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Pre-operative risk factors and clinical outcomes associated with vasoplegia in recipients of orthotopic heart transplantation in the contemporary era
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Pre-operative risk factors and clinical outcomes associated with vasoplegia in recipients of orthotopic heart transplantation in the contemporary era Maria Patarroyo, MD, Cesar Simbaqueba, MD, Kevin Shrestha, MS, Randall C. Starling, MD, MPH, Nicholas Smedira, MD, W.H. Wilson Tang, MD, and David O. Taylor, MD From the Department of Cardiovascular Medicine and Cardiothoracic Surgery, Heart and Vascular Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
KEYWORDS: heart transplantation; vasoplegia; risk factors
BACKGROUND: Patients who underwent orthotopic heart transplant (OHT) can develop vasoplegia, which is associated with high mortality and morbidity. Herein we examine the pre-operative risk in OHT recipients at our institution. METHODS: We reviewed peri-operative data from 311 consecutive adult patients who underwent OHT between January 2003 and June 2008. Vasoplegia was defined as persistent low systemic vascular resistance, despite multiple intravenous pressor drugs at high dose, between 6 and 48 hours after surgery. RESULTS: In our cohort of 311 patients, 35 (11%) patients developed vasoplegia syndrome; these patients were more likely to be UNOS Status 1A, with a higher body surface area (1.8 ⫾ 0.25 vs 1.63 ⫾ 0.36, p ⫽ 0.0007), greater history of thyroid disease (38.2% vs 18.5%, p ⫽ 0.0075) and a higher rate of previous cardiothoracic surgery (79% vs 48%, p ⫽ 0.0006). Pre-operatively, they were more frequently treated with aspirin (73% vs 48%, p ⫽ 0.005) and mechanical assist devices (ventricular assist devices [VADs]: 45% vs 17%, p ⬍ 0.0001; total artificial hearts: 8.6% vs 0%, p ⬍ 0.0001), and less treated with milrinone (14.7% vs 45.8%, p ⫽ 0.0005). Bypass time (118 ⫾ 37 vs 142 ⫾ 39 minutes, p ⫽ 0.0002) and donor heart ischemic time (191 ⫾ 46 vs 219 ⫾ 51 minutes, p ⫽ 0.002) were longer, with higher mortality (3.2% vs 17.1%, p ⫽ 0.0003) and morbidity in the first 30 days after transplant. In the multivariate analysis, history of thyroid disease (odds ratio [OR] ⫽ 2.7, 95% CI 1.0 to 7.0, p ⫽ 0.04) and VAD prior to transplant (OR ⫽ 2.8, 95% CI 1.07 to 7.4, p ⫽ 0.03) were independent risk factors for development of vasoplegia syndrome. CONCLUSIONS: High body mass index, long cardiopulmonary bypass time, prior cardiothoracic surgery, mechanical support, use of aspirin, and thyroid disease are risk factors associated with development of vasoplegia syndrome. J Heart Lung Transplant 2012;31:282–7 © 2012 International Society for Heart and Lung Transplantation. All rights reserved.
There has been significant progress in the medical management of recipients of orthotopic heart transplantation (OHT), although peri-operative complications remain a major contributor to morbidity and mortality. Five to fifteen
Reprint requests: David O. Taylor, MD, Cardiovascular Medicine, Section of Heart Failure, Cleveland Clinic Foundation, J3-4, 9500 Euclid Avenue, Cleveland, OH 44195. Telephone: 216-444-2492. Fax: 216-4456193. E-mail address: [email protected]
percent of patients develop a severe vasodilatory state known as “vasoplegia,” presumably secondary to a postoperative inflammatory response, and this state is associated with delayed extubation and prolonged intensive care unit (ICU) stay and increased morbidity and mortality.1 There is no standard definition of vasoplegia, but the syndrome is characterized by severe systemic arterial hypotension (mean arterial pressure ⬍50 mm Hg), low systemic vascular resistance (systemic vascular resistance ⬍800 dyne/s/cm5) and normal or high cardiac index (⬎2.5 liters/min/m2) that
1053-2498/$ -see front matter © 2012 International Society for Heart and Lung Transplantation. All rights reserved. doi:10.1016/j.healun.2011.10.010
Patarroyo et al.
Vasoplegia After Heart Transplantation
is refractory to vasopressor therapies (e.g., intravenous norepinephrine infusion ⱖ0.5 g/kg/min). Vasoplegia is usually present immediately after surgery or in the first 6 hours after weaning from cardiopulmonary bypass,2,3 although some investigators have suggested that can be seen until 4 days after cardiopulmonary bypass.6 Findings have suggested that vasoplegia associated with OHT is more likely to occur in the setting of acidosis, vasodilation, longer ischemic times or donor/recipient weight mismatch, whereas African Americans and those with ventricular assist devices (VADs) have shown a lower incidence.4 Other studies have indicated an increased risk for developing vasoplegia syndrome after OHT with preoperative use of heparin, and a higher body surface area (BSA).5 In this study we sought to assess pre-operative risk in recipients of OHT in the contemporary era from a singleinstitution experience at our high-volume transplant center.
Methods Study design After approval from our institutional review board we reviewed data from consecutive adult patients (ⱖ18 years old) who underwent OHT from January 2003 until June 2008. The data obtained included demographic and clinical variables, peri-operative management and laboratory results. Pre-operative data included demographics, United Network of Organ Sharing (UNOS) status, laboratory and echocardiographic data, use of VADs, and days with the device before transplant. Intra-operative data included cardiopulmonary bypass (CBP) time, donor heart ischemic time, use of inotropes or vasopressors during surgery, and use of blood products. Post-operative data included laboratory findings, immunosuppressive medications, need for mechanical support, blood transfusions after surgery, blood and urine cultures at time of surgery, and hemodynamics recorded in the intensive care unit (ICU) during the first 48 hours. History of hypertension, hyperlipidemia and thyroid disease was assessed by chart review and use of medications at the time of evaluation. History of chronic obstructive pulmonary disease (COPD) was based on pulmonary function test results and use of inhalers at the time of surgery.
Definition of vasoplegia We define vasoplegia syndrome as persistent low systemic vascular resistance (⬍800 dyne/s/cm5 for more than 2 consecutive readings) despite multiple (ⱖ2) intravenous pressor drugs at high dose (epinephrine ⱖ4 g/min, norepinephrine ⱖ4 g/min, dopamine ⱖ5 g/kg/min, vasopressin ⱖ1 U/h) with preserved cardiac index (⬎2.5) between 6 and 48 hours after surgery. This definition is a combination of the most commonly cited ones.2,3,6
Evaluation of hemodynamics We obtained the hemodynamics data recorded in the ICU nursing flow sheets since admission. These hemodynamics are usually obtained from a pulmonary artery catheter. On each evaluation the
283 nurses recorded heart rate, central venous pressure, systolic/diastolic and mean pulmonary artery pressure, and pulmonary capillary wedge pressure at the end of expiration with a balloon-tipped catheter placed in the pulmonary artery with the patient in the supine position. Cardiac output was calculated according to the assumed Fick equation using a sample of mixed central venous blood gas from the pulmonary artery catheter. The hemodynamics used were those at around 24 hours of admission to the ICU or if the patient had more than 2 consecutive similar measurements.
