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Incidence and Impact of On-Cardiopulmonary Bypass Vasoplegia During Heart Transplantation

Truby, Lauren, K.*; Takeda, Koji*; Farr, Maryjane*; Beck, James; Yuzefpolskaya, Melana*; Colombo, Paolo, C.*; Topkara, Veli, K.*; Mancini, Donna*; Naka, Yoshifumi; Takayama, Hiroo

doi: 10.1097/MAT.0000000000000623
Adult Circulatory Support
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Despite significant advances in the medical management of heart transplant (HT) recipients, perioperative complications, including vasoplegia, remain a significant contributor to morbidity and mortality. This is a retrospective review of patients who received HT at our institution between 2012 and 2015. Mean systemic vascular resistance (SVR) was calculated during the bypass run. Vasoplegia was defined as a mean SVR <800 dynes s/cm5 despite a high pressor requirement (>1,500 μg neosynephrine bolused). The primary outcome of interest was 30 day post-transplant survival. There were 138 patients included in the current study. A total of 16% (n = 22) patients were identified as having developed on-cardiopulmonary bypass vasoplegia. Vasoplegic patients had a significantly higher body mass index (BMI) (30.1 ± 5.0 vs. 26.5 ± 4.7; p = 0.005) and were more likely to be male (95.5% vs. 66.4%; p = 0.004). Use of continuous-flow left ventricular assist device (CF-LVAD) as bridge-to-transplant (BTT) was prevalent among vasoplegic patients (81.8% vs. 57.8%; p = 0.033). These patients had significantly decreased survival at 30 and 60 days (86.4% vs. 99.1% at 30 days; 77.3% vs. 92.8% at 60 days). Bridge-to-transplant with CF-LVAD was an independent predictor of on-cardiopulmonary bypass (CPB) vasoplegia. On-CPB vasoplegia complicated 16% of HTs in the current study and was associated with increased mortality. Bridge-to-transplant with CF-LVAD was an independent predictor of this phenomenon.

From the *Department of Surgery, Columbia University Medical Center, New York, New York; and Department of Medicine, Columbia University Medical Center, New York, New York.

Submitted for consideration November 2016; accepted for publication in revised form June 2017.

Disclosure: Yoshifumi Naka receives a consultant fee from Thoratec corporation. The other authors have no conflicts of interest to report.

Correspondence: Hiroo Takayama, Department of Medicine, Columbia University Medical Center, 177 Fort Washington Ave, New York, NY 10032. Email: hirofu2@hotmail.com.

Heart transplantation (HT) remains the only definitive therapy for end-stage heart failure. Although the demand for organs has grown, transplant centers have not seen a similar increase in organ availability, leading to lower volumes of annual transplants and significantly longer waitlist times.1 In many patients, because of body habitus, blood type, or United Network of Organ Sharing (UNOS) region, expected wait times inevitably exceed pretransplant life expectancy. In the era of mechanical circulatory support, however, more patients are receiving left ventricular assist devices (continuous-flow left ventricular assist device [CF-LVAD]) as a “bridge-to-transplant” (BTT) in an effort to improve both quantity and quality of life while awaiting transplantation.2,3 Many previous studies have identified age,4 weight,5 cause of death,6 total ischemic time,7,8 and donor–recipient gender9,10 and weight11 mismatch as pretransplant donor, recipient, and procedural risk factors for poor post-transplant outcomes. With the number of patients transplanted from CF-LVAD rising, transplant centers are becoming increasingly aware of the consequences of prolonged exposure to nonpulsatile blood flow and its potential impact on transplant outcomes.12 In recent years, one such complication that has been observed with increasing frequency is vasoplegia. Though it lacks a universal definition, vasoplegia is characterized by arterial hypotension and low systemic vascular resistance (SVR) with preserved cardiac output that is often refractory to high doses of vasopressors.13–16 Among cardiac surgery patients, it has been reported to complicate 5–15% of cardiopulmonary bypass (CPB) runs and has been associated with delayed extubation, increased bleeding complications, prolonged intensive care unit (ICU) stay, and multisystem organ dysfunction that ultimately contributes to increased mortality.13,17,18 Previous studies have identified HT recipients as particularly at risk for the development of this syndrome. Although its exact pathophysiology is unknown, many speculate that it results from release of pro-inflammatory cytokines and increased nitric oxide synthesis and release in the setting of CPB-induced endothelial injury.15,18 Prior small series have described vasoplegia as occurring in the immediate postoperative period, and some even suggest that on early on-CPB hypotension could predict which patients will develop this devastating syndrome, suggesting that vasoplegia might develop much earlier in the operative course.15 No prior studies, however, have identified or analyzed the development of on-CPB vasoplegia and its impact on post-transplant outcomes. Thus, in the current study, we sought to identify patients in whom on-CPB vasoplegia was developed, identify recipient risk factors for this syndrome, and assess its impact on post-transplant morbidity and mortality.

