Abstract
Aims
The impact of mechanical ventilation (MV) at the time of heart transplantation is not well understood. In addition, MV was recently removed as a criterion from the new US heart transplantation allocation system. We sought to assess for the association between MV at transplantation and 1-year mortality.
Methods and results
We utilized the United Network for Organ Sharing database and included all adult, single organ heart transplantations from 1990 to 2019. We utilized multivariable logistic regression adjusting for demographics, comorbidities, and markers of clinical acuity. We identified 60 980 patients who underwent heart transplantation, 2.4% (n = 1431) of which required MV at transplantation. Ventilated patients were more likely to require temporary mechanical support, previous dialysis, and had a shorter median waitlist time (21 vs. 95 days, P < 0.001). At 1 year, the mortality was 33.7% (n = 484) for ventilated patients and 11.7% (n = 6967) for those not ventilated at the time of transplantation (log-rank P < 0.001). After multivariable adjustment, patients requiring MV continued to have a substantially higher 90-day [odds ratio (OR) 3.20, 95% confidence interval (CI): 2.79–3.66, P < 0.001] and 1-year mortality (OR 2.67, 95% CI: 2.36–3.03, P < 0.001). For those that survived to 90 days, the adjusted mortality at 1 year continued to be higher (OR 1.48, 95% CI: 1.16–1.89, P = 0.002).
Conclusion
We found a strong association between the presence of MV at heart transplantation and 90-day and 1-year mortality. Future studies are needed to identify which patients requiring MV have reasonable outcomes, and which are associated with substantially poorer outcomes.
Keywords: Mechanical ventilation, Heart transplantation, End-stage heart failure
Graphical Abstract
Introduction
Heart transplantation remains the gold standard treatment for patients with end-stage heart failure.1 In order to equitably allocate a very limited resource, risk prediction and prioritizing transplantation aligned with prognosis remains incredibly important. Starting in October 2018, the United Network for Organ Sharing (UNOS) Thoracic Organ Transplantation Committee began a new allocation system to minimize regional variability and to more accurately group patients according to their acuity.2 The new US allocation system largely groups patients according to haemodynamic parameters and subsequent necessity of mechanical circulatory support. In particular, a notable change from the previous allocation system includes the removal of continuous mechanical ventilation, which previously designated a patient as 1A status.2 Similarly, mechanical ventilation is not included in most UK or European allocations schemes.3,4
However, the use of mechanical ventilation, presumably to support respiratory failure, identifies a particularly critically ill patient population and may be a potentially more impartial criterion for assessing acuity.5–7 In a similar population of patients from a national registry undergoing implantation of a left ventricular assist device (LVAD), pre-implant mechanical ventilation identified a population with particularly poor outcomes.7 Similarly, mechanical ventilation has also been a poor prognostic indicator for those undergoing heart transplantation.8,9 However, additional investigation into the associated risk would be clinically useful to clinicians and may also help guide improvements to the allocation system.
Given these gaps in the literature, we assessed for the association between mechanical ventilation at the time of heart transplantation and 1-year mortality. We also assessed for the additional risk of mechanical ventilation stratified by allocation status, mechanical ventilation utilization trends over time, and predictors of 1-year mortality for those requiring mechanical ventilation.
Methods
Data source and study cohort
We utilized the cardiac transplant data from UNOS, which publishes the Organ Procurement and Transplant Network (OPTN) database. The database includes all solid organ transplantations since 1 October 1987 and includes patient information, timing of waitlist and transplant, and post-transplant outcomes. The data are publicly available and therefore deemed exempt by the institutional review board.
We queried the UNOS database for all adult (aged ≥ 18 years) heart transplantations between 1 January 1990 and 12 June 2019 to allow for at least 1 year of follow-up for each patient. Those undergoing multiorgan transplantation were excluded from this analysis. Patients were separated into two cohorts based on the presence of mechanical ventilation at transplantation.
Outcomes
The primary outcome of interest was all-cause 1-year mortality, which was selected since it is a key quality metric.10 Secondary outcomes included 90-day all-cause mortality, mortality at 1 year for those that survived to 90 days, and the additional risk of mechanical ventilation stratified by allocation status at the time of transplantation. We also assessed for trends in the proportion of patients requiring mechanical ventilation per year as well as 1-year mortality for those ventilated at the time of transplantation.
