Eur J Cardiothorac Surg 2004;25:327-332
© 2004 Elsevier Science NL
Risk factors and outcomes for ‘vasoplegia syndrome’ following cardiac transplantation
John G. Byrnea*,
Marzia Leacchea,
Subroto Paula,
Tomislav Mihaljevica,
James D. Rawna,
Stanton K. Shernanb,
Gilbert H. Mudgec,
Lynne W. Stevensonc
a Division of Cardiac Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
b Department of Anesthesiology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
c The Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
Received 15 September 2003;
received in revised form 20 November 2003;
accepted 25 November 2003.
* Corresponding author. Tel.: +1-617-732-7678; fax: +1-617-732-6559
e-mail: jbyrne{at}partners.org
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Abstract
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Objective: Vasoplegia syndrome after orthotopic heart transplantation (OHT) is a rare but highly lethal syndrome of unknown etiology, characterized by severe refractory hypotension, metabolic acidosis, and decreased systemic vascular resistance (SVR). The objective of this retrospective study was to identify the risk factors contributing to the development of vasoplegia syndrome after OHT in order to provide potential algorithms for its management. Methods: Between October 1992 and July 2001, 187 consecutive patients underwent OHT. Complete pre- and post-data were available in 147 patients (78%). Mean age was 49±11 years, 82% (120/147) were male, and donor ischemic time was 117±62 min. Twenty-eight of 147 (19%) developed vasoplegia syndrome, defined as SVR <800 dyn s per cm5 with serum bicarbonate <20 mEq/l. Results: Patients who developed vasoplegia syndrome demonstrated greater hospital mortality (25 vs. 9%, P=0.031) compared to those who did not. Multivariate logistic regression identified pre-operative use of intravenous heparin (OR 2.8, CI 1–7.4, P=0.039) and body surface area >1.9 m2 (OR 7, CI 0.98–50, P=0.052) as independent predictors for the development of post-operative vasoplegia syndrome. Pre-operative use of inotropic support conferred protection against the development of post-operative vasoplegia syndrome (OR 0.25, CI 0.08–0.79, P=0.018). Pre-operative use of ACE inhibitors was not associated with increased risk (55 vs. 59%, P=0.441). Conclusions: Vasoplegia syndrome following OHT is associated with high early mortality. The development of a risk stratification profile may help in patient selection as well as the post-operative management of vasoplegia syndrome following OHT.
Key Words: Heart transplant • Hypotension • Acidosis • Vasoplegia syndrome
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1. Introduction
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During cardiopulmonary bypass (CPB), the generation of a systemic inflammatory response is considered responsible for the release and activation of pro-inflammatory cytokines [10,16] causing generalized vasodilatation (‘vasoplegia syndrome’). This syndrome, characterized by severe and persistent hypotension, decreased systemic vascular resistance (SVR), low intra-cardiac filling pressures, and normal or increased cardiac output is refractory to cathecolamines agents and is associated with high mortality [7]. Among cardiac surgical patients, vasoplegia syndrome has been described after prolonged CPB [10], OHT [4], and left ventricular assist device (VAD) placement [2]. Although more common among patients with low ejection fraction who undergo cardiac surgery, vasoplegia syndrome can also develop in those patients with normal left ventricular function [12]. The subsequent generalized low perfusion results in multisystem organ dysfunction with increased morbidity and mortality [4].
Since there is limited literature on the incidence and risks factors of vasoplegia syndrome following OHT [4], we undertook this retrospective study to identify pre-operative and intra-operative predictors for its development.
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2. Material and methods
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2.1. Study population
Between January 1992 and July 2001, 187 consecutive patients underwent orthotopic heart transplantation (OHT) at the Brigham and Women's Hospital. Complete donor as well as recipient data were available for analysis in 147 of the 187 (78%) patients, who represent the study population for this report. Of the 147 patients, 120 (82%) were males, 106 (86%) Caucasian and 5 (4%) were African-American. Mean age was 49±11 years. Etiologies for the development of heart failure leading to OHT in this population included ischemic cardiomyopathy (100/147, 68%), dilated cardiomyopathy (34/147, 23%), hypertrophic cardiomyopathy (7/147, 5%), and myocarditis (4/147, 3%). According to the criteria of United Network for Organ Sharing, the recipient status was classified as status I in 66/147 (45%), and as status II in 81/147 (55%). In the recipients, the mean pulmonary vascular resistance was 230±131 dynes·sec·cm-5. Angiotensin converting enzyme inhibitors (ACE-I) were used pre-operatively in 85/147 (58%) patients, ß-blockers in 33/147 (22%), amiodarone in 57/147 (39%) and inotropic support (defined as any type of inotropic support of any dosage) in 42/147 (29%). VAD was present at the time of OHT in 33 (22%) of the 147 patients (BiVAD, n=9; LVAD, n=24).