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Methods

Study Design, Variables, and Definitions

This is a retrospective review of all patients 18 years old and older who underwent HT at our institution from 2012 to 2015. All data, including patient past medical history, demographics, hemodynamics, and laboratory results, were retrospectively collected from the electronic medical record. Preoperative data also included UNOS status, echocardiographic evaluation, and data regarding CF-LVAD usage before transplant.

The operative course was represented in three phases: induction (the time from endotracheal intubation to initiation of CPB), CPB, and post-CPB (Figure 1). The three discrete time points of data collection utilized were anesthesia induction, initiation of CPB, and termination of CPB. At these time points, hemodynamics and inotrope score (IS = dopamine dose [μg/kg/min] + dobutamine dose [μg/kg/min] + 100 × epinephrine dose [μg/kg/min] + 15 × milrinone dose [μg/kg/min] + 10,000 × vasopressin dose [unit/kg/min] + 100 × norepinephrine dose [μg/kg/min]) were collected.19 During the induction and CPB periods, fluid and blood product use, urine output, procedural time, and cumulative doses of vasoactive medications were documented. On-CPB mean SVR was calculated by averaging the SVR from each hemodynamic data point available while the patient was on “full flow” CPB. Based on the data available, most patients had approximately 800 data points available from which the average was calculated. Thus, the mean SVR takes into account the entire CPB run while on full flow. We recognize that this does take into account some contribution of graft function, as the aorta is declamped while on full flow. However, retrospectively we felt this was the most appropriate way to ensure we were including all appropriate data points. The total amount of neosynephrine given as boluses during full flow CPB was also recorded. On-CPB vasoplegia was defined as an on-CPB mean SVR less than or equal to 800 dynes s/cm5 despite greater than or equal to 1,500 μg of cumulative neosynephrine doses during the bypass run.14,20

Figure 1

Figure 1

The primary post-transplant outcome of interest was 30 day survival. Primary graft dysfunction (PGD) was defined as the need for mechanical circulatory support device (MCSD) excluding intra-aortic balloon pump (IABP) within the first 24 hours post-transplant. The current study was approved by the Columbia University Institutional Review Board.

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Intraoperative Management of Heart Transplant

Donor heart preservation during organ procurement was achieved using cold preservation solution and topical hypothermia. University of Wisconsin solution was utilized until 2015, and subsequently histidine-tryptophan-ketoglutarate (HTK) solution was used. Intraoperative monitoring included systemic arterial pressures (via arterial line), pulmonary artery catheterization, and transesophageal echocardiography. Oral anticoagulants were reversed with vitamin K and fresh frozen plasma (FFP) before the CPB run per surgeon’s discretion.

Blood flow rate on CPB was preserved at a cardiac index of 2.4 L/min/m2. If hypotension was noted, attempts were made to increase pump flow by 1–2 L over calculated rate in combination with vasopressors. Once on full CPB support, flow rate was substituted for cardiac output allowing for calculation of SVR. Our goal was a confidence interval (CI) of 2.4–3 L/min/m2 with mean arterial pressure (MAP) of 60–70 mm Hg and an SVR of 800–1,200 dynes s/cm5. Neosynephrine of 80–160 μg/cc was utilized for intermittent bolus delivery while on CPB.