Statistical analysis
Baseline characteristics were stratified by utilization of mechanical ventilation at the time of heart transplantation. Continuous variables were reported with the median and interquartile range compared using the Wilcoxon rank-sum test and categorical variables were described as frequencies and percentage using the chi-squared test. Multivariable logistic regression was utilized to assess for the association with 1-year all-cause mortality because the proportional hazards assumption was not met after assessment of Schoenfeld residuals. Our multivariable logistic regression model included a priori selected variables including year of transplantation (continuous), demographics (age, gender, race, tobacco use, insurance status private or public), medical history and comorbidities (primary cardiomyopathy diagnosis, diabetes, dialysis, stroke, malignancy, primary cardiac surgery, automated implantable cardioverter-defibrillator), and haemodynamic support at the time of transplantation [inotropes, intra-aortic balloon pump (IABP), extracorporeal membrane oxygenation (ECMO), LVAD, total artificial heart, or other ventricular assist devices].
Given the prolonged study period, we also assessed for all-cause 1-year mortality stratified by decade (1990–1999, 2000–2010, and 2011–2019). These analyses were adjusted with the same covariates except for transplant year. In order to investigate the added risk of mechanical ventilation at the time of transplantation, we conducted an unadjusted analysis stratified by UNOS status. Due to a much smaller sample size after the new allocation system, status 1 through 3 (equivalent to old status 1A) were included for patients transplanted after 18 October 2018. Linear regression was used to assess the proportion of mechanical ventilation utilization at the time of heart transplantation per year as well as for trends in 1-year mortality.
In addition, we performed several sensitivity analyses. First, given shorter waitlist times for those ventilated at transplantation, we assessed for the association between 1-year mortality for those ventilated only at listing and also for those ventilated at both listing and transplant. Second, we assessed for the association between 1-year mortality with key types of haemodynamic support in patients ventilated and not ventilated at the time of transplantation. We included inotropes, IABP, ECMO, and any support defined as the presence of IABP, ECMO, right ventricular assist device (RVAD) ± LVAD, or mechanical circulatory support unspecified. Finally, in order to assess for variables associated with additive risk amongst mechanically ventilated patients, we conducted univariate and multivariable logistic regression models including only the mechanically ventilated cohort (n = 1431). A conservative threshold of P < 0.20 was used to select univariate variables included in the multivariable model. All analyses were performed on STATA 16.0 (Stata Corp, College Station, TX, USA) and trend graphics were produced by GraphPad Prism version 8.3.0 (GraphPad Software, La Jolla, CA, USA). Statistical significance was considered at a two-tailed P < 0.05.
Results
Baseline characteristics
From 1990 to 2019, we identified 60 980 patients who underwent heart transplantation, 1431 (2.4%) of which required mechanical ventilation at the time of transplantation. Baseline patient characteristics stratified by mechanical ventilation utilization are shown in Table 1. Patients requiring mechanical ventilation were more likely to be younger (median age 55 vs. 53 years), female, listed as status 1A in the old allocation system (42.1% vs. 70.1%) and status 1 in the new system, had a history of previous dialysis, and more likely to have a primary diagnosis of ischaemic compared to dilated cardiomyopathy (all, P < 0.05). A higher proportion of those not requiring pre-transplant mechanical ventilation had a history of diabetes, tobacco use, cancer, and prior cardiac surgery (all, P < 0.05). Ventilated patients had a lower median cardiac output, higher median pulmonary diastolic, systolic, and mean pressures, and higher median pulmonary capillary wedge pressure at transplantation.
Table 1.
