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Adjuvant Therapy With Methylene Blue in the Treatment of Postoperative Vasoplegic Syndrome Caused by Carcinoid Crisis After Tricuspid Valve Replacement
CASE REPORTS Adjuvant Therapy With Methylene Blue in the Treatment of Postoperative Vasoplegic Syndrome Caused by Carcinoid Crisis After Tricuspid Valve Replacement Jayashree K. Raikhelkar, MD,*† Aaron J. Weiss, BA,† Laurie Maysick, DO,* and Corey Scurlock, MD, MBA*†
A
N INCREASING BODY of literature continues to show the benefits of methylene blue in cases of refractory hypotension caused by the systemic inflammatory response syndrome (SIRS), septic shock, or vasoplegic syndrome.1,2 Methylene blue, by its indirect inhibition of bradykinin, may alleviate the hypotension associated with carcinoid crisis. The authors report the successful use of methylene blue to treat refractory hypotension in a patient with carcinoid syndrome who underwent a tricuspid valve replacement. CASE PRESENTATION A 74-year-old man was referred for tricuspid valve surgery after being diagnosed with tricuspid insufficiency as a result of carcinoid syndrome. His past medical history was significant for small intestinal carcinoid tumor resection 5 years prior and radiation for liver metastases secondary to carcinoid. His medications included octreotide (200 g subcutaneously, 3 times a day), tamsulosin, folic acid, furosemide, mometasone, and psyllium. His body mass index was 23 kg/m2. A transthoracic echocardiogram performed before surgery revealed severe tricuspid regurgitation, normal biventricular function, the absence of pulmonary hypertension, and thickening of the tricuspid valve leaflets. Before surgery, the patient had been experiencing New York Heart Association class IV symptoms. In addition, he also had complained of flushing and diarrhea over the past 4 months that were being controlled with octreotide. The patient was admitted to the hospital 2 days before surgery and was placed on 300 g of octreotide subcutaneously 3 times a day. On the day of the surgery, he was given his regular 300-g subcutaneous dose of octreotide followed by a 500-g dose subcutaneously 3 hours later. This was all done in an effort to reduce his risk of perioperative carcinoid crisis. The patient was taken to the operating room where general anesthesia was induced, and he was intubated without difficulty. On induction of anesthesia, an octreotride infusion was begun at 100 g/h. He also was given 11 g of the antifibrinolytic -aminocaproic acid during the case. On insertion of his pulmonary artery catheter, he had a baseline central venous pressure (CVP) of 20 mmHg and pulmonary artery pressures (PAP) of approximately 35/18 mmHg. An intraoperative tranesophageal echocardiogram (TEE) was performed that agreed with his preoperative echocardiographic findings. A median sternotomy was performed, and the patient was anticoagulated with 31,000 U of heparin and placed on cardiopulmonary bypass. A tricuspid valve replacement was performed through a right atriotomy. After bypass, the CVP was noted to be 22 mmHg, with PAPs of approxi-
From the Departments of *Anesthesia and †Cardiothoracic Surgery, Mount Sinai School of Medicine, New York, NY. Address reprint requests to Corey Scurlock, MD, MBA, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1010, New York, NY 10029. E-mail: [email protected] © 2012 Elsevier Inc. All rights reserved. 1053-0770/2605-0021$36.00/0 doi:10.1053/j.jvca.2011.03.180 Key words: methylene blue, vasoplegic shock, carcinoid crisis 878