All patients underwent HT with bicaval anastomoses and received standard immunosuppressive therapy. Patients received 1 g of solu-medrol and 1,500 mg of oral mycophenolic acid intraoperatively. Postoperatively patients received 125 mg of methylprednisolone every 8 hours for a total of three doses followed by a prednisone taper from 100 mg daily to 30 mg daily over a 2 week period. All HT recipients received mycophenolic acid and calcineurin inhibitors, either tacrolimus with goal of 10–12 or cyclosporine with goal of 250–300, depending on renal function. There were some patients who also received induction therapy with basiliximab, 20 mg on day 0 and day 4, although this practice was discontinued in 2014.

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Statistical Analysis

Descriptive analyses were conducted for all baseline variables and are presented as means and standard deviations for continuous variables and numbers and percentages for categorical variables. Non-normally distributed variables are presented as median and interquartile range (IQR). Comparisons between patients who did and did not develop on-CPB vasoplegia during heart transplant were performed using Fisher exact t-test, chi-squared tests, or Kruskal–Wallis tests. Univariate logistic regression analysis was used to assess odds ratios and CIs of independent predictors of intraoperative vasoplegia. Kaplan–Meier survival estimates were used to quantify the effect of on-bypass vasoplegia on overall survival. All p values are reported as two-sided tests with p < 0.05 considered statistically significant. STATA version 13.1 (Stata corp., College Station, TX) was used to perform statistical analysis.

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Results

Patient Population

A total of 194 HTs were performed in adults at our institution during the study period. Fifty-six patients were excluded from the current study because of lack of sufficient intraoperative data to assess whether the patient met our definition of on-bypass vasoplegia. As shown in Figure 2, a total of 138 consecutive HT patients were included in the current study. Eighty-five patients were transplanted from CF-LVAD, the proportion of which increased each year during the study period. Twenty-two patients (16%) were identified as having developed on-bypass vasoplegia based on the above definition. When a subgroup analysis was performed to identify potential differences between the study cohort and those excluded, there was a trend toward increased CF-LVAD use (61.5% vs. 51.2%; p = 0.065) in those excluded, but not differences in other preoperative variables including age, body mass index (BMI), gender, and past medical history. Pre-HT laboratory values including creatinine, bilirubin, and hemoglobin were similar, but a lower albumin was noted in those excluded (4.07 ± 0.52 vs. 3.91 ± 0.47; p = 0.005).

Figure 2

Figure 2

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Recipient Characteristics

Table 1 summarizes the baseline characteristics of the study population. Overall, vasoplegic patients were more likely to be male (95.4% vs. 66.4%; p = 0.004) and more likely to have a higher BMI (30.09 ± 5.02 vs. 26.53 ± 4.73; p = 0.005) than their nonvasoplegic counterparts. The distribution of other comorbidities including hypertension, diabetes, and prior stroke were not significantly different between groups. With regards to the etiology of heart failure, nonischemic dilated cardiomyopathy was the most common reason for transplant (n = 68, 49.3%) followed by ischemic cardiomyopathy (n = 40, 29.0%). Although the etiology of heart failure did not differ significantly between groups, there were no patients with congenital heart disease and no retransplanted patients in whom on-bypass vasoplegia was developed. Baseline laboratory values were compared between groups in Table 2 to evaluate preoperative end-organ function. Vasoplegic patients had slightly worse baseline renal function as suggested by trend toward higher preoperative creatinine (1.3 [1.1–1.6] vs. 1.2 [0.9–1.5]; p = 0.087). There appeared to be no difference in synthetic hepatic function between groups as measured by albumin and total bilirubin, respectively. Model of End-Stage Liver Disease Excluding INR (MELD-Xi) scores were calculated for all patients, and the proportion of patients in both groups with a high score (defined as MELD-Xi ≥ 17) was compared.21 Although there were a higher number of patients with high MELD-Xi scores in the vasoplegic group (18.2% vs. 13.8%), this difference was not statistically significant (p = 0.527). There was also no difference in the proportion of patients treated for infection with antibiotics within 1 month of transplant between groups. When pretransplant medications were compared between groups, vasoplegic patients were less likely to be on inotropic support (18.2% vs. 35.3%; p = 0.141) though more likely to be treated with antiarrhythmics including amiodarone, sotalol, and mexiletine (59.1% vs. 42.2%; p = 0.166). Pulmonary vasodilator use was also more common among vasoplegic patients (36.4% vs. 19.8%; p = 0.100) but not to a significant degree.