Statistical analysis Continuous variables were summarized as mean ⫾ standard deviation if normally distributed. Non–normally distributed continuous variables were summarized as median and interquartile range [IQR]. Categorical variables were summarized as proportions and frequencies. Normality was assessed by the Shapiro–Wilk W-test. Clinical characteristics were compared between patients who developed vasoplegia and those who did not, using Student’s t-test for normally distributed variables and Wilcoxon’s rank sum test for non–normally distributed variables. Clinical characteristics were compared between patients who developed vasoplegia and those who did not by using contingency table analysis. Odds ratios for the prediction of vasoplegia were calculated through logistic regression analysis (x, y, z, etc.) modeled as continuous variables and evaluated according to the likelihood ratio test. All p-values reported are from 2-sided tests with p ⬍0.05 considered statistically significant. Multivariate analysis was done using those variables that were statistically significant, such as body mass index (BMI), thyroid disease, use of aspirin and milrinone, VAD, prior heart surgery, pump time and ischemic time, and history of thyroid disease. All statistical analyses were performed using JMP 8.0 software (SAS Institute, Cary, NC). All investigators had full access to the data and assume responsibility for its integrity.
Results During the period of study, 348 OHTs were performed at our institution, and complete pre- and peri-operative clinical and outcomes data were available for 311 patients (89%). Table 1 indicates the baseline characteristics according to the presence or absence of vasoplegia. According to UNOS criteria, 115 patients (37%) were classified as Status IA, 124 (40%) Status IB and 72 (23%) Status II, and 8 underwent their second OHT. Two-hundred sixty-six patients were Caucasian (85%), 40 were African American (13%) and 5 were of other ethnicity (2%). The most common blood types were A positive in 123 patients (39%) and O positive in 102 patients (33%). In our study cohort, 35 (11%) developed vasoplegia syndrome based on our definition. These patients were more likely to be patients in UNOS Status 1A, with higher body surface area (BSA, 1.8 ⫾ 0.25 vs 1.63 ⫾ 0.36, p ⫽ 0.0007) and higher body mass index (BMI, 27 ⫾ 3.9 vs 25.5 ⫾ 5.2, p ⫽ 0.02). They also had a more frequent history of prior thyroid disease (38.2% vs 18.5%, p ⫽ 0.0075) and cardiothoracic surgery (79% vs 48%, p ⫽ 0.0006). There was no difference in other comorbidities and etiologies of heart failure (Table 1 and Figure 1A). After reviewing the thyroid function test within 3 months pre-transplant, we found that vasoplegia patients had more hypothyroidism, as defined by high thyroid-stimulating hormone (TSH) and low T4 or free T4, compared with those patients who did not develop vasoplegia (16% vs 4%, p ⫽ 0.03; Figure 1B), with no difference in use of amiodarone prior to surgery between patients with vs those with-
284 Table 1
The Journal of Heart and Lung Transplantation, Vol 31, No 3, March 2012 Baseline Characteristics
Age (years) Gender (male) UNOS status IA IB 2 Race Caucasian African American Other Heart failure etiology Ischemic Congenital Dilated Hypertrophic BSA BMI Co-morbidities Diabetes mellitus Hypertension Hyperlipidemia History of smoking Thyroid disease COPD Previous cardiothoracic surgery
No vasoplegia (n ⫽ 276)
Vasoplegia (n ⫽ 35)
p-value
52.7 ⫾ 12 76%
55.3 ⫾ 11 82%
0.19 0.37
95 (34%) 119 (44%) 62 (21.8%)
20 (57%) 5 (14.3) 10 (28.5%)
0.0035
232 (84%) 39 (14%) 5 (2%)
34 (97%) 1 (2.9%) 0
131 (47%) 8 (2.9%) 128 (46.5%) 9 (3.2%) 1.63 ⫾ 0.36 25.5 ⫾ 5.2
21 (60%) 0 13 (37%) 1 (2.8%) 1.8 ⫾ 0.25 27 ⫾ 3.9
0.16 0.3 0.3 0.89 0.0007 0.02
70 136 148 101 51 44 124
12 16 19 11 13 6 27
0.22 0.79 0.81 0.61 0.0075 0.8 0.0006
0.11
(25.4%) (49%) (53.8%) (36.7%) (18.5%) (16%) (48%)
(35.3%) (47%) (55.8%) (32.3%) (38.2%) (17.6%) (79%)
(6.9 ⫾ 9.7 vs 3.49 ⫾ 3.2, p ⫽ 0.04) than those without vasoplegia, with no difference in other laboratory findings prior to surgery (Table 5). Post-operatively, patients with vasoplegia tended to be more acidotic (p ⫽ 0.06), have worse renal function and elevated liver enzymes, compared to those without vasoplegia (Table 5). Post-operatively, transplant patients with vasoplegia were treated more often with thymoglobulin (47% vs 25%, p ⫽ 0.007) and plasmapheresis (8.8% vs 1.1%), and less often with cyclosporine (26% vs 54%, p ⫽ 0.0017), mycophenolate mofetil (88.2% vs 98.9%, p ⬍ 0.0001) and steroids (91% vs 98%, p ⫽ 0.0179), with no difference in use of OKT3 (2.9% vs 4.8%, p ⫽ 0.6) or basiliximab (17.6 vs 14.3%, p ⫽ 0.61). In the multivariate analysis, history of thyroid disease (odds ratio [OR] ⫽ 2.7, 95% confidence interval [CI] 1.0 to 7.0, p ⫽ 0.04) and use of VAD prior to transplant (OR ⫽ 2.8, 95% CI 1.07 to 7.4, p ⫽ 0.03) were independent risk factors for development of vasoplegia syndrome after OHT, whereas pre-operative use of milrinone was associated with lower risk of vasoplegia (OR ⫽ 0.29, 95% CI 0.07 to 0.87, p ⫽ 0.027). In the subgroup of patients with mechanical support devices, 9 (2.9%) had biventricular VAD, 2 (0.6%) had a right VAD, 52 (16.7%) had a left VAD, and 3 (0.96%) had a TAH. Of these patients, 41 (62%) have persistent moderate–to-severe right ventricular dysfunction by the time of transplant. Also, although we do not have all the data regarding infections prior to transplant, patients with mechanical support devices received more antibiotics
BMI, body mass index (kg/m2); BSA, body surface area; COPD, chronic obstructive pulmonary disease.
out hypothyroidism (38% vs 43%, p ⫽ 0.74). Patients with vasoplegia were more likely to receive amiodarone prior to transplant. However, this finding was not statistically significant (p ⫽ 0.057). Table 2 shows the pre-operative treatment in our study cohort. Patients who developed vasoplegia syndrome were more likely to be treated with aspirin (73% vs 48%, p ⫽ 0.005) and mechanical assist devices, including VADs (45% vs 17%, p ⬍ 0.0001) and total artificial hearts (TAHs) (8.6% vs 0%, p ⬍ 0.0001), and less likely to receive intravenous milrinone pre-operatively (14.7% vs 45.8%, p ⫽ 0.0005) compared with those not developing vasoplegia syndrome. In the post-operative period, milrinone was used more frequently in patients who did not develop vasoplegia syndrome (83.3% vs 16%, p ⫽ 0.0002). Intra-operative data show that the cardiopulmonary bypass time (118 ⫾ 37 vs 142 ⫾ 39 minutes, p ⫽ 0.0002) and donor heart ischemic time (191 ⫾ 46 vs 219 ⫾ 51 min, p ⫽ 0.002) were longer in patients who developed vasoplegia compared with those who did not. There were no significant differences in use of vasopressors or inotropes at any dose, but there was an increased need for transfusions of blood products during surgery (Table 3). Mortality in the first 30 days after OHT, re-operation for bleeding, mediastinitis and open chest were all statistically significantly more frequent in patients with vasoplegia (Table 4). Regarding laboratory data, those who developed vasoplegia syndrome were more likely to have a lower albumin level (3.4 ⫾ 0.6 vs 4.0 ⫾ 2.7, p ⫽ 0.0067) and higher TSH level
Figure 1 (A) Percentage of patients with a history of hypoparthyroidism who developed vasoplegia compared with those with a history of hypoparathyroidism who did not develop vasoplegia. (B) Percentage of patients with a history of hypoparathyroidism based on high TSH and low T4 or low free T4, within 3 months prior to transplant, who developed vasoplegia compared with those who did not develop vasoplegia.