Baseline recipient characteristics by mechanical ventilation
| No mechanical ventilation (N = 59 549) | Mechanical ventilation (N = 1431) | P-value | |
|---|---|---|---|
| Demographics | |||
| Age, years | 55 (46–61) | 53 (43–60) | <0.001 |
| Men | 45 282 (76.0%) | 1046 (73.1%) | 0.010 |
| Race | 0.006 | ||
| White | 43 635 (73.3%) | 1096 (76.6%) | |
| Black | 9878 (16.6%) | 186 (13.0%) | |
| Hispanic | 3974 (6.7%) | 103 (7.2%) | |
| Asian | 1443 (2.4%) | 35 (2.4%) | |
| Other | 619 (1.0%) | 11 (0.8%) | |
| Body mass index, kg/m2 | 26.1 (23.0–29.6) | 25.2 (22.1–28.8) | <0.001 |
| Old status | <0.001 | ||
| 1A | 20 496 (42.1%) | 663 (70.2%) | |
| 1B | 14 286 (29.3%) | 156 (16.5%) | |
| 2 | 12 070 (24.8%) | 75 (7.9%) | |
| Current status | <0.001 | ||
| 1 | 124 (0.3%) | 37 (3.9%) | |
| 2 | 842 (1.7%) | 13 (1.4%) | |
| 3 | 492 (1.0%) | 0 (0.0%) | |
| 4 | 342 (0.7%) | 1 (0.1%) | |
| 5 | 7 (0.0%) | 0 (0.0%) | |
| 6 | 66 (0.1%) | 0 (0.0%) | |
| Blood type | 0.11 | ||
| A | 25 168 (42.3%) | 620 (43.3%) | |
| B | 8344 (14.0%) | 175 (12.2%) | |
| AB | 3214 (5.4%) | 66 (4.6%) | |
| O | 22 823 (38.3%) | 570 (39.8%) | |
| Insurance | <0.001 | ||
| Private | 27 576 (46.3%) | 737 (51.5%) | |
| Public | 22 373 (37.6%) | 401 (28.0%) | |
| Comorbidities | |||
| Heart failure cause | <0.001 | ||
| Non-ischaemic dilated | 26 796 (45.0%) | 464 (32.4%) | |
| Ischaemic | 16 948 (28.5%) | 439 (30.7%) | |
| Other | 16 948 (28.5%) | 439 (30.7%) | |
| History of diabetes | 12 140 (20.4%) | 233 (16.3%) | <0.001 |
| Previous dialysis | 2020 (3.4%) | 161 (11.3%) | <0.001 |
| Tobacco history | 14 667 (24.6%) | 233 (16.3%) | <0.001 |
| AICD | 28 553 (47.9%) | 434 (30.3%) | <0.001 |
| History of stroke | 2366 (4.0%) | 57 (4.0%) | 0.98 |
| History of cancer | 3191 (5.4%) | 46 (3.2%) | <0.001 |
| Prior cardiac surgery | 12 440 (20.9%) | 264 (18.4%) | 0.03 |
| Haemodynamics | |||
| Cardiac output, L/min | 4.3 (3.5–5.3) | 4.2 (3.3–5.3) | 0.04 |
| PA diastolic pressure, mm Hg | 20 (14–26) | 22 (16–28) | <0.001 |
| PA systolic pressure, mm Hg | 40 (31–51) | 42 (32–53) | 0.02 |
| PA mean, mm HG | 28 (21–35) | 29 (22–37) | <0.001 |
| PCWP, mm Hg | 18 (12–25) | 20 (14–27) | <0.001 |
Data are presented as median (interquartile range) for continuous measures, and n (%) for categorical variables.
AICD, automated implantable cardioverter-defibrillator; PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure.
At the time of transplantation, medical therapy differed significantly between those with and without mechanical ventilation (Table 2). The mechanical ventilation group was more likely to be receiving intravenous inotropes (66.9 vs. 39.8%), IABP (34.7% vs. 5.8%), and ECMO (11.6% vs. 0.4%) (all, P < 0.001). In comparison, a greater proportion of patients that were non-ventilated at transplant had an LVAD (19.2% vs. 8.0%, P < 0.001).
Table 2.
Haemodynamic support and transplant specifics
| No mechanical ventilation (N = 59 549) | Mechanical ventilation (N = 1431) | P-value | |
|---|---|---|---|
| Medical therapy | |||
| Inotropes | 23 687 (39.8%) | 957 (66.9%) | <0.001 |
| Intra-aortic balloon pump | 3448 (5.8%) | 496 (34.7%) | <0.001 |
| LVAD | 11 408 (19.2%) | 114 (8.0%) | <0.001 |
| Total artificial heart | 368 (0.6%) | 12 (0.8%) | 0.29 |
| Extracorporeal membrane oxygenation | 218 (0.4%) | 166 (11.6%) | <0.001 |
| RVAD ± LVAD or MCS unspecified | 3711 (6.2%) | 323 (22.6%) | <0.001 |
| Transplant specifics | |||
| Days on waitlist | 95 (30–260) | 21 (5–87) | <0.001 |
| Ischaemic time, h | 3.0 (2.3–3.7) | 3.1 (2.4–3.8) | <0.001 |
| Distance travelled, miles | 76 (9–220) | 91 (13–276) | <0.001 |
Data are presented as median (interquartile range) for continuous measures, and n (%) for categorical variables.
LVAD, left ventricular assist device; MCS, mechanical circulatory support; RVAD, right ventricular assist device.
Median days on the waitlist were substantially shorter for those on mechanical ventilation (21 vs. 95 days, P < 0.001). Ischaemic time in hours was clinically similar while the median distance travelled for organ procurement was longer in the mechanical ventilation cohort (76 vs. 91 miles, P < 0.001). Further details on donor characteristics are detailed in the Supplementary material online, Table S1.