Table 1

Table 1

Table 2

Table 2

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Bridge-to-Transplant with Continuous-Flow Left Ventricular Assist Device

As seen in Table 2, 85 patients (61.6%) were BTT with CF-LVAD (HeartMate II [Thoratec Inc., Pleasanton, CA; St. Jude Medical, St. Paul, MN], n = 72, 84.7%; HeartWare HVAD [HeartWare, Framingham, MA], n = 13, 15.5%). Median time of CF-LVAD support was 321 days (IQR: 227–579) and was slightly shorter in vasoplegic patients (283 [192–439] vs. 324 [236–616]) though not to a significant degree (p = 0.126). Among BTT patients, 53.9% had evidence of aortic valve opening on most recent echocardiogram before transplant. Four patients included in the study were transplanted directly from short-term MCSDs (one Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO), three CentriMag Biventricular Assist Device (BiVAD; Thoratec Corp, Pleasanton, CA)), none of whom developed on-pump vasoplegia. A total of 64 patients who were bridged to transplant with CF-LVAD were listed as UNOS 1A for transplant due to complication of CF-LVAD support. Among the 22 patients with intraoperative vasoplegia, 12 (54.5%) were UNOS 1A as a result of CF-LVAD complication.

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Intraoperative Events: Intubation and Induction

Tables 3 and 4 summarize detailed intraoperative events. At the time of intubation or anesthesia induction, vasoplegic patients appeared to have a more robust MAP (94.75 ± 11.64 vs. 90.83 ± 13.53) with a lower proportion of patients requiring inotropic or vasoactive medications (13.6% vs. 35.4%; p = 0.049). During induction (the period from anesthesia intubation to CPB initiation), vasoplegic and nonvasoplegic patients received similar amounts of crystalloid and colloid resuscitation with a slightly higher number of vasoplegic patients receiving ≥2 units FFP (45.5% vs. 25.9%). Overall net volume, taking into account fluid and product resuscitation with urine output, was similar between groups at the termination of the induction. Vasoplegic patients were less likely to receive high doses of neosynephrine (22.7% vs. 32.8%) and less likely to receive boluses of norepinephrine (0.0% vs. 7.8%). The total time spent in the induction phase was substantially longer in the vasoplegic patient (190.19 ± 42.96 vs. 169.46 ± 48.80; p = 0.071) suggestive of a more complicated surgical dissection.

Table 3

Table 3

Table 4

Table 4

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Intraoperative Events: Initiation, Duration, and Termination of Cardiopulmonary Bypass

In complete contrast to the time of induction, vasoplegic patients were more likely to have an IS of at least 10 despite similar MAPs at the time of CPB initiation (68.2% vs. 31.9%; p = 0.001). During CPB, vasoplegic patients were more likely to receive >1 L crystalloid and ≥2 units FFP, with a smaller proportion of patients requiring ≥3 units packed red blood cells. Despite similar urine output, vasoplegic patients had a higher net volume during CPB (2,122.75 ± 1,728.25 vs. 1,564.46 ± 1,621.90 cc; p = 0.166). The median neosynephrine requirement for vasoplegic patients was 2,840 μg (IQR: 2,360–3,800 μg) as compared to 1,140 μg (IQR: 220–2980 μg) for nonvasoplegic patients (p < 0.001). Mean SVR calculated from an average of 800 time points during each bypass run was 695 dynes s/cm5 (IQR: 606–726) in vasoplegic patients as compared to 983 dynes s/cm5 (IQR: 872–1,168) in nonvasoplegic patients (Figure 3A). Despite the aforementioned resuscitation, this vasodilatory state was associated with on-bypass hypotension with median MAP of 58.4 mm Hg (IQR: 54.2–61.4 mm Hg) vs. 64.4 mm Hg (IQR: 59.7–70.0 mm Hg) in nonvasoplegic patients (p < 0.001) (Figure 3B). Total time on CPB did not differ between the groups (178 minutes [IQR: 145–246] vs. 167 minutes [IQR: 135–212]; p = 0.150). At the termination of CPB, vasoplegic patients were persistently more hypotensive (67.14 ± 12.71 vs. 73.88 ± 14.19 mm Hg; p = 0.044) despite significantly higher inotropes scores (47.55 ± 28.44 vs. 34.59 ± 23.73; p = 0.025).