Patarroyo et al. Table 2
Vasoplegia After Heart Transplantation
Pre-transplant Treatment
285 Table 4
Post-operative Complications
No vasoplegia Vasoplegia (n ⫽ 276) (n ⫽ 35) p-value Aspirin Coumadin ACE inhibitors ARB Digoxin Beta-blockers Aldosterone antagonist CCB Diuretic Hydralazine Isordil Statin Amiodarone Oral hypoglycemics Insulin Milrinone Dobutamine Nitroprusside Intravenous heparin ECMO IABP VAD TAH
131 110 138 33 128 118 141 6 235 79 87 113 113 19 32 126 52 20 75 8 17 47 0
(48%) (40.7%) (51%) (12%) (47.4%) (43.7%) (52%) (2.2%) (87%) (29%) (32%) (41%) (41%) (7%) (11.8%) (45.8%) (19.4%) (7.3%) (27.8%) (2.95) (6.25%) (17%)
25 16 12 3 9 15 17 3 27 5 4 9 20 1 8 5 4 0 10 1 1 16 3
(73%) (47%) (35%) (8.8%) (26.4%) (44%) (50%) (8.8%) (79%) (14%) (11.7%) (26.4%) (58.8%) (2.9%) (23.5%) (14.7%) (11.7%)
0.005 0.48 0.08 0.56 0.06 0.93 0.8 0.03 0.22 0.07 0.014 0.08 0.057 0.36 0.057 0.0005 0.27 0.1 (29.4%) 0.85 (2.9%) 0.99 (2.9%) 0.43 (45%) ⬍0.0001 ⬍0.0001
ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium-channel blocker; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; TAH, total artificial heart; VAD, ventricular assist device.
No vasoplegia Vasoplegia (n ⫽ 276) (n ⫽ 35) p-value Days in ICU 4.2 ⫾ 2.9 Extubation (days) 1.4 ⫾ 1.1 30-day mortality 9 (3.2%) ECMO 3 (1.1%) IABP 9 (3.3%) Re-operation ⫻ 21 (7.6%) bleeding Open chest 1 (0.36%) Mediastinitis 1 (0.36%) Days in hospital after 16.7 ⫾ 9.8 OHT
Table 3
Intra-operative Data
Pump time (min) Aortic clamp (min) Ischemic time (min) Vasopressor use Inotrope use PRBCs transfusion FFP transfusion Platelet transfusion
No vasoplegia (n ⫽ 276)
Vasoplegia (n ⫽ 35)
p-value
118 ⫾ 37 71.4 ⫾ 55 191 ⫾ 46 212 (81%) 118 (45.5%) 134 (61%) 155 (61%) 87 (34%)
142 ⫾ 39 77 ⫾ 27 219 ⫾ 51 29 (87.8%) 19 (59.3%) 26 (76%) 26 (76%) 22 (64.7%)
0.0002 0.06 0.0022 0.34 0.13 0.08 0.08 0.0005
FFP, fresh frozen plasma; PRBCs, red blood cell products.
2 (5.7%) 0.0023 4 (11.4%) ⬍0.0001 26.5 ⫾ 29 0.023
ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; OHT, orthotropic heart transplant.
Discussion There are several new findings to be taken from this study, which is among the largest contemporary-era series to have been undertaken. First, we confirmed that previously reported pre-operative risk factors, such as recipient body habitus, aspirin use, previous cardiothoracic surgery and mechanical support, as well as peri-operative factors, such as CBP time, are still associated with higher risks of developing vasoplegia syndrome. Some studies have suggested
Table 5 prior to surgery than those without mechanical support (36.2% vs 11.2%, p ⬍ 0.0001), and required more platelet transfusion during surgery (62% vs 31%, p ⬍ 0.0001) and after surgery (37.8% vs 19.6%, p ⫽ 0.002). Also, these patients were more frequently treated with OKT3 (8.8% vs 3.2%) and plasmapheresis (5.9% vs 1.2%, p ⫽ 0.0183), with no difference in use of thymoglobulin (35.8% vs 24%, p ⫽ 0.06), basiliximab (16.4% vs 15.2%, p ⫽ 0.8) and need for renal replacement therapy after transplant (1.37% vs 1.99%, p ⫽ 0.71). There was no difference in development of vasoplegia syndrome between patients with a continuous vs pulsatile VAD (p ⫽ 0.66) or in their UNOS status (p ⫽ 0.47), although the numbers are too low to make appropriate conclusions.
11.6 ⫾ 22 ⬍0.0001 3.6 ⫾ 3.6 ⬍0.0001 6 (17.1%) 0.0003 2 (6.25%) 0.0312 4 (12.1%) 0.0187 9 (25.7%) 0.0006
Pre- and Post-transplant Laboratory Data No vasoplegia Vasoplegia (n ⫽ 276) (n ⫽ 35)
Pre-operative Bicarbonate (mmol/liter) Creatinine (mg/dl) AST (U/liter) ALT (U/liter) Albumin (g/dl) Leukocyte count (k/l) Hemoglobin (g/dl) Platelets (k/l) TSH (U/ml) T4 (g/dl) Post-operative Arterial pH Creatinine (mg/dl) BUN (mg/dl) AST (U/liter) ALT (U/liter) Leukocyte count (k/l) Hemoglobin (g/dl) Platelets (k/l)
24.7 ⫾ 3.38
24.9 ⫾ 3.0
p-value 0.65
1.22 32.4 29.6 4 7.5
⫾ ⫾ ⫾ ⫾ ⫾
0.5 28 33.6 2.7 3.2
1.27 40 25.9 3.4 8.6
⫾ ⫾ ⫾ ⫾ ⫾
0.47 39 27 0.6 3.3
0.29 0.36 0.11 0.0067 0.07
11.3 217 3.49 7.92
⫾ ⫾ ⫾ ⫾
2.1 85 3.2 2.0
11.2 238 6.9 8.2
⫾ ⫾ ⫾ ⫾
5.5 120 9.7 1.55
0.88 0.62 0.04 0.6
7.4 1.3 25 138 48 16.3
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.04 0.57 10 114 58 6.4
7.3 1.5 28 247 117 16
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.07 0.06 0.6 0.0046 9.5 0.0241 232 ⬍0.0001 141 0.0006 6.3 0.58
9.8 ⫾ 1.8 149 ⫾ 58
10.4 ⫾ 3.4 163 ⫾ 66
0.46 0.27
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; TSH, thyroid-stimulating hormone.