Post-transplant mortality
At 1 year, the all-cause mortality was 33.7% (n = 484) and 11.7% (n = 6967) for patients ventilated and not ventilated at the time of transplantation, respectively (Figure 1, P < 0.001). After multivariable adjustment, patients mechanically ventilated continued to have a substantially higher 1-year mortality [adjusted odds ratio (aOR) 2.67, 95% confidence interval (CI): 2.36–3.03, P < 0.001]. The top 10 causes of death within 1 year were similar between groups, including rejection and infections, with the exception of multiorgan failure, which was higher in the ventilated cohort (20.7% vs. 11.2%, P < 0.001) (Supplementary material online, Table S2). The 90-day mortality was 28.0% (n = 400) in the ventilated group and 7.5% (n = 4462) in the non-ventilated group (P < 0.001). Similarly, the adjusted 90-day mortality was a higher in the mechanically ventilated cohort (aOR 3.20, 95% CI: 2.79–3.66, P < 0.001). For those that survived to 90 days, mortality at 1 year continued to be higher (aOR 1.48, 95% CI: 1.16–1.89, P = 0.002).
Figure 1.
Survival in patients stratified by mechanical ventilation. MV, mechanical ventilation.
Given the substantially long study period, adjusted analyses were repeated during each 10-year span for the primary outcome. Starting with the oldest cohort (1990–1999), patients ventilated cohort had an increased mortality (aOR 2.60, 95% CI: 2.15–3.13, P < 0.001), which was similar to the middle cohort (2000–2009) (aOR 2.61, 95% CI: 2.12–3.22, P < 0.001). However, patients ventilated at transplantation in the most contemporary cohort (2010–2019) had the highest odds of 1-year mortality (aOR 2.96, 95% CI: 2.20–3.98, P < 0.001).
Next, we assessed for the unadjusted association with mechanical ventilation at transplantation stratified by UNOS status. Including the old allocation system first, compared to non-ventilated 1A patients, those that were ventilated had an increased 1-year mortality [odds ratio (OR) 4.24, 95% CI: 3.59–5.01, P < 0.001]. Similarly, patients that were status 1B (OR 3.90, 95% CI: 2.76–5.51) and 2 (OR 4.11, 95% CI: 2.57–6.59) at transplantation had an increased mortality compared to non-ventilated patients (both, P < 0.001). Ventilated patients transplanted with status 1 through 3 in the new allocation system likewise had an increased 1-year mortality (OR 2.15, 95% CI: 1.02–4.52, P = 0.04).
Trends in incidence and mortality
The incidence of mechanical ventilation utilization at the time of transplantation ranged from 0.6% in 2017 to a maximum of 5.1% in 1999 (Figure 2). Over the study period, the overall trend was a decrease in the proportion of patients supported with mechanical ventilation at transplantation (P < 0.001). The all-cause 1-year mortality per year varied widely from 5.6% in 2015 to 50.0% in 2012 (Figure 3), and similarly showed a trend towards a decreased mortality over the study period (P = 0.02).
Figure 2.
Mechanical ventilation trends at the time of transplantation per year. Best fit (solid line) and 95% confidence interval (dotted line).
Figure 3.
Mortality trends for those requiring mechanical ventilation at the time of transplantation. Best fit (solid line) and 95% confidence interval (dotted line).
Predictors of mortality
Including only the mechanically ventilated cohort (n = 1431), the association between clinical covariates and 1-year mortality are listed in Table 3. A history of previous dialysis, ECMO at transplantation, and body mass index (BMI) >35 kg/m2 had the greatest additional impact. For mechanically ventilated patients with and without a history of previous dialysis, the 1-year mortality was 61.5% and 30.3%, respectively. Ventilated patients on ECMO had a 1-year mortality of 44.6% compared to 32.5% in those ventilated but not on ECMO. Finally, ventilated patients with a BMI >35 kg/m2 had a 1-year mortality of 44.9% compared to 33.2% in those with lower BMIs. After inclusion of univariate variables with a P < 0.20 into a multivariable analysis (total model c-statistic = 0.71), independent variables associated with increased 1-year mortality included age ≥60 years, BMI >35 kg/m2, creatinine >2.0 mg/dL, total bilirubin >2.0 mg/dL, ECMO, RVAD ± LVAD or unspecified mechanical circulatory support, previous dialysis, and waitlist days >30 (all, P < 0.05).
Table 3.