mately 35/15 mmHg and systemic blood pressures of approximately 90/60 mmHg. The patient then was started on 100 ng/kg/min of epinephrine (7.7 g/min) and 150 ng/kg/min of norepinephrine (11.5 g/min), and his octreotide infusion was continued at 100 g/h. This resulted in a successful wean from cardiopulmonary bypass. To reverse his anticoagulation, 200 mg of protamine were given over 30 minutes. In the immediate post-bypass period, his CVP lowered to 18 mmHg, and his systemic mean blood pressure was maintained at 65 mmHg with this regimen. His TEE again showed normal ventricular function with minimal tricuspid regurgitation. The chest was closed without difficulty, and the patient was transferred to the intensive care unit (ICU). After admission to the ICU, the patient became progressively hypotensive with mean arterial pressures of approximately 60 mmHg despite the addition of 2.4 U/h of vasopressin. His arterial lactate levels continued to climb, and the dosage of norepinephrine had to be increased to maintain perfusion pressure. During this time, multiple boluses of crystalloid and colloids (approximately 2 L of fluid) were given in addition to boluses of octreotide in an effort to alleviate his hypotension. Despite this, he remained vasoplegic and was unable to wean from vasopressors. Five hours after surgery, his pulmonary artery catheter data were notable for a CVP of approximately 20 mmHg and PAP of approximately 33/20. A loading dose of methylene blue was given (2 mg/kg over 30 minutes) followed by a maintenance infusion rate of 0.5 mg/kg/h for 6 hours as has been reported in the literature (Fig 1).3 During the infusion of methylene blue, his norepinephrine and vasopressin infusions were able to be discontinued. There was also a concomitant and noticeable decrease in arterial lactate (from 4.5 U/L to 3.8 U/L) and a reduction in acidosis to a pH of 7.38. Over the next few hours, the epinephrine infusion was able to be discontinued, and he was able to tolerate the vasodilatory effects of milrinone at 0.25 g/kg/min. Throughout this time, he remained on the octreotide infusion and was hemodynamically stable throughout the rest of his ICU stay. The patient was extubated on postoperative day 2 and transferred to the cardiac step-down unit on postoperative day 5, where he was converted to subcutaneous octreotide at a dose of 250 g 3 times a day. The remainder of his postoperative course was notable for a number of genitourinary problems related to his Foley catheter. He was discharged from the hospital to a subacute rehabilitation facility on postoperative day 22 without any further hemodynamic complications. DISCUSSION
Although relatively rare, carcinoid crisis is a major concern in patients with carcinoid syndrome who are having surgery. In addition to facial flushing and bronchospasm, a common manifestation of carcinoid crisis is hemodynamic instability, ranging from severe hypotension to hypertensive crisis, depending on the location of the tumor, the secretory products produced, the receptors that bind the products, and the resting vascular tone of the individual patient.4 Carcinoid tumors produce a wide range of physiologically active molecules including histamine, 5-hydroxytryptamine (serotonin), and 5-hydroxytryptophan. Serotonin has both vasodilatory and vasoconstrictive properties depending on the specific receptor it binds. Addi-
Journal of Cardiothoracic and Vascular Anesthesia, Vol 26, No 5 (October), 2012: pp 878-879
ADJUVANT THERAPY IN METHYLENE BLUE
"Norepinephrine ng/kg/min
879
Vasopressin u/hr
300 250 200 150
Methylene Blue
100 50 0 1
3
5
7
9
11 13 15 17 Time (hours)
19
21
23
Fig 1. Norepinephrine and vasopressin requirements during methylene blue administration. (Color version of figure is available online.)