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The Journal of Heart and Lung Transplantation, Vol 31, No 3, March 2012
that this higher incidence of vasoplegia in heart failure patients is associated with an activation of an inflammatory response after CBP in patients who already have an inflammatory response secondary to the heart failure8 and present with higher levels of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-␣) and interleukin-6 (IL-6) in patients who undergo OHT, compared with those undergoing coronary artery bypass graft surgery.9 The direct relation between CBP time and development of vasoplegia syndrome is most likely due to the increased production of inflammatory cytokines just noted, especially IL-6 and TNF-␣,9 –11 with increased levels of atrial natriuretic peptide that inhibit the vasopressin secretion,7 endothelial injury and arginine vasopressin impairment, leading to increased levels of nitric oxide with more vasodilation.2 Obesity is also associated with a persistent inflammatory state with an increase of inflammatory cytokines and increase in the secretion of acute-phase proteins by the liver such as C-reactive protein.12–15 Furthermore, we speculate that the use of aspirin, previous surgery and mechanical support are also in part related to an increased propensity for bleeding, longer CBP times, ischemic disease as cause of heart failure, and higher risk of infections in these patients. Second, unlike other studies, we found an association between history of thyroid disease (defined as use of thyroid hormonal replacement at the time of transplant) and development of vasoplegia. Although this observation has limitations due to the small number of patients who developed vasoplegia, it may be related to the endothelial dysfunction associated with hypothyroidism16 and the decreased thyroid hormone levels after CBP, which have previously been associated with a decreased peripheral conversion to the active hormone, increased cytokine levels, hypothermia and hemodilution.17,18 Like Byrne et al,6 we found that pre-operative use of inotropic support with milrinone conferred protection against vasoplegia syndrome. Other investigators have suggested that the use of inotropic support could lead to normalization of the neurohumoral and inflammatory system with a decrease in cytokines before transplant. However, this theory cannot explain why patients in our cohort who were on other types of inotropic therapy did not have the same protective effect with milrinone. In contrast, patients without inotropic support may have lower myocardial reserve at the time of OHT beyond what is expected from hemodynamic calculations. Also, this finding could be due to the decreased use of milrinone in patients with mechanical support devices (8.6% vs 51.8%, p ⬍ 0.0001). We cannot fully explain the reason for this effect due to the small number of patients, and therefore more studies are necessary. In the past several years, the use of oral antagonists of the renin–angiotensin–aldosterone system (RAAS) has been associated with development of vasoplegia in patients undergoing heart surgery.1 There has been some speculation that it may be due to the effects of angiotensin-converting enzyme inhibition on decreasing levels of angiotensin II and increasing the levels of bradykinin in the lungs that are being bypassed during surgery.19 Like previous studies in
the OHT literature, we did not find an association between RAAS antagonists and vasoplegia. Finally, it is of interest that patients with vasoplegia were treated more frequently with VADs and TAHs. Given the retrospective nature of our study we do not have all the information about the time these patients were on mechanical support. However, the presence of vasoplegia in this population may be related to the presence of infections and the higher rates of intra-operative bleeding, as suggested by the fact that these patients were more frequently on antibiotics prior to surgery and required more blood transfusions. However, due to the relatively limited number of patients with mechanical support devices, we cannot ascertain the independent effect of these devices on the development of vasoplegia. There are several limitations to this retrospective, singlecenter study. We did not directly measure the cytokine or inflammatory biomarker levels of those who did or did not develop vasoplegia and we did not have information regarding use of intra- or post-operative methylene blue, which has been used for treatment of vasoplegia syndrome in several studies. Also, we did not determine the specific type of thyroid disease and the dose of pre- or post-operative replacement therapy and/or its adequacy. In conclusion, in this contemporary-era, single-center experience we identified a history of thyroid disease as a new relationship associated with development of vasoplegia syndrome beyond previously identified risk factors such as longer CBP time, higher BMI, prior cardiothoracic surgery, mechanical support, and use of aspirin. However, further studies are needed to evaluate the effect of thyroid disease and its appropriate treatment on the development of the vasoplegia syndrome in this population. The authors have no conflicts of interest to disclose.
References 1. Carrel T, Englberger L, Mohacsi P, et al. Low systemic vascular resistance after cardiopulmonary bypass: incidence, etiology, and clinical importance. J Card Surg 2000;15:347-53. 2. Ganesh S. Vasoplegic syndrome the role of methylene blue. Eur J Cardiothorac Surg 2005;28:705-10. 3. 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. 4. Chemmalakuzhy J, Costanzo MR, Meyer P, et al. Hypotension, acidosis, and vasodilatation syndrome post– heart transplant: prognostic variables and outcomes. J Heart Lung Transplant 2001;20:1075-83. 5. Argenziano M, Choudhri AF, Oz MC, et al. A prospective randomized trial of arginine vasopressin in the treatment of vasodilatory shock after left ventricular assist device placement. Circulation 1997;96:286-90. 6. Byrne J, Leacche M, Paul S, et al. Risk factor and outcomes for “vasopelgia syndrome” following cardiac transplantion. Eur J Cardiothorac Surg 2004;25:327-32. 7. Argenziano M, Chen JM, Choudhri AF, et al. Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent. J Thorac Cardiovasc Surg 1998;116:973-80. 8. Mekontso-Dessap A, Houël R, Soustelle C, et al. Risk factors for post-cardiopulmonary bypass vasoplegia in patients with preserved left ventricular function. Ann Thorac Surg 2001;71:1428-32.
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9. Wan S, Marchant A, DeSmet JM, et al. Human cytokine responses to cardiac transplantation and coronary artery bypass grafting. J Thorac Cardiovasc Surg 1996;111:469-77. 10. Boyle EM Jr, Pohlman TH, Johnson MC, et al. Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response. Ann Thorac Surg 1997;63:277-84. 11. Strüber M, Cremer JT, Gohrbandt B, et al. Human cytokine responses to coronary artery bypass grafting with and without cardiopulmonary bypass. Ann Thorac Surg 1999;68:1330-5. 12. Grady KL, White-Williams C, Naftel D, et al. Are preoperative obesity and cachexia risk factors for post heart transplant morbidity and mortality? A multi-institutional study of preoperative weight-height indices. J Heart Lung Transplant 1999;18:750-63. 13. Grady KL, Costanzo MR, Fisher S, et al. Preoperative obesity is associated with decreased survival after heart transplantation. J Heart Lung Transplant 1996;15:863-71.
287 14. O’Rourke RW. Inflammation in obesity-related diseases. Surgery 2009;145:255-9. 15. Mathieu P, Poirier P, Pibarot P, et al. Visceral obesity: the link among inflammation, hypertension, and cardiovascular disease. Hypertension 2009;53:577-84. 16. Taddei S, Caraccio N, Virdis A, et al. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab 2003;88:3731-7. 17. Bettendorf M, Schmidt KG, Tiefenbacher U, et al. Transient secondary hypothyroidism in children after cardiac surgery. Pediatr Res 1997;41:375-9. 18. Taggart DP, Fraser W, Gray CE, et al. The effects of systemic intraoperative hypothermia on the acute-phase and endocrine response to cardiac surgery. Thorac Cardiovasc Surg 1992;40:74-8. 19. Cugno M, Nussberger J, Biglioli P, et al. Cardiopulmonary bypass increases plasma bradykinin concentrations. Immunopharmacology 1999;43:145.