Univariate and multivariable logistic regression analysis for 1-year mortality including only mechanically ventilated patients
| Variable | Univariate | Multivariable |
|---|---|---|
| Odds ratio (95% CI) | Odds ratio (95% CI) | |
| Age ≥60 years | 1.31 (1.03–1.66) | 1.52 (1.08–2.14) |
| Female | 0.95 (0.74–1.22) | |
| Black | 1.06 (0.77–1.46) | |
| Hispanic | 1.01 (0.66–1.54) | |
| White | 0.94 (0.73–1.21) | |
| BMI >35 kg/m2 | 1.64 (1.03–2.60) | 1.89 (1.04–3.44) |
| BMI <20 kg/m2 | 1.01 (0.70–1.46) | |
| Inotropes | 1.00 (0.80–1.27) | |
| Transplant status | 0.87 (0.74–1.01) | 0.91 (0.76–1.09) |
| Creatinine >2.0 mg/dL | 1.69 (1.34–2.23) | 1.48 (1.01–2.16) |
| Total bilirubin >2.0 mg/dL | 1.82 (1.46–2.27) | 1.84 (1.32–2.57) |
| Private insurance | 0.88 (0.71–1.10) | |
| Public insurance | 1.01 (0.79–1.28) | |
| ECMO | 1.68 (1.21–2.33) | 2.13 (1.38–3.28) |
| IABP | 0.80 (0.64–1.01) | 0.79 (0.55–1.12) |
| LVAD | 0.86 (0.57–1.30) | |
| TAH | 3.96 (1.19–13.22) | 2.88 (0.73–11.39) |
| RVAD ± LVAD or MCS unspecified | 1.32 (1.02–1.70) | 1.58 (1.08–2.31) |
| Previous dialysis | 3.67 (2.61–5.15) | 2.67 (1.72–4.13) |
| Dilated cardiomyopathy | 0.64 (0.51–0.82) | 0.72 (0.51–1.03) |
| Ischaemic cardiomyopathy | 0.90 (0.70–1.14) | |
| Diabetes | 0.83 (0.62–1.13) | |
| Stroke | 1.81 (1.06–3.07) | 1.56 (0.76–3.22) |
| AICD | 0.80 (0.63–1.02) | 0.99 (0.70–1.40) |
| Smoking | 0.65 (0.47–0.89) | 0.72 (0.48–1.07) |
| Cancer | 0.76 (0.40–1.47) | |
| Prior cardiac surgery | 1.22 (0.92–1.61) | 1.25 (0.86–1.80) |
| Blood type | 0.98 (0.91–1.06) | |
| Distance travelled >100 miles | 1.00 (0.80–1.25) | |
| Days on waitlist >30 days | 1.38 (1.10–1.72) | 1.71 (1.23–2.38) |
| Ischaemic time >3.2 h | 1.30 (1.03–1.63) | 1.26 (0.92–1.72) |
| Centre | 1.00 (1.00–1.00) | 1.00 (1.00–1.00) |
In univariate analysis, P < 0.20 was considered significant, while P < 0.05 was considered significant in multivariable analysis (bold).
AICD, automated implantable cardioverter defibrillator; BMI, body mass index; CI, confidence interval; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; LVAD, left ventricular assist device; RVAD, right ventricular assist device; TAH, total artificial heart.
Sensitivity analyses
The median waitlist time in days for patients ventilated only at the time of listing or both listing and transplantation was 72 and 6 days, respectively. The mortality for patients ventilated only at listing was not significantly different than those not mechanically ventilated at listing (aOR 0.96, 95% CI: 0.80–1.15, P = 0.67). However, patients ventilated at both listing and transplant had an increased mortality at 1 year (aOR 1.71; 95% CI: 1.37–2.14, P < 0.001). Compared to patients not ventilated and requiring inotropes at the time of transplant, requirement of mechanical ventilation and inotropes was associated with a higher 1-year mortality (aOR 2.42, 95% CI: 2.06–2.85, P < 0.001). Similarly, compared to patients requiring the corresponding mechanical circulatory support but not mechanical ventilation, patients ventilated with IABP (aOR 1.81, 95% CI: 1.42–2.32, P < 0.001), ECMO (aOR 3.30; 95% CI: 1.76–6.18, P < 0.001), or any support (aOR 2.12, 95% CI: 1.78–2.54, P < 0.001) was associated with a higher 1-year mortality.
