012;4:212–5.
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