Pre-operative risk factors and clinical outcomes associated with vasoplegia in recipients of orthotopic heart transplantation in the contemporary era Maria Patarroyo, MD, Cesar Simbaqueba, MD, Kevin Shrestha, MS, Randall C. Starling, MD, MPH, Nicholas Smedira, MD, W.H. Wilson Tang, MD, and David O. Taylor, MD From the Department of Cardiovascular Medicine and Cardiothoracic Surgery, Heart and Vascular Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
KEYWORDS: heart transplantation; vasoplegia; risk factors
BACKGROUND: Patients who underwent orthotopic heart transplant (OHT) can develop vasoplegia, which is associated with high mortality and morbidity. Herein we examine the pre-operative risk in OHT recipients at our institution. METHODS: We reviewed peri-operative data from 311 consecutive adult patients who underwent OHT between January 2003 and June 2008. Vasoplegia was defined as persistent low systemic vascular resistance, despite multiple intravenous pressor drugs at high dose, between 6 and 48 hours after surgery. RESULTS: In our cohort of 311 patients, 35 (11%) patients developed vasoplegia syndrome; these patients were more likely to be UNOS Status 1A, with a higher body surface area (1.8 ⫾ 0.25 vs 1.63 ⫾ 0.36, p ⫽ 0.0007), greater history of thyroid disease (38.2% vs 18.5%, p ⫽ 0.0075) and a higher rate of previous cardiothoracic surgery (79% vs 48%, p ⫽ 0.0006). Pre-operatively, they were more frequently treated with aspirin (73% vs 48%, p ⫽ 0.005) and mechanical assist devices (ventricular assist devices [VADs]: 45% vs 17%, p ⬍ 0.0001; total artificial hearts: 8.6% vs 0%, p ⬍ 0.0001), and less treated with milrinone (14.7% vs 45.8%, p ⫽ 0.0005). Bypass time (118 ⫾ 37 vs 142 ⫾ 39 minutes, p ⫽ 0.0002) and donor heart ischemic time (191 ⫾ 46 vs 219 ⫾ 51 minutes, p ⫽ 0.002) were longer, with higher mortality (3.2% vs 17.1%, p ⫽ 0.0003) and morbidity in the first 30 days after transplant. In the multivariate analysis, history of thyroid disease (odds ratio [OR] ⫽ 2.7, 95% CI 1.0 to 7.0, p ⫽ 0.04) and VAD prior to transplant (OR ⫽ 2.8, 95% CI 1.07 to 7.4, p ⫽ 0.03) were independent risk factors for development of vasoplegia syndrome. CONCLUSIONS: High body mass index, long cardiopulmonary bypass time, prior cardiothoracic surgery, mechanical support, use of aspirin, and thyroid disease are risk factors associated with development of vasoplegia syndrome. J Heart Lung Transplant 2012;31:282–7 © 2012 International Society for Heart and Lung Transplantation. All rights reserved.
There has been significant progress in the medical management of recipients of orthotopic heart transplantation (OHT), although peri-operative complications remain a major contributor to morbidity and mortality. Five to fifteen
Reprint requests: David O. Taylor, MD, Cardiovascular Medicine, Section of Heart Failure, Cleveland Clinic Foundation, J3-4, 9500 Euclid Avenue, Cleveland, OH 44195. Telephone: 216-444-2492. Fax: 216-4456193. E-mail address: [email protected]
percent of patients develop a severe vasodilatory state known as “vasoplegia,” presumably secondary to a postoperative inflammatory response, and this state is associated with delayed extubation and prolonged intensive care unit (ICU) stay and increased morbidity and mortality.1 There is no standard definition of vasoplegia, but the syndrome is characterized by severe systemic arterial hypotension (mean arterial pressure ⬍50 mm Hg), low systemic vascular resistance (systemic vascular resistance ⬍800 dyne/s/cm5) and normal or high cardiac index (⬎2.5 liters/min/m2) that
1053-2498/$ -see front matter © 2012 International Society for Heart and Lung Transplantation. All rights reserved. doi:10.1016/j.healun.2011.10.010
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Vasoplegia After Heart Transplantation
is refractory to vasopressor therapies (e.g., intravenous norepinephrine infusion ⱖ0.5 g/kg/min). Vasoplegia is usually present immediately after surgery or in the first 6 hours after weaning from cardiopulmonary bypass,2,3 although some investigators have suggested that can be seen until 4 days after cardiopulmonary bypass.6 Findings have suggested that vasoplegia associated with OHT is more likely to occur in the setting of acidosis, vasodilation, longer ischemic times or donor/recipient weight mismatch, whereas African Americans and those with ventricular assist devices (VADs) have shown a lower incidence.4 Other studies have indicated an increased risk for developing vasoplegia syndrome after OHT with preoperative use of heparin, and a higher body surface area (BSA).5 In this study we sought to assess pre-operative risk in recipients of OHT in the contemporary era from a singleinstitution experience at our high-volume transplant center.
Methods Study design After approval from our institutional review board we reviewed data from consecutive adult patients (ⱖ18 years old) who underwent OHT from January 2003 until June 2008. The data obtained included demographic and clinical variables, peri-operative management and laboratory results. Pre-operative data included demographics, United Network of Organ Sharing (UNOS) status, laboratory and echocardiographic data, use of VADs, and days with the device before transplant. Intra-operative data included cardiopulmonary bypass (CBP) time, donor heart ischemic time, use of inotropes or vasopressors during surgery, and use of blood products. Post-operative data included laboratory findings, immunosuppressive medications, need for mechanical support, blood transfusions after surgery, blood and urine cultures at time of surgery, and hemodynamics recorded in the intensive care unit (ICU) during the first 48 hours. History of hypertension, hyperlipidemia and thyroid disease was assessed by chart review and use of medications at the time of evaluation. History of chronic obstructive pulmonary disease (COPD) was based on pulmonary function test results and use of inhalers at the time of surgery.
Definition of vasoplegia We define vasoplegia syndrome as persistent low systemic vascular resistance (⬍800 dyne/s/cm5 for more than 2 consecutive readings) despite multiple (ⱖ2) intravenous pressor drugs at high dose (epinephrine ⱖ4 g/min, norepinephrine ⱖ4 g/min, dopamine ⱖ5 g/kg/min, vasopressin ⱖ1 U/h) with preserved cardiac index (⬎2.5) between 6 and 48 hours after surgery. This definition is a combination of the most commonly cited ones.2,3,6
Evaluation of hemodynamics We obtained the hemodynamics data recorded in the ICU nursing flow sheets since admission. These hemodynamics are usually obtained from a pulmonary artery catheter. On each evaluation the
283 nurses recorded heart rate, central venous pressure, systolic/diastolic and mean pulmonary artery pressure, and pulmonary capillary wedge pressure at the end of expiration with a balloon-tipped catheter placed in the pulmonary artery with the patient in the supine position. Cardiac output was calculated according to the assumed Fick equation using a sample of mixed central venous blood gas from the pulmonary artery catheter. The hemodynamics used were those at around 24 hours of admission to the ICU or if the patient had more than 2 consecutive similar measurements.