tionally, it works indirectly to potentiate the actions of histamines, norepinephrine, and angiotensin II.4 Carcinoid tumors also produce kallikreins,5 which enzymatically modify kininogen to bradykinin. Excess levels of bradykinin result in increased capillary permeability, vasodilation, edema, and hypotension.5-7 Thus, the hypotensive carcinoid crisis is thought to be precipitated mainly by the increased amount of bradykinin. To prevent the development of carcinoid crisis in patients undergoing surgery, intravenous or subcutaneous somatostatin analogs such as octreotide are given during the perioperative period. In addition to their usual dose of octreotide, patients can be started on a continuous infusion of 100 g/h preoperatively and intraoperatively to prevent and ameliorate crisis. If additional octreotide is needed, boluses of 25 to 100 g can be given to help quell crises.8 Traditionally, the use of catecholamines in carcinoid crisis has been contraindicated because cat-
echolamines can trigger the release of kallikrein and can increase bradykinin levels, which then may potentiate hypotension.9-11 However, Castillo et al12 showed that in 7 patients receiving direct adrenergic agonists no additional requirements of octreotide were required. Clearly, larger studies are needed to elicit the effects of these medications in the setting of carcinoid syndrome and carcinoid crisis during cardiac surgery. Vasoplegic syndrome occurs in 8% to 10% of patients after cardiac surgery.3 The pathophysiology behind the refractory vasoplegia is multifactorial and includes increased cyclic guanosine monophosphate (cGMP), vasopressin deficiency, and excessive nitric oxide production. Methylene blue, a competitive inhibitor of inducible nitric oxide synthase, has been used in postoperative patients to help improve mean arterial pressure and systemic vascular resistance.1,13-15 By inhibiting the production of nitric oxide, the production of cGMP is suppressed, preventing vascular smooth muscle relaxation. Additionally, the production of bradykinin, a known inducer of nitric oxide from kallikrein, may also induce hypotension as seen in the present patient. Therefore, the authors postulated that the administration of methylene blue in patients with vasoplegic syndrome caused by carcinoid crisis refractory to octreotide would prove beneficial. Within 6 hours of administering the methylene blue, the patient was able to be weaned from all vasopressors and was hemodynamically stable. Early intervention in patients with catecholamine-refractory vasoplegic syndrome is paramount because mortality rates still remain high.13,16 Furthermore, methylene blue may be a potential alternative to escalating catecholamine dosages that are needed to maintain mean arterial pressure, thus bypassing the adrenergic system in this select group of patients. CONCLUSION
The authors present the 1st published case of the use of methylene blue as an adjuvant in the management of vasoplegic syndrome induced by carcinoid crisis after tricuspid valve replacement. The addition of methylene blue may provide prompt reversal of refractory vasoplegia in this patient population.
REFERENCES 1. Leyh RG, Kofidis T, Struber M, et al: Methylene blue: The drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass? J Thorac Cardiovasc Surg 125:1426-1431, 2003 2. Friedrich M, Brauer A, Tirilomis T, et al: Methylene blue administration in severe systemic inflammatory response syndrome (SIRS) after thoracic surgery. Ann Thorac Cardiovasc Surg 8:306-310, 2010 3. Shanmugam G: Vasoplegic syndrome—The role of methylene blue. Eur J Cardiothorac Surg 28:705-710, 2005 4. Anderson AS, Krauss D, Lang R: Cardiovascular complications of malignant carcinoid disease. Am Heart J 134:693-702, 1997 5. Oates JA, Melmon K, Sjoerdsma A, et al: Release of a kinin peptide in the carcinoid syndrome. Lancet 1:514-517, 1964 6. Gustafsen J, Boesby S, Nielsen F, et al: Bradykinin in carcinoid syndrome. Gut 28:1417-1419, 1987 7. Lucas KJ, Feldman JM: Flushing in the carcinoid syndrome and plasma kallikrein. Cancer 58:2290-2293, 1986 8. Dierdorf SF: Carcinoid tumor and carcinoid syndrome. Curr Opin Anaesthesiol 16:343-347, 2003 9. Adamson AR, Grahame-Smith DG, Peart WS, et al: Pharmacological blockade of carcinoid flushing provoked by catecholamines and alcohol. Lancet 2:293-297, 1969