Figure 3

Figure 3

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Outcomes

Table 5 summarizes the primary and secondary post-HT outcomes of interest in this patient population. A total of 20 patients (14.5%) received an IABP intraoperatively: four out of 22 vasoplegic patients (18.2%) and 16 out of 116 nonvasoplegic patients (13.8%). Two patients, both vasoplegic, received methylene blue. Importantly, PGD defined as need for MCSD other than IABP within the first 24 hours post-transplant, was “not” more prevalent among vasoplegic patients (n = 5, 22.4% vs. n = 18, 15.5%; p = 0.369)—a finding which was corroborated by the similarity between ejection fractions during the end of procedure intraoperative transesophageal echocardiography (TEE) between groups (49.05% ± 11.69% vs. 49.78% ± 10.67%; p = 0.775). There were no vasoplegic patients who were treated for rejection within 24 hours of transplantation. Despite lack of difference in rates of PGD, 30 day survival was significantly impacted by the development of on-bypass vasoplegia: 86.4% of vasoplegic patients survived to 30 days as compared to 99.1% of nonvasoplegic patients (p = 0.001; Figure 4). Vasoplegic patients were also found to have longer ICU stays (7 [6–14] vs. 5 [4–7] days; p = 0.007) and were more likely to require postoperative initiation of continuous venovenous hemodialysis (22.7% vs. 7.8%; p = 0.049).

Table 5

Table 5

Figure 4

Figure 4

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Predictors of On-Bypass Vasoplegia

Univariate logistic regression analysis was performed on all pre-bypass variables to identify predictors of on-bypass vasoplegia and is summarized in Table 6. Independent predictors identified included male gender (Odds Ratio (OR): 10.6; CI: 1.38–82.02; p = 0.023), BMI (OR: 1.17; CI: 1.07–1.29; p = 0.001), BTT with CF-LVAD (OR: 3.29; CI: 05–10.34; p = 0.041), and IS ≥10 at the time of CPB initiation (OR: 4.57; CI: 1.72–12.17; p = 0.002). Multivariate analysis was not performed due to small sample size and low event rate; however, it was noted that male gender and high BMI were both highly correlated with CF-LVAD use.

Table 6

Table 6

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Discussion

The current study addresses the identification and impact of on-CPB vasoplegia during HT. We found that 16% of our patient population experienced this on-CPB phenomenon, which was associated with significant mortality at 30 and 60 days. Bridge-to-transplant with CF-LVAD was a significant predictor of on-CPB vasoplegia, as was a high IS at the time of bypass initiation—suggesting that this process might begin even before the patient is exposed to CPB.

The current study is unique in that, rather than defining vasoplegia in the postoperative period, we chose to define and identify this phenomenon while on CPB. This is important because 1) we are able to eliminate most but not all of the contribution of donor characteristics to this state; 2) we can be certain that the hypotension and high inotrope requirements we observed are a result of the low peripheral vasculature resistance and not low cardiac output due to dysfunction of the new graft; and 3) any contributions of post-bypass support (IABP, VA-ECMO) do not influence our definition.