Discussion
In this analysis of the UNOS database, we describe the incidence and clinical outcomes associated with mechanical ventilation at the time of heart transplantation. We found that 2.4% of patients required mechanical ventilation at transplantation and that the all-cause mortality at 1 year was 33.7%. Over the last 30 years, we found a trend towards a decreased incidence and 1-year mortality for those ventilated at transplant. After multivariable analysis for other variables of clinical acuity, ventilated patients continued to have an approximately 3 times higher mortality at 90 days and 2.5 times higher at 1 year, which was similar over each decade and additive when stratified by each UNOS allocation status. Although the majority of the risk appears to be early, ventilated patients that survive to 90 days continued to have an increased mortality at 1 year. Overall, these findings suggest that patients awaiting heart transplantation who require mechanical ventilation represent a critically ill population which require early transplant consideration.
Our results are particularly relevant given the recent changes in the UNOS allocation system in 2018, which removed the use of mechanical ventilation as a criterion for transplantation status.11 In the new allocation system, need and acuity is largely based on haemodynamic measures such as intravenous inotropes and mechanical circulatory support (both durable and temporary). However, our findings suggest that the use of mechanical ventilation at transplantation represents a population with additional risk above these well-established risk factors.
To our knowledge, no studies have specifically assessed mechanical ventilation as a primary analysis. A recent study from the Scientific Registry of Transplant Recipients (SRTR) database, using machine learning methods, identified pre-transplant mechanical ventilation as an independent predictor of poorer outcomes.8 Similarly, in a German report including 774 heart transplant patients from 2006 to 2008 assessing risk factors, Kutschmann et al.12 found that ventilator dependency was associated with over a 3 times increased risk of death (hazard ratio 3.17; 95% CI: 2.21–6.34), which persisted after multivariable adjustment. A Korean study, including 210 transplanted patients, which investigated for clinical trends over time found that mechanical ventilation was more common in their most contemporary period (post-2009), and also associated with worse post-transplant survival.13 In addition to a substantially larger population than the latter studies and longer study period, our report has several additional strengths, including an assessment of the additive risk of mechanical ventilation by UNOS status and to various types of haemodynamic support, incidence and mortality trends over time, predictors of mortality amongst ventilated patients, and the impact of ventilator use at listing.
There were two additional novel findings from our study. First, compared to patients not ventilated at transplant, mechanically ventilated patients had additional risk at 1 year compared to each corresponding UNOS level. This is particularly important given the changes in the new allocation system, which was designed to prioritize organ allocation while not jeopardizing transplant outcomes.2 Specifically, the use of continuous mechanical ventilation was removed from the Status 1A criteria. Second, we found no additional risk for patients ventilated at listing but not transplantation, which suggests that centres can consider the transplant process while a patient requires ventilator support.
The need for respiratory support is clearly a marker of overall illness, but whether mechanical ventilation may independently influence outcomes is not readily clear.14 Although frequently lifesaving, prolonged mechanical ventilation is also associated with several potential complications which occur in upwards of 20–30% of patients.15 These adverse effects may be especially prominent in frail and chronically ill patients with end-stage heart failure.16 In addition to obvious complications such as ventilator-associated infections,17 mechanical ventilation may expose patients to interruptions in nutrition, delirium, ventilator-induced lung injury, and immobilization.14,18–20 All of these factors could potentially delay recovery following heart transplantation.
Although not unexpected, our findings demonstrate the importance of respiratory failure on post-transplant outcomes, which are additive to other markers of acuity included in current allocation schemas, such as mechanical circulatory support. Given these findings and limited organ availability, serious consideration should be given to which patients requiring mechanical ventilation represent a prohibitively high post-transplant risk and which patients should be given priority equivalent to the presence of mechanical circulatory support. For example, we found that ventilated patients undergoing dialysis before transplantation had an approximately 60% mortality at 1 year. Alternatively, the overall 1-year mortality for patients requiring mechanical ventilation are similar to patients requiring ECMO, which currently affords patients priority status in current allocation schemes.2–4 Overall, we believe these findings should not exclude candidacy of patients requiring mechanical ventilation, but instead should lead to a comprehensive, patient-specific risk evaluation. In addition, it is important to note that we lack important details that require further research, such as right ventricular function, infection specific details, level of ventilator support (which can influence the unique cardiopulmonary interactions with right and left ventricular failure), and length of ventilator support. A patient on maximum ventilator support for 10 days likely represents a significantly different phenotype than someone on their second day of ventilator support with improving settings. Future studies should investigate whether time limits, similar to mechanical circulatory support criteria (e.g. ECMO within the first 14 days), impact post-transplant outcomes.