10. Levine RJ, Sjoerdsma A: Pressor amines and the carcinoid flush. Ann Intern Med 58:818-828, 1963 11. Peart WS, Robertson JI, Andrews TM: Facial flushing produced in patients with carcinoid syndrome by intravenous adrenaline and noradrenaline. Lancet 2:715-716, 1959 12. Castillo JG, Filsoufi F, Adams DH, et al: Management of patients undergoing multivalvular surgery for carcinoid heart disease: the role of the anaesthetist. Br J Anaesth 101:618-626, 2008 13. Levin RL, Degrange MA, Bruno GF, et al: Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg 77:496-499, 2004 14. Cremer J, Martin M, Redl H, et al: Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg 61:17141720, 1996 15. Mekontso-Dessap A, Houel R, Soustelle C, et al: Risk factors for post-cardiopulmonary bypass vasoplegia in patients with preserved left ventricular function. Ann Thorac Surg 71:1428-1432, 2005 16. Gomes WJ, Carvalho AC, Palma JH, et al: Vasoplegic syndrome after open heart surgery. J Cardiovasc Surg (Torino) 39:619623, 1998
A
N INCREASING BODY of literature continues to show the benefits of methylene blue in cases of refractory hypotension caused by the systemic inflammatory response syndrome (SIRS), septic shock, or vasoplegic syndrome.1,2 Methylene blue, by its indirect inhibition of bradykinin, may alleviate the hypotension associated with carcinoid crisis. The authors report the successful use of methylene blue to treat refractory hypotension in a patient with carcinoid syndrome who underwent a tricuspid valve replacement. CASE PRESENTATION A 74-year-old man was referred for tricuspid valve surgery after being diagnosed with tricuspid insufficiency as a result of carcinoid syndrome. His past medical history was significant for small intestinal carcinoid tumor resection 5 years prior and radiation for liver metastases secondary to carcinoid. His medications included octreotide (200 g subcutaneously, 3 times a day), tamsulosin, folic acid, furosemide, mometasone, and psyllium. His body mass index was 23 kg/m2. A transthoracic echocardiogram performed before surgery revealed severe tricuspid regurgitation, normal biventricular function, the absence of pulmonary hypertension, and thickening of the tricuspid valve leaflets. Before surgery, the patient had been experiencing New York Heart Association class IV symptoms. In addition, he also had complained of flushing and diarrhea over the past 4 months that were being controlled with octreotide. The patient was admitted to the hospital 2 days before surgery and was placed on 300 g of octreotide subcutaneously 3 times a day. On the day of the surgery, he was given his regular 300-g subcutaneous dose of octreotide followed by a 500-g dose subcutaneously 3 hours later. This was all done in an effort to reduce his risk of perioperative carcinoid crisis. The patient was taken to the operating room where general anesthesia was induced, and he was intubated without difficulty. On induction of anesthesia, an octreotride infusion was begun at 100 g/h. He also was given 11 g of the antifibrinolytic -aminocaproic acid during the case. On insertion of his pulmonary artery catheter, he had a baseline central venous pressure (CVP) of 20 mmHg and pulmonary artery pressures (PAP) of approximately 35/18 mmHg. An intraoperative tranesophageal echocardiogram (TEE) was performed that agreed with his preoperative echocardiographic findings. A median sternotomy was performed, and the patient was anticoagulated with 31,000 U of heparin and placed on cardiopulmonary bypass. A tricuspid valve replacement was performed through a right atriotomy. After bypass, the CVP was noted to be 22 mmHg, with PAPs of approxi-
From the Departments of *Anesthesia and †Cardiothoracic Surgery, Mount Sinai School of Medicine, New York, NY. Address reprint requests to Corey Scurlock, MD, MBA, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1010, New York, NY 10029. E-mail: [email protected] © 2012 Elsevier Inc. All rights reserved. 1053-0770/2605-0021$36.00/0 doi:10.1053/j.jvca.2011.03.180 Key words: methylene blue, vasoplegic shock, carcinoid crisis 878