Statistical analysis Continuous variables were summarized as mean ⫾ standard deviation if normally distributed. Non–normally distributed continuous variables were summarized as median and interquartile range [IQR]. Categorical variables were summarized as proportions and frequencies. Normality was assessed by the Shapiro–Wilk W-test. Clinical characteristics were compared between patients who developed vasoplegia and those who did not, using Student’s t-test for normally distributed variables and Wilcoxon’s rank sum test for non–normally distributed variables. Clinical characteristics were compared between patients who developed vasoplegia and those who did not by using contingency table analysis. Odds ratios for the prediction of vasoplegia were calculated through logistic regression analysis (x, y, z, etc.) modeled as continuous variables and evaluated according to the likelihood ratio test. All p-values reported are from 2-sided tests with p ⬍0.05 considered statistically significant. Multivariate analysis was done using those variables that were statistically significant, such as body mass index (BMI), thyroid disease, use of aspirin and milrinone, VAD, prior heart surgery, pump time and ischemic time, and history of thyroid disease. All statistical analyses were performed using JMP 8.0 software (SAS Institute, Cary, NC). All investigators had full access to the data and assume responsibility for its integrity.
Results During the period of study, 348 OHTs were performed at our institution, and complete pre- and peri-operative clinical and outcomes data were available for 311 patients (89%). Table 1 indicates the baseline characteristics according to the presence or absence of vasoplegia. According to UNOS criteria, 115 patients (37%) were classified as Status IA, 124 (40%) Status IB and 72 (23%) Status II, and 8 underwent their second OHT. Two-hundred sixty-six patients were Caucasian (85%), 40 were African American (13%) and 5 were of other ethnicity (2%). The most common blood types were A positive in 123 patients (39%) and O positive in 102 patients (33%). In our study cohort, 35 (11%) developed vasoplegia syndrome based on our definition. These patients were more likely to be patients in UNOS Status 1A, with higher body surface area (BSA, 1.8 ⫾ 0.25 vs 1.63 ⫾ 0.36, p ⫽ 0.0007) and higher body mass index (BMI, 27 ⫾ 3.9 vs 25.5 ⫾ 5.2, p ⫽ 0.02). They also had a more frequent history of prior thyroid disease (38.2% vs 18.5%, p ⫽ 0.0075) and cardiothoracic surgery (79% vs 48%, p ⫽ 0.0006). There was no difference in other comorbidities and etiologies of heart failure (Table 1 and Figure 1A). After reviewing the thyroid function test within 3 months pre-transplant, we found that vasoplegia patients had more hypothyroidism, as defined by high thyroid-stimulating hormone (TSH) and low T4 or free T4, compared with those patients who did not develop vasoplegia (16% vs 4%, p ⫽ 0.03; Figure 1B), with no difference in use of amiodarone prior to surgery between patients with vs those with-
284 Table 1
The Journal of Heart and Lung Transplantation, Vol 31, No 3, March 2012 Baseline Characteristics
Age (years) Gender (male) UNOS status IA IB 2 Race Caucasian African American Other Heart failure etiology Ischemic Congenital Dilated Hypertrophic BSA BMI Co-morbidities Diabetes mellitus Hypertension Hyperlipidemia History of smoking Thyroid disease COPD Previous cardiothoracic surgery
No vasoplegia (n ⫽ 276)
Vasoplegia (n ⫽ 35)
p-value
52.7 ⫾ 12 76%
55.3 ⫾ 11 82%
0.19 0.37
95 (34%) 119 (44%) 62 (21.8%)
20 (57%) 5 (14.3) 10 (28.5%)
0.0035
232 (84%) 39 (14%) 5 (2%)
34 (97%) 1 (2.9%) 0
131 (47%) 8 (2.9%) 128 (46.5%) 9 (3.2%) 1.63 ⫾ 0.36 25.5 ⫾ 5.2
21 (60%) 0 13 (37%) 1 (2.8%) 1.8 ⫾ 0.25 27 ⫾ 3.9
0.16 0.3 0.3 0.89 0.0007 0.02
70 136 148 101 51 44 124
12 16 19 11 13 6 27
0.22 0.79 0.81 0.61 0.0075 0.8 0.0006
0.11
(25.4%) (49%) (53.8%) (36.7%) (18.5%) (16%) (48%)
(35.3%) (47%) (55.8%) (32.3%) (38.2%) (17.6%) (79%)
(6.9 ⫾ 9.7 vs 3.49 ⫾ 3.2, p ⫽ 0.04) than those without vasoplegia, with no difference in other laboratory findings prior to surgery (Table 5). Post-operatively, patients with vasoplegia tended to be more acidotic (p ⫽ 0.06), have worse renal function and elevated liver enzymes, compared to those without vasoplegia (Table 5). Post-operatively, transplant patients with vasoplegia were treated more often with thymoglobulin (47% vs 25%, p ⫽ 0.007) and plasmapheresis (8.8% vs 1.1%), and less often with cyclosporine (26% vs 54%, p ⫽ 0.0017), mycophenolate mofetil (88.2% vs 98.9%, p ⬍ 0.0001) and steroids (91% vs 98%, p ⫽ 0.0179), with no difference in use of OKT3 (2.9% vs 4.8%, p ⫽ 0.6) or basiliximab (17.6 vs 14.3%, p ⫽ 0.61). In the multivariate analysis, history of thyroid disease (odds ratio [OR] ⫽ 2.7, 95% confidence interval [CI] 1.0 to 7.0, p ⫽ 0.04) and use of VAD prior to transplant (OR ⫽ 2.8, 95% CI 1.07 to 7.4, p ⫽ 0.03) were independent risk factors for development of vasoplegia syndrome after OHT, whereas pre-operative use of milrinone was associated with lower risk of vasoplegia (OR ⫽ 0.29, 95% CI 0.07 to 0.87, p ⫽ 0.027). In the subgroup of patients with mechanical support devices, 9 (2.9%) had biventricular VAD, 2 (0.6%) had a right VAD, 52 (16.7%) had a left VAD, and 3 (0.96%) had a TAH. Of these patients, 41 (62%) have persistent moderate–to-severe right ventricular dysfunction by the time of transplant. Also, although we do not have all the data regarding infections prior to transplant, patients with mechanical support devices received more antibiotics
BMI, body mass index (kg/m2); BSA, body surface area; COPD, chronic obstructive pulmonary disease.
out hypothyroidism (38% vs 43%, p ⫽ 0.74). Patients with vasoplegia were more likely to receive amiodarone prior to transplant. However, this finding was not statistically significant (p ⫽ 0.057). Table 2 shows the pre-operative treatment in our study cohort. Patients who developed vasoplegia syndrome were more likely to be treated with aspirin (73% vs 48%, p ⫽ 0.005) and mechanical assist devices, including VADs (45% vs 17%, p ⬍ 0.0001) and total artificial hearts (TAHs) (8.6% vs 0%, p ⬍ 0.0001), and less likely to receive intravenous milrinone pre-operatively (14.7% vs 45.8%, p ⫽ 0.0005) compared with those not developing vasoplegia syndrome. In the post-operative period, milrinone was used more frequently in patients who did not develop vasoplegia syndrome (83.3% vs 16%, p ⫽ 0.0002). Intra-operative data show that the cardiopulmonary bypass time (118 ⫾ 37 vs 142 ⫾ 39 minutes, p ⫽ 0.0002) and donor heart ischemic time (191 ⫾ 46 vs 219 ⫾ 51 min, p ⫽ 0.002) were longer in patients who developed vasoplegia compared with those who did not. There were no significant differences in use of vasopressors or inotropes at any dose, but there was an increased need for transfusions of blood products during surgery (Table 3). Mortality in the first 30 days after OHT, re-operation for bleeding, mediastinitis and open chest were all statistically significantly more frequent in patients with vasoplegia (Table 4). Regarding laboratory data, those who developed vasoplegia syndrome were more likely to have a lower albumin level (3.4 ⫾ 0.6 vs 4.0 ⫾ 2.7, p ⫽ 0.0067) and higher TSH level
Figure 1 (A) Percentage of patients with a history of hypoparthyroidism who developed vasoplegia compared with those with a history of hypoparathyroidism who did not develop vasoplegia. (B) Percentage of patients with a history of hypoparathyroidism based on high TSH and low T4 or low free T4, within 3 months prior to transplant, who developed vasoplegia compared with those who did not develop vasoplegia.