Limitations
In addition to being retrospective in nature, there are several notable limitations of our study. First, we lack data on the length of mechanical ventilation, both in relation to transplantation and to other therapies such as mechanical circulatory support. Therefore, we are unable to assess a time or ‘dose’ relationship between ventilator length and mortality or the temporal relationship with other therapies. Second, data on post-transplant respiratory outcomes, such as post-implant respiratory failure or need for tracheostomy were not included due to limitations of the dataset. Third, we lack the aetiology of respiratory failure and important information on ventilator management such as the mode and ventilator settings (e.g. tidal volume, oxygen, pressure levels), which may influence outcomes. Finally, there was not sufficient numbers to make clear comparisons with the new allocation system. However, in sensitivity analysis, we found that the presence of mechanical ventilation was additive to a key criterion for Status 1 listing in the new allocation system.
Conclusions
In this analysis of the UNOS database, we found that mechanical ventilation at the time of heart transplantation was associated with substantially worse 1-year mortality. Our findings persisted despite multivariable adjustment for other markers of acuity, and importantly was additive to each level of UNOS status. Given the recent change in the allocation system and removal of continuous mechanical ventilation as a criterion, we believe these findings should lead to a re-evaluation of mechanical ventilation in the listing criteria.
Supplementary material
Supplementary material is available at European Heart Journal: Acute Cardiovascular Care online.
Data availability
UNOS is a publicly available dataset and can be obtained by data request from OPTN.
Funding
P.E.M. reports funding through the Yale National Clinician Scholars Program and by CTSA (TL1 TR001864) from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH.
Conflict of interest: R.F. is the President of the American Society of Transplantation, Member of the OPTN/UNOS Membership and Professional Standards Committee, and the Member of the Visiting Committee for the Scientific Registry of Transplant Recipients. J.G.R. is the President-elect of the International Society for Heart and Lung Transplantation. Results and views in this manuscript do not represent views of these organizations. No other authors have anything to disclose.
Supplementary Material
References
- 1. Stehlik J, Edwards LB, Kucheryavaya AY, Aurora P, Christie JD, Kirk R, Dobbels F, Rahmel AO, Hertz MI.. The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh official adult heart transplant report–2010. J Heart Lung Transplant 2010;29:1089–1103. [DOI] [PubMed] [Google Scholar]
- 2.Organ Procurement and Transplantation Network: Policies. http://optn.transplant.hrsa.gov/PoliciesandBylaws2/policies/pdfs/policy_9.pdf (2 December 2020).
- 3. Dorent R, Jasseron C, Audry B, Bayer F, Legeai C, Cantrelle C, Smits JM, Eisen H, Jacquelinet C, Leprince P, Bastien O.. New French heart allocation system: comparison with Eurotransplant and US allocation systems. Am J Transplant 2020;20:1236–1243. [DOI] [PubMed] [Google Scholar]
- 4. Rushton S, Parameshwar J, Lim S, Dar O, Callan P, Al-Attar N, Tsui S, MacGowan GA.. The introduction of a super-urgent heart allocation scheme in the UK: a 2-year review. J Heart Lung Transplant 2020;39:1109–1117. [DOI] [PubMed] [Google Scholar]
- 5. Miller PE, Patel S, Saha A, Guha A, Pawar S, Poojary P, Ratnani P, Chan L, Kamholz SL, Alviar CL, van Diepen S, Nasir K, Ahmad T, Nadkarni GN, Desai NR.. National trends in incidence and outcomes of patients with heart failure requiring respiratory support. Am J Cardiol 2019;124:1712–1719. [DOI] [PubMed] [Google Scholar]
- 6. Miller PE, van Diepen S, Ahmad T.. Acute decompensated heart failure complicated by respiratory failure. Circ Heart Fail 2019;12:e006013. [DOI] [PubMed] [Google Scholar]
- 7. Miller PE, Caraballo C, Ravindra NG, Mezzacappa C, McCullough M, Gruen J, Levin A, Reinhardt S, Ali A, Desai NR, Ahmad T.. Clinical implications of respiratory failure in patients receiving durable left ventricular assist devices for end-stage heart failure. Circ Heart Fail 2019;12:e006369. [DOI] [PubMed] [Google Scholar]