Donors had a mean age of 33±13 years, 60% (88/147) were males and 82% (121/147) Caucasian. Inotropic support was administered to 96% of the donors. Mean donor ischemic time was 118±63 min. The principal cause of death was head trauma (41%) followed by motor vehicles accident (27%), gunshot wound (7%), anoxia (7%) and miscellaneous (28%).
2.2. Study design
Institutional Review Board approved retrospective analysis of patient's medical records. Post-operative data were recorded from the time of admission in the ICU to hospital discharge.
2.3. Definitions
Hospital mortality was defined as death for any reason occurring within 30 days following OHT or during the same hospitalization. Vasoplegia syndrome was defined, as previously reported, as a single reading of an SVR <800 dynes·sec·cm-5 with serum bicarbonate <20 mEq/l (30 min after CPB until 4 days) [4].
2.4. Donor and recipient operative management
Donor myocardial protection was accomplished utilizing antegrade cold crystalloid cardioplegia and topical hypothermia with iced saline early in the series. Since 1997, the University of Wisconsin solution was used for initial cardioplegia and transport of the donor heart. Prior to implantation, the donor heart was perfused with cold antegrade blood cardioplegia delivered via the aortic root. In all recipients, general anesthesia was induced with fentanyl, sodium thiopental or etomidate, and a mucsle relaxant (pancuronium bromide or vecuronium). General anesthesia was maintained using a balanced technique including narcotics (fentanyl and morphine), volatile agents (isoflurane), sedatives/amnestic agents (midazolam and propofol) and muscle relaxants. Intra-operative hemodynamic monitoring included systemic arterial pressure (femoral or radial artery), pulmonary artery catheterization and transesophageal echocardiography.
For recipients, non-pulsatile CPB was conducted at a mean temperature of 28±4 °C. Transplantation technique included the bicaval approach in 90/147 patients (62%), while the remainder (55/147, 38%) underwent biatrial technique, primarily early in the series. Mean CPB duration was 169±60 min. Aortic clamp duration was 98±45 min, which included recipient cardiectomy and implantation of the new heart. Immunosuppressive therapy included intravenous methylprednisolone (500 mg before myocardial reperfusion and 375 mg over the first 24 post-operative hours) followed by oral prednisone 25 mg/day and cyclosporine (2.5 mg/kg) started within 24 h following OHT.
2.5. Statistical analysis
For continuous variables a Mann–Whitney test was used. A two-tailed Fischer's exact test was used for categorical variables. Variables with a P value <0.2 in the univariate analysis were entered in the logistic regression model for multivariate analysis. A P value 
0.05 was used to indicate statistical significance. Statistical analysis was performed using STATA 6.0 and STATISTICA 6.0 for Windows.
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3. Results
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Pre-operative and intra-operative recipient and donor univariate data are presented in Tables 1–4. Notably, patients who developed vasoplegia syndrome were more likely to be receiving intravenous heparin (39 vs. 27%, P=0.129), and less likely to be supported by inotropic agents (18 vs. 31%, P=0.116). The use of ACE-I agents was not different between groups (59 vs. 55%, P=0.441). Ischemic cardiomyopathy was the predominant etiology in the patients who developed vasoplegia (P=0.068), whereas dilated cardiomyopathy was more common in the non-vasoplegic group (P=0.018). The body surface area was greater in the vasoplegic group (1.9 vs. 1.8 kg/m2, P=0.011) as was the difference between donor weight and recipient weight (7 vs. -1 kg, P=0.072). Pre-operative laboratory values were comparable in the two groups except for hemoglobin concentration, which was lower in the non-vasoplegic group (11.3 vs. 12.5 g/dl, P=0.05; Table 2). There were no differences in donor characteristics (Table 3) or intra-operative variables (Table 4).