Patarroyo et al. Table 2
Vasoplegia After Heart Transplantation
Pre-transplant Treatment
285 Table 4
Post-operative Complications
No vasoplegia Vasoplegia (n ⫽ 276) (n ⫽ 35) p-value Aspirin Coumadin ACE inhibitors ARB Digoxin Beta-blockers Aldosterone antagonist CCB Diuretic Hydralazine Isordil Statin Amiodarone Oral hypoglycemics Insulin Milrinone Dobutamine Nitroprusside Intravenous heparin ECMO IABP VAD TAH
131 110 138 33 128 118 141 6 235 79 87 113 113 19 32 126 52 20 75 8 17 47 0
(48%) (40.7%) (51%) (12%) (47.4%) (43.7%) (52%) (2.2%) (87%) (29%) (32%) (41%) (41%) (7%) (11.8%) (45.8%) (19.4%) (7.3%) (27.8%) (2.95) (6.25%) (17%)
25 16 12 3 9 15 17 3 27 5 4 9 20 1 8 5 4 0 10 1 1 16 3
(73%) (47%) (35%) (8.8%) (26.4%) (44%) (50%) (8.8%) (79%) (14%) (11.7%) (26.4%) (58.8%) (2.9%) (23.5%) (14.7%) (11.7%)
0.005 0.48 0.08 0.56 0.06 0.93 0.8 0.03 0.22 0.07 0.014 0.08 0.057 0.36 0.057 0.0005 0.27 0.1 (29.4%) 0.85 (2.9%) 0.99 (2.9%) 0.43 (45%) ⬍0.0001 ⬍0.0001
ACE, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium-channel blocker; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; TAH, total artificial heart; VAD, ventricular assist device.
No vasoplegia Vasoplegia (n ⫽ 276) (n ⫽ 35) p-value Days in ICU 4.2 ⫾ 2.9 Extubation (days) 1.4 ⫾ 1.1 30-day mortality 9 (3.2%) ECMO 3 (1.1%) IABP 9 (3.3%) Re-operation ⫻ 21 (7.6%) bleeding Open chest 1 (0.36%) Mediastinitis 1 (0.36%) Days in hospital after 16.7 ⫾ 9.8 OHT
Table 3
Intra-operative Data
Pump time (min) Aortic clamp (min) Ischemic time (min) Vasopressor use Inotrope use PRBCs transfusion FFP transfusion Platelet transfusion
No vasoplegia (n ⫽ 276)
Vasoplegia (n ⫽ 35)
p-value
118 ⫾ 37 71.4 ⫾ 55 191 ⫾ 46 212 (81%) 118 (45.5%) 134 (61%) 155 (61%) 87 (34%)
142 ⫾ 39 77 ⫾ 27 219 ⫾ 51 29 (87.8%) 19 (59.3%) 26 (76%) 26 (76%) 22 (64.7%)
0.0002 0.06 0.0022 0.34 0.13 0.08 0.08 0.0005
FFP, fresh frozen plasma; PRBCs, red blood cell products.
2 (5.7%) 0.0023 4 (11.4%) ⬍0.0001 26.5 ⫾ 29 0.023
ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; OHT, orthotropic heart transplant.
Discussion There are several new findings to be taken from this study, which is among the largest contemporary-era series to have been undertaken. First, we confirmed that previously reported pre-operative risk factors, such as recipient body habitus, aspirin use, previous cardiothoracic surgery and mechanical support, as well as peri-operative factors, such as CBP time, are still associated with higher risks of developing vasoplegia syndrome. Some studies have suggested
Table 5 prior to surgery than those without mechanical support (36.2% vs 11.2%, p ⬍ 0.0001), and required more platelet transfusion during surgery (62% vs 31%, p ⬍ 0.0001) and after surgery (37.8% vs 19.6%, p ⫽ 0.002). Also, these patients were more frequently treated with OKT3 (8.8% vs 3.2%) and plasmapheresis (5.9% vs 1.2%, p ⫽ 0.0183), with no difference in use of thymoglobulin (35.8% vs 24%, p ⫽ 0.06), basiliximab (16.4% vs 15.2%, p ⫽ 0.8) and need for renal replacement therapy after transplant (1.37% vs 1.99%, p ⫽ 0.71). There was no difference in development of vasoplegia syndrome between patients with a continuous vs pulsatile VAD (p ⫽ 0.66) or in their UNOS status (p ⫽ 0.47), although the numbers are too low to make appropriate conclusions.
11.6 ⫾ 22 ⬍0.0001 3.6 ⫾ 3.6 ⬍0.0001 6 (17.1%) 0.0003 2 (6.25%) 0.0312 4 (12.1%) 0.0187 9 (25.7%) 0.0006
Pre- and Post-transplant Laboratory Data No vasoplegia Vasoplegia (n ⫽ 276) (n ⫽ 35)
Pre-operative Bicarbonate (mmol/liter) Creatinine (mg/dl) AST (U/liter) ALT (U/liter) Albumin (g/dl) Leukocyte count (k/l) Hemoglobin (g/dl) Platelets (k/l) TSH (U/ml) T4 (g/dl) Post-operative Arterial pH Creatinine (mg/dl) BUN (mg/dl) AST (U/liter) ALT (U/liter) Leukocyte count (k/l) Hemoglobin (g/dl) Platelets (k/l)
24.7 ⫾ 3.38
24.9 ⫾ 3.0
p-value 0.65
1.22 32.4 29.6 4 7.5
⫾ ⫾ ⫾ ⫾ ⫾
0.5 28 33.6 2.7 3.2
1.27 40 25.9 3.4 8.6
⫾ ⫾ ⫾ ⫾ ⫾
0.47 39 27 0.6 3.3
0.29 0.36 0.11 0.0067 0.07
11.3 217 3.49 7.92
⫾ ⫾ ⫾ ⫾
2.1 85 3.2 2.0
11.2 238 6.9 8.2
⫾ ⫾ ⫾ ⫾
5.5 120 9.7 1.55
0.88 0.62 0.04 0.6
7.4 1.3 25 138 48 16.3
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.04 0.57 10 114 58 6.4
7.3 1.5 28 247 117 16
⫾ ⫾ ⫾ ⫾ ⫾ ⫾
0.07 0.06 0.6 0.0046 9.5 0.0241 232 ⬍0.0001 141 0.0006 6.3 0.58
9.8 ⫾ 1.8 149 ⫾ 58
10.4 ⫾ 3.4 163 ⫾ 66
0.46 0.27
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; TSH, thyroid-stimulating hormone.