mately 35/15 mmHg and systemic blood pressures of approximately 90/60 mmHg. The patient then was started on 100 ng/kg/min of epinephrine (7.7 g/min) and 150 ng/kg/min of norepinephrine (11.5 g/min), and his octreotide infusion was continued at 100 g/h. This resulted in a successful wean from cardiopulmonary bypass. To reverse his anticoagulation, 200 mg of protamine were given over 30 minutes. In the immediate post-bypass period, his CVP lowered to 18 mmHg, and his systemic mean blood pressure was maintained at 65 mmHg with this regimen. His TEE again showed normal ventricular function with minimal tricuspid regurgitation. The chest was closed without difficulty, and the patient was transferred to the intensive care unit (ICU). After admission to the ICU, the patient became progressively hypotensive with mean arterial pressures of approximately 60 mmHg despite the addition of 2.4 U/h of vasopressin. His arterial lactate levels continued to climb, and the dosage of norepinephrine had to be increased to maintain perfusion pressure. During this time, multiple boluses of crystalloid and colloids (approximately 2 L of fluid) were given in addition to boluses of octreotide in an effort to alleviate his hypotension. Despite this, he remained vasoplegic and was unable to wean from vasopressors. Five hours after surgery, his pulmonary artery catheter data were notable for a CVP of approximately 20 mmHg and PAP of approximately 33/20. A loading dose of methylene blue was given (2 mg/kg over 30 minutes) followed by a maintenance infusion rate of 0.5 mg/kg/h for 6 hours as has been reported in the literature (Fig 1).3 During the infusion of methylene blue, his norepinephrine and vasopressin infusions were able to be discontinued. There was also a concomitant and noticeable decrease in arterial lactate (from 4.5 U/L to 3.8 U/L) and a reduction in acidosis to a pH of 7.38. Over the next few hours, the epinephrine infusion was able to be discontinued, and he was able to tolerate the vasodilatory effects of milrinone at 0.25 g/kg/min. Throughout this time, he remained on the octreotide infusion and was hemodynamically stable throughout the rest of his ICU stay. The patient was extubated on postoperative day 2 and transferred to the cardiac step-down unit on postoperative day 5, where he was converted to subcutaneous octreotide at a dose of 250 g 3 times a day. The remainder of his postoperative course was notable for a number of genitourinary problems related to his Foley catheter. He was discharged from the hospital to a subacute rehabilitation facility on postoperative day 22 without any further hemodynamic complications. DISCUSSION
Although relatively rare, carcinoid crisis is a major concern in patients with carcinoid syndrome who are having surgery. In addition to facial flushing and bronchospasm, a common manifestation of carcinoid crisis is hemodynamic instability, ranging from severe hypotension to hypertensive crisis, depending on the location of the tumor, the secretory products produced, the receptors that bind the products, and the resting vascular tone of the individual patient.4 Carcinoid tumors produce a wide range of physiologically active molecules including histamine, 5-hydroxytryptamine (serotonin), and 5-hydroxytryptophan. Serotonin has both vasodilatory and vasoconstrictive properties depending on the specific receptor it binds. Addi-
Journal of Cardiothoracic and Vascular Anesthesia, Vol 26, No 5 (October), 2012: pp 878-879
ADJUVANT THERAPY IN METHYLENE BLUE
"Norepinephrine ng/kg/min
879
Vasopressin u/hr
300 250 200 150
Methylene Blue
100 50 0 1
3
5
7
9
11 13 15 17 Time (hours)
19
21
23
Fig 1. Norepinephrine and vasopressin requirements during methylene blue administration. (Color version of figure is available online.)
tionally, it works indirectly to potentiate the actions of histamines, norepinephrine, and angiotensin II.4 Carcinoid tumors also produce kallikreins,5 which enzymatically modify kininogen to bradykinin. Excess levels of bradykinin result in increased capillary permeability, vasodilation, edema, and hypotension.5-7 Thus, the hypotensive carcinoid crisis is thought to be precipitated mainly by the increased amount of bradykinin. To prevent the development of carcinoid crisis in patients undergoing surgery, intravenous or subcutaneous somatostatin analogs such as octreotide are given during the perioperative period. In addition to their usual dose of octreotide, patients can be started on a continuous infusion of 100 g/h preoperatively and intraoperatively to prevent and ameliorate crisis. If additional octreotide is needed, boluses of 25 to 100 g can be given to help quell crises.8 Traditionally, the use of catecholamines in carcinoid crisis has been contraindicated because cat-