Post-operative recipient hemodynamic, laboratory and morbidity and mortality univariate data are presented in Tables 5–7. Twenty-eight of 147 (19%) developed vasoplegia syndrome (as early as 1 up to 39 h after CPB). As expected, the vasoplegic group demonstrated significantly lower SVR, lower mean arterial pressure and metabolic acidosis, despite use of pressors cathecolamines and volume replacement (Table 5). Patients presenting with signs of vasoplegia syndrome were treated with volume replacement and pharmacological support with dopamine >7 µg/kg per min and/or norepinephrine, for at least 3 h (doses varying from 2.5 up to 20 µg/kg per min) in order to increase SVR and maintain a mean arterial pressure >70 mmHg. The vasoplegic group also demonstrated increased serum concentrations of hepatic enzymes (Table 6). Major complications that were more common in the vasoplegic group included reoperation for bleeding (P=0.041), requirement for extracorporeal membrane oxygenation (ECMO; P=0.035), and requirement to leave the chest open due to hemodynamic instability (P=0.075; Table 7). Hospital mortality was also significantly greater in the vasoplegic group (7/28, 25% vs. 11/119, 9%; P=0.031). Patients in the vasoplegic group who died, did so from severe vasodilatatory shock unresponsive to maximal pharmacological treatment. During the time period 1992–1996 and 1997–2001, 14/46 (23%) and 14/73 (16%), P=0.188, respectively, developed vasoplegia syndrome.
3.1. Multivariate analysis
Stepwise logistic regression analysis identified pre-operative use of intravenous heparin (OR 2.8, CI 1–7.4, P=0.039) as an independent risk factor for the development of post-operative vasoplegia syndrome. Body surface area showed a strong tendency toward statistical significance (OR 7, 0.98–50, P=0.052). Pre-operative use of inotropic support conferred protection against development of post-operative vasoplegia (OR 0.25, CI 0.08–0.79, P=0.018).
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4. Discussion
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Arteriolar tone is regulated by a complex interplay between neurohumoral pathways and endothelial cell function and is depressed in patients who develop vasoplegia syndrome after CPB. The exact mechanisms that lead to the development of vasoplegia syndrome are unknown, but may be related to the release of vasodilatory inflammatory mediators such as interleukin (IL)-6, IL-8 and tumor necrosis factor [16], the depletion of vasopressive substances, (i.e. arginine-vasopresin) during CPB [1] or extensive complement activation [10].
In OHT, the release of pro-inflammatory cytokines is more pronounced than in conventional coronary artery bypass surgery [16]. Furthermore, severe heart failure is consistently itself associated with elevated markers of inflammation. This may explain the high incidence (19%) of vasoplegia syndrome after OHT found in this and in a previous study compared to conventional cardiac surgery. Decreases in vascular tone after OHT may be aggravated by the systematic inflammatory response activated by the host immune system due the release of antigens from graft tissue. In addition, heart failure is associated in some patients with high vasopressin levels [5], that could lead to altered vascular responsivity after cardiac transplantation. Consequently, the severity of vasoplegia syndrome after OHT may be greater than in other cardiac procedures, leading to a high operative mortality (26%) as demonstrated in the present report.
For reasons not entirely clear, pre-operative use of intravenous heparin was found to be an independent risk factor for the development of post-operative vasoplegia syndrome. Heart failure patients awaiting OHT are often hospitalized for longer periods of time and receive anticoagulation in the setting of severely reduced ventricular function. Thus heparin may be a surrogate marker for sicker patients with other co-morbidities. In our study, intravenous heparin was administered in those patients who required pre-operative artificial cardiac support (intra-aortic balloon pump, VAD, ECMO), had pre-operative arrhythmias or deep vein thrombosis or were in frank congestive heart failure (CHF). Thus, intravenous heparin may be a statistical confounder of the results. Interestingly, in a case-control study, pre-operative use of intravenous heparin in patients with unstable angina or recent myocardial infarction, was identified as an independent predictor for vasoplegia syndrome after CPB [12]. Alternatively, heparin has been shown to increase the release of nitric oxide in cultured endothelial cells of rats, pigs and humans [11,13,17]. However, the clinical significance of these studies is still unknown.
In patients with chronic CHF, the presence of an LVAD is associated with decreased plasma neuro-hormones [9], cytokines [6], which are characteristically increased, and a reduced incidence of vasoplegia syndrome following OHT [4]. Patients with pre-operative mechanical circulatory assistance may have a reduced activation and incremental response of pro-inflammatory cytokines after OHT compared to those without mechanical circulatory assistance. We could not confirm those findings in our study, but in our population pre-operative inotropic support was associated with a reduced incidence of vasoplegia syndrome.