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The Journal of Heart and Lung Transplantation, Vol 31, No 3, March 2012
that this higher incidence of vasoplegia in heart failure patients is associated with an activation of an inflammatory response after CBP in patients who already have an inflammatory response secondary to the heart failure8 and present with higher levels of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-␣) and interleukin-6 (IL-6) in patients who undergo OHT, compared with those undergoing coronary artery bypass graft surgery.9 The direct relation between CBP time and development of vasoplegia syndrome is most likely due to the increased production of inflammatory cytokines just noted, especially IL-6 and TNF-␣,9 –11 with increased levels of atrial natriuretic peptide that inhibit the vasopressin secretion,7 endothelial injury and arginine vasopressin impairment, leading to increased levels of nitric oxide with more vasodilation.2 Obesity is also associated with a persistent inflammatory state with an increase of inflammatory cytokines and increase in the secretion of acute-phase proteins by the liver such as C-reactive protein.12–15 Furthermore, we speculate that the use of aspirin, previous surgery and mechanical support are also in part related to an increased propensity for bleeding, longer CBP times, ischemic disease as cause of heart failure, and higher risk of infections in these patients. Second, unlike other studies, we found an association between history of thyroid disease (defined as use of thyroid hormonal replacement at the time of transplant) and development of vasoplegia. Although this observation has limitations due to the small number of patients who developed vasoplegia, it may be related to the endothelial dysfunction associated with hypothyroidism16 and the decreased thyroid hormone levels after CBP, which have previously been associated with a decreased peripheral conversion to the active hormone, increased cytokine levels, hypothermia and hemodilution.17,18 Like Byrne et al,6 we found that pre-operative use of inotropic support with milrinone conferred protection against vasoplegia syndrome. Other investigators have suggested that the use of inotropic support could lead to normalization of the neurohumoral and inflammatory system with a decrease in cytokines before transplant. However, this theory cannot explain why patients in our cohort who were on other types of inotropic therapy did not have the same protective effect with milrinone. In contrast, patients without inotropic support may have lower myocardial reserve at the time of OHT beyond what is expected from hemodynamic calculations. Also, this finding could be due to the decreased use of milrinone in patients with mechanical support devices (8.6% vs 51.8%, p ⬍ 0.0001). We cannot fully explain the reason for this effect due to the small number of patients, and therefore more studies are necessary. In the past several years, the use of oral antagonists of the renin–angiotensin–aldosterone system (RAAS) has been associated with development of vasoplegia in patients undergoing heart surgery.1 There has been some speculation that it may be due to the effects of angiotensin-converting enzyme inhibition on decreasing levels of angiotensin II and increasing the levels of bradykinin in the lungs that are being bypassed during surgery.19 Like previous studies in
the OHT literature, we did not find an association between RAAS antagonists and vasoplegia. Finally, it is of interest that patients with vasoplegia were treated more frequently with VADs and TAHs. Given the retrospective nature of our study we do not have all the information about the time these patients were on mechanical support. However, the presence of vasoplegia in this population may be related to the presence of infections and the higher rates of intra-operative bleeding, as suggested by the fact that these patients were more frequently on antibiotics prior to surgery and required more blood transfusions. However, due to the relatively limited number of patients with mechanical support devices, we cannot ascertain the independent effect of these devices on the development of vasoplegia. There are several limitations to this retrospective, singlecenter study. We did not directly measure the cytokine or inflammatory biomarker levels of those who did or did not develop vasoplegia and we did not have information regarding use of intra- or post-operative methylene blue, which has been used for treatment of vasoplegia syndrome in several studies. Also, we did not determine the specific type of thyroid disease and the dose of pre- or post-operative replacement therapy and/or its adequacy. In conclusion, in this contemporary-era, single-center experience we identified a history of thyroid disease as a new relationship associated with development of vasoplegia syndrome beyond previously identified risk factors such as longer CBP time, higher BMI, prior cardiothoracic surgery, mechanical support, and use of aspirin. However, further studies are needed to evaluate the effect of thyroid disease and its appropriate treatment on the development of the vasoplegia syndrome in this population. The authors have no conflicts of interest to disclose.
References 1. Carrel T, Englberger L, Mohacsi P, et al. Low systemic vascular resistance after cardiopulmonary bypass: incidence, etiology, and clinical importance. J Card Surg 2000;15:347-53. 2. Ganesh S. Vasoplegic syndrome the role of methylene blue. Eur J Cardiothorac Surg 2005;28:705-10. 3. 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. 4. Chemmalakuzhy J, Costanzo MR, Meyer P, et al. Hypotension, acidosis, and vasodilatation syndrome post– heart transplant: prognostic variables and outcomes. J Heart Lung Transplant 2001;20:1075-83. 5. Argenziano M, Choudhri AF, Oz MC, et al. A prospective randomized trial of arginine vasopressin in the treatment of vasodilatory shock after left ventricular assist device placement. Circulation 1997;96:286-90. 6. Byrne J, Leacche M, Paul S, et al. Risk factor and outcomes for “vasopelgia syndrome” following cardiac transplantion. Eur J Cardiothorac Surg 2004;25:327-32. 7. Argenziano M, Chen JM, Choudhri AF, et al. Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent. J Thorac Cardiovasc Surg 1998;116:973-80. 8. Mekontso-Dessap A, Houël R, Soustelle C, et al. Risk factors for post-cardiopulmonary bypass vasoplegia in patients with preserved left ventricular function. Ann Thorac Surg 2001;71:1428-32.
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9. Wan S, Marchant A, DeSmet JM, et al. Human cytokine responses to cardiac transplantation and coronary artery bypass grafting. J Thorac Cardiovasc Surg 1996;111:469-77. 10. Boyle EM Jr, Pohlman TH, Johnson MC, et al. Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response. Ann Thorac Surg 1997;63:277-84. 11. Strüber M, Cremer JT, Gohrbandt B, et al. Human cytokine responses to coronary artery bypass grafting with and without cardiopulmonary bypass. Ann Thorac Surg 1999;68:1330-5. 12. Grady KL, White-Williams C, Naftel D, et al. Are preoperative obesity and cachexia risk factors for post heart transplant morbidity and mortality? A multi-institutional study of preoperative weight-height indices. J Heart Lung Transplant 1999;18:750-63. 13. Grady KL, Costanzo MR, Fisher S, et al. Preoperative obesity is associated with decreased survival after heart transplantation. J Heart Lung Transplant 1996;15:863-71.
287 14. O’Rourke RW. Inflammation in obesity-related diseases. Surgery 2009;145:255-9. 15. Mathieu P, Poirier P, Pibarot P, et al. Visceral obesity: the link among inflammation, hypertension, and cardiovascular disease. Hypertension 2009;53:577-84. 16. Taddei S, Caraccio N, Virdis A, et al. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab 2003;88:3731-7. 17. Bettendorf M, Schmidt KG, Tiefenbacher U, et al. Transient secondary hypothyroidism in children after cardiac surgery. Pediatr Res 1997;41:375-9. 18. Taggart DP, Fraser W, Gray CE, et al. The effects of systemic intraoperative hypothermia on the acute-phase and endocrine response to cardiac surgery. Thorac Cardiovasc Surg 1992;40:74-8. 19. Cugno M, Nussberger J, Biglioli P, et al. Cardiopulmonary bypass increases plasma bradykinin concentrations. Immunopharmacology 1999;43:145.