echolamines can trigger the release of kallikrein and can increase bradykinin levels, which then may potentiate hypotension.9-11 However, Castillo et al12 showed that in 7 patients receiving direct adrenergic agonists no additional requirements of octreotide were required. Clearly, larger studies are needed to elicit the effects of these medications in the setting of carcinoid syndrome and carcinoid crisis during cardiac surgery. Vasoplegic syndrome occurs in 8% to 10% of patients after cardiac surgery.3 The pathophysiology behind the refractory vasoplegia is multifactorial and includes increased cyclic guanosine monophosphate (cGMP), vasopressin deficiency, and excessive nitric oxide production. Methylene blue, a competitive inhibitor of inducible nitric oxide synthase, has been used in postoperative patients to help improve mean arterial pressure and systemic vascular resistance.1,13-15 By inhibiting the production of nitric oxide, the production of cGMP is suppressed, preventing vascular smooth muscle relaxation. Additionally, the production of bradykinin, a known inducer of nitric oxide from kallikrein, may also induce hypotension as seen in the present patient. Therefore, the authors postulated that the administration of methylene blue in patients with vasoplegic syndrome caused by carcinoid crisis refractory to octreotide would prove beneficial. Within 6 hours of administering the methylene blue, the patient was able to be weaned from all vasopressors and was hemodynamically stable. Early intervention in patients with catecholamine-refractory vasoplegic syndrome is paramount because mortality rates still remain high.13,16 Furthermore, methylene blue may be a potential alternative to escalating catecholamine dosages that are needed to maintain mean arterial pressure, thus bypassing the adrenergic system in this select group of patients. CONCLUSION
The authors present the 1st published case of the use of methylene blue as an adjuvant in the management of vasoplegic syndrome induced by carcinoid crisis after tricuspid valve replacement. The addition of methylene blue may provide prompt reversal of refractory vasoplegia in this patient population.
REFERENCES 1. Leyh RG, Kofidis T, Struber M, et al: Methylene blue: The drug of choice for catecholamine-refractory vasoplegia after cardiopulmonary bypass? J Thorac Cardiovasc Surg 125:1426-1431, 2003 2. Friedrich M, Brauer A, Tirilomis T, et al: Methylene blue administration in severe systemic inflammatory response syndrome (SIRS) after thoracic surgery. Ann Thorac Cardiovasc Surg 8:306-310, 2010 3. Shanmugam G: Vasoplegic syndrome—The role of methylene blue. Eur J Cardiothorac Surg 28:705-710, 2005 4. Anderson AS, Krauss D, Lang R: Cardiovascular complications of malignant carcinoid disease. Am Heart J 134:693-702, 1997 5. Oates JA, Melmon K, Sjoerdsma A, et al: Release of a kinin peptide in the carcinoid syndrome. Lancet 1:514-517, 1964 6. Gustafsen J, Boesby S, Nielsen F, et al: Bradykinin in carcinoid syndrome. Gut 28:1417-1419, 1987 7. Lucas KJ, Feldman JM: Flushing in the carcinoid syndrome and plasma kallikrein. Cancer 58:2290-2293, 1986 8. Dierdorf SF: Carcinoid tumor and carcinoid syndrome. Curr Opin Anaesthesiol 16:343-347, 2003 9. Adamson AR, Grahame-Smith DG, Peart WS, et al: Pharmacological blockade of carcinoid flushing provoked by catecholamines and alcohol. Lancet 2:293-297, 1969
10. Levine RJ, Sjoerdsma A: Pressor amines and the carcinoid flush. Ann Intern Med 58:818-828, 1963 11. Peart WS, Robertson JI, Andrews TM: Facial flushing produced in patients with carcinoid syndrome by intravenous adrenaline and noradrenaline. Lancet 2:715-716, 1959 12. Castillo JG, Filsoufi F, Adams DH, et al: Management of patients undergoing multivalvular surgery for carcinoid heart disease: the role of the anaesthetist. Br J Anaesth 101:618-626, 2008 13. Levin RL, Degrange MA, Bruno GF, et al: Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg 77:496-499, 2004 14. Cremer J, Martin M, Redl H, et al: Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg 61:17141720, 1996 15. Mekontso-Dessap A, Houel R, Soustelle C, et al: Risk factors for post-cardiopulmonary bypass vasoplegia in patients with preserved left ventricular function. Ann Thorac Surg 71:1428-1432, 2005 16. Gomes WJ, Carvalho AC, Palma JH, et al: Vasoplegic syndrome after open heart surgery. J Cardiovasc Surg (Torino) 39:619623, 1998