Vasoplegia, though inconsistently defined in the literature, has been estimated to complicate 10–27% of cardiac surgery cases.13,16,22,23 Previously identified risk factors include longer duration of CPB and increased blood transfusions, possibly mediated by increased systemic inflammation.15,24 In cardiac transplantation specifically, Byrne et al.14 analyzed 187 consecutive heart transplants, among whom 19% (n = 28) developed postoperative vasoplegia as defined by SVR less than 800 dynes s/cm5 with serum bicarbonate <20 mEq/L. In this population, vasoplegia also was associated with increased in-hospital mortality (25% vs. 9%; p = 0.031). The concept that pretransplant CF-LVAD might contribute to a postoperative vasoplegic state following HT has been previously suggested by Patarroyo et al.20 Among 348 HTs performed during their study, 11% developed postoperative vasoplegia, and CF-LVAD use before transplant was found to be an independent risk factor (OR: 2.8; CI: 1.1–7.4; p = 0.03). Those who developed vasoplegia were more likely to receive VA-ECMO (6.3% vs. 1.1%; p = 0.0312) or IABP (12.1% vs. 3.3%; p = 0.0187). Importantly, 40% of patients who required intraoperative IABP ultimately required transition to MCS—suggesting that in cases of PGD, IABP support likely “not” sufficient, and an early, aggressive MCSD strategy may be beneficial.

With the number of patients transplanted from CF-LVAD rising, transplant centers are becoming increasingly aware of the consequences of prolonged exposure to minimally pulsatile blood flow and its potential impact on post-transplant outcomes. For example, it is now well understood that nearly all CF-LVAD patients will develop acquired Von Willebrand syndrome, with an inverse relationship between bleeding risk and pulsatility.25,26 Neurohormonal axes, including the renin-aldosterone-angiotensin system and the sympathetic nervous system, are affected by continuous flow, albeit with uncertain clinical significance.27,28 Perhaps most importantly, continuous flow seems to alter vascular biology, with blunting of normal vasomotor activity, likely changes in nitric oxide synthesis and release in the setting of chronic shearing forces.29 Over time, maladaptive structural remodeling of the vessels may contribute to alterations in end-organ function and increased risk of cardiovascular events.30 These changes could contribute to the increased risk of perioperative vasoplegia observed in BTT patients in the current study.

One interesting observation was the increased requirement of vasopressors, fluid, and blood products in vasoplegic patients even before the initiation of CPB. Although we do not have sufficient hemodynamic data to calculate SVR during this period, the increase in fluid and product utilization was likely in the setting of increased coagulopathy and hypotension—both of which are characteristic of the vasoplegic syndrome. Taken together with the lower MAP and higher ISs even before the initiation of CPB, the authors believe that the phenomenon of vasoplegia begins even before the shearing forces of CPB are in play.

It remains unclear whether vasoplegia is a distinct entity from PGD, or whether these two perioperative phenomenon remain on the same spectrum. Because of previous lack of a universal definition, however, it is highly probable that prior studies have labeled patients with vasoplegia as having PGD due to their similar clinical phenotype of refractory hypotension and high vasopressor requirements. In the current study, we identified only five patients who demonstrated both intraoperative vasoplegic physiology and would go on to require MCSD for PGD. Among these, two patients had preserved biventricular function at the time of bypass weaning, but required VA-ECMO support for profound hypotension. We hypothesize that these patients suffered predominantly from vasoplegia, but were classified as primary graft failure (PGF) based upon the need for MCS within the first 24 hours of HT.

The current study is unique in that it is the first to identify and describe the phenomenon of on-CPB vasoplegia and its impact on post-transplant survival. We identified BTT with CF-LVAD to be a significant risk factor for the development of this syndrome. Importantly, our analysis suggests that intraoperative vasoplegia during orthotopic heart transplant (OHT) is a phenomenon which develops even before the initiation of CPB, suggesting that patient factors, pretransplant medications (particularly antiarrhythmics and pulmonary vasodilators), and device support might interact with general anesthesia in ways not fully understood to create a provasodilatory state. It is important to note that with the current data available, it is impossible to determine whether it is the device/medication itself or the underlying patient factors necessitating these therapies (i.e., more severe heart failure, right ventricular failure) that are the causative agents for this phenomenon. More research, particularly in basic and translational science, will be needed to further define these relationships. Additional limitations of our study include its retrospective nature and some center-specific intraoperative management strategies, which could limit generalizability of the conclusions.

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Conclusions

In summary, we conclude that vasoplegia occurred 16% of HT recipients during the CPB run, and contributed significantly to post-transplant mortality. Bridge-to-transplant with CF-LVAD was identified as independent predictor of this syndrome.

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References

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Keywords:

vasoplegia; left ventricular assist device; heart transplant

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