Our data suggest that the pre-operative use of inotropic support provided protection against post-operative vasoplegia syndrome. This may have been the result of unloading the recipient's circulatory system and normalization of the neuro-humoral and inflammatory system before OHT. The use of inotropic agents also likely improved recipients' overall clinical status, making them better candidates for OHT. However, another consideration is that the use of inotropic support may have had the unexpected effect of upgrading patients' UNOS status at the time of OHT. Because patients receiving inotropic support are listed at a higher UNOS status, they are more likely to receive a transplant. This ‘upgrading’ of the UNOS status may have brought to OHT overall healthier patients. Thus, inotropic support may be a surrogate for overall healthier recipients. This could explain why neither pre-operative NYHA classification or UNOS status were found significantly different in vasoplegic vs. non-vasoplegic patients.
The risk factors for developing vasoplegia syndrome after OHT that we identified are similar to those previously demonstrated. In a study of 70 consecutive OHT, Chemmalakuzhy et al. [4], have described a similar syndrome consisting of severe hypotension, metabolic acidosis and decrease SVR. Previously, vasoplegia syndrome had been defined as a severe persistent hypotension (mean arterial pressure <70 mmHg), occurring within 6 h after weaning from CPB, with SVR <1400 dynes·sec·cm-5, normal or increased cardiac output (cardiac index >2.5 l·min-1·m-2), and/or needing of dopamine >10 µg·kg-1·m-1 or norepineprhine [12]. This definition, however, has never been used in OHT patients, and consequently we decided to adopt the previously established definition [4]. In the aforementioned study increased donor and recipient weight has been shown to predict vasoplegia syndrome [4]. Other authors have reported obesity to portend a poor prognosis after OHT [8].
Multivariate analysis revealed that patients with greater body surface are at increased risk of vasoplegia syndrome (P=0.052). Increased body surface area and overall size may place a strain on the newly transplanted heart and recipient vasculature that initially cannot be overcome in some patients leading to the development of vasoplegia syndrome. Furthermore, patients with greater body surface area are at increased risk to size mismatch (small donor–large recipient) which has been associated with increased operative mortality [18].
Angiotensin converting enzyme inhibitors are commonly used in the treatment of CHF. There is increasing evidence in the literature to suggest their association with increased vasoconstrictors requirements after CPB [15], and that they may be a risk factor for vasodilatatory shock after cardiac surgery [3,12]. Neither our study nor Chemmalakuzhy et al.'s [4] identified a correlation between pre-operative treatment with ACE-inhibitors and the development of vasoplegia syndrome. Different pathways of neuro-humoral activation with increased activity of the renin–angiotensin system present before surgery in patients undergoing OHT and conventional cardiac surgery could explain the reason for such difference.
As previously described [4], patients experiencing vasoplegia syndrome post-OHT had increased hepatic markers. Hepatic failure is a contributory factor for the development of vasoplegia syndrome due a reduction in clearance of various pharmacological agents. However, the elevation of hepatic markers may also represent a sign of liver hypoperfusion related to the vasoplegia syndrome.
The length of donor ischemic time has been associated with adverse early and late outcomes after OHT [14]. Additionally, an average ischemic time >200 min seems to strongly correlate with the development of vasoplegia syndrome after OHT [4]. However, since our median ischemic time in both groups, vasoplegic and non-vasoplegic, was relatively short (100 and 131 min, respectively), we could not find an association between donor ischemic time and vasoplegic syndrome.
This study is significant in that it represents the largest report of development of vasoplegia syndrome in OHT patients. The major limitation of this study lies in its retrospective nature thereby making it impossible to examine the serum of patients with vasoplegia syndrome for levels of vasoactive substances. Nonetheless, the identification of perioperative risk factors for developing vasoplegia syndrome in patients undergoing OHT may help to stratify and triage high-risk patients accordingly.
Patients with multimorbid conditions, necessitating pre-operative intravenous heparin are at increased risk for vasoplegia syndrome after OHT. Pre-operative inotropic support confers protection against vasoplegia syndrome. Thus, their use may be beneficial in those at high risk for vasoplegia syndrome. Greater body surface area showed a strong tendency to be a risk factor for vasoplegia syndrome. An adequate body-size match, donor to recipient, and strict pre-OHT weight control may be important tools to reduce the risk of vasoplegia syndrome.
Further prospective studies are needed to elucidate the precise molecular mechanisms leading to vasoplegic syndrome following OHT.
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Footnotes
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Presented at the joint 17th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 11th Annual Meeting of the European Society of Thoracic Surgeons, Vienna, Austria, October 12–15, 2003.
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Abstract
1. Introduction