- 8. Hsich EM, Blackstone EH, Thuita LW, McNamara DM, Rogers JG, Yancy CW, Goldberg LR, Valapour M, Xu G, Ishwaran H.. Heart transplantation: an in-depth survival analysis. JACC Heart Fail 2020;8:557–568. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Nilsson J, Ohlsson M, Hoglund P, Ekmehag B, Koul B, Andersson B.. The International Heart Transplant Survival Algorithm (IHTSA): a new model to improve organ sharing and survival. PLoS One 2015;10:e0118644. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Kasiske BL, McBride MA, Cornell DL, Gaston RS, Henry ML, Irwin FD, Israni AK, Metzler NW, Murphy KW, Reed AI, Roberts JP, Salkowski N, Snyder JJ, Sweet SC.. Report of a consensus conference on transplant program quality and surveillance. Am J Transplant 2012;12:1988–1996. [DOI] [PubMed] [Google Scholar]
- 11. Cogswell R, John R, Estep JD, Duval S, Tedford RJ, Pagani FD, Martin CM, Mehra MR.. An early investigation of outcomes with the new 2018 donor heart allocation system in the United States. J Heart Lung Transplant 2020;39:1–4. [DOI] [PubMed] [Google Scholar]
- 12. Kutschmann M, Fischer-Fröhlich C-L, Schmidtmann I, Bungard S, Zeissig SR, Polster F, Kirste G, Frühauf NR.. The joint impact of donor and recipient parameters on the outcome of heart transplantation in Germany after graft allocation. Transpl Int 2014;27:152–161. [DOI] [PubMed] [Google Scholar]
- 13. Lee JH, Yeom SY, Hwang HY, Choi JW, Cho HJ, Lee HY, Huh JH, Kim KB.. Twenty-year experience of heart transplantation: early and long-term results. Korean J Thorac Cardiovasc Surg 2016;49:242–249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Alviar CL, Miller PE, McAreavey D, Katz JN, Lee B, Moriyama B, Soble J, van Diepen S, Solomon MA, Morrow DA; ACC Critical Care Cardiology Working Group. Positive pressure ventilation in the cardiac intensive care unit. J Am Coll Cardiol 2018;72:1532–1553. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Neto AS, Barbas CSV, Simonis FD, Artigas-Raventós A, Canet J, Determann RM, Anstey J, Hedenstierna G, Hemmes SNT, Hermans G, Hiesmayr M, Hollmann MW, Jaber S, Martin-Loeches I, Mills GH, Pearse RM, Putensen C, Schmid W, Severgnini P, Smith R, Treschan TA, Tschernko EM, Melo MFV, Wrigge H, de Abreu MG, Pelosi P, Schultz MJ; PRoVENT; PROVE Network investigators. Epidemiological characteristics, practice of ventilation, and clinical outcome in patients at risk of acute respiratory distress syndrome in intensive care units from 16 countries (PRoVENT): an international, multicentre, prospective study. Lancet Respir Med 2016;4:882–893. [DOI] [PubMed] [Google Scholar]
- 16. Damluji AA, Forman DE, van Diepen S, Alexander KP, Page RL 2nd, Hummel SL, Menon V, Katz JN, Albert NM, Afilalo J, Cohen MG; American Heart Association Council on Clinical Cardiology and Council on Cardiovascular and Stroke Nursing. Older adults in the cardiac intensive care unit: factoring geriatric syndromes in the management, prognosis, and process of care: a scientific statement from the American Heart Association. Circulation 2020;141:e6–e32. [DOI] [PubMed] [Google Scholar]
- 17. Miller PE, Guha A, Khera R, Chouairi F, Ahmad T, Nasir K, Addison D, Desai NR.. National trends in healthcare-associated infections for five common cardiovascular conditions. Am J Cardiol 2019;124:1140–1148. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Binnekade JM, Tepaske R, Bruynzeel P, Mathus-Vliegen EM, de Hann RJ.. Daily enteral feeding practice on the ICU: attainment of goals and interfering factors. Crit Care 2005;9:R218– R225. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Dres M, Dube BP, Mayaux J, Delemazure J, Reuter D, Brochard L, Similowski T, Demoule A.. Coexistence and impact of limb muscle and diaphragm weakness at time of liberation from mechanical ventilation in medical intensive care unit patients. Am J Respir Crit Care Med 2017;195:57–66. [DOI] [PubMed] [Google Scholar]
- 20. Fordyce CB, Katz JN, Alviar CL, Arslanian-Engoren C, Bohula EA, Geller BJ, Hollenberg SM, Jentzer JC, Sims DB, Washam JB, van Diepen S; American Heart Association Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; and Stroke Council. Prevention of complications in the cardiac intensive care unit: a scientific statement from the American Heart Association. Circulation 2020;142:e379–e406. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
UNOS is a publicly available dataset and can be obtained by data request from OPTN.