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Acute lung injury is a known complication of pulmonary artery reconstruction for peripheral pulmonary artery stenosis. Severe cases may require support with extracorporeal membrane oxygenation. The purpose of this study was to evaluate the characteristics of patients requiring extracorporeal membrane oxygenation after pulmonary artery reconstruction.
This was a retrospective study of 150 patients who underwent surgical repair of peripheral pulmonary artery stenosis at our institution from 2002 to 2022. Underlying diagnoses included Williams syndrome (n = 44), Alagille syndrome (n = 43), elastin arteriopathy (n = 21), tetralogy of Fallot (n = 21), and other (n = 21). Characteristics of patients who required extracorporeal membrane oxygenation were compared with those who did not require extracorporeal membrane oxygenation.
Eleven of the 150 patients undergoing pulmonary artery reconstruction (7.3%) required postoperative extracorporeal membrane oxygenation support (10 for acute lung injury and 1 for cardiac insufficiency). Four patients receiving extracorporeal membrane oxygenation had Williams syndrome, 3 patients had Alagille, and 4 patients had tetralogy of Fallot. Patients requiring extracorporeal membrane oxygenation had a higher preoperative right ventricle to aortic peak systolic pressure ratios (mean 1.14 vs 0.95), greater number of pulmonary artery ostial interventions (median, 23 vs 17), and longer duration of cardiopulmonary bypass (median, 597 vs 400 minutes). There were 3 in-hospital deaths (2.0%), 2 of whom required postoperative extracorporeal membrane oxygenation support.
The data demonstrate multiple differences between patients who did and did not require extracorporeal membrane oxygenation after surgical repair of peripheral pulmonary artery stenosis. These results suggest that the preoperative extent of disease may predispose to the development of acute lung injury requiring extracorporeal membrane oxygenation support.
A total of 150 patients underwent surgical repair of PPAS. Of these, 11 (7.3%) required ECMO. Predisposing factors included preoperative and postoperative RV/Ao pressure ratio, CPB time, and number of ostial stenoses.
Acute lung injury is a known complication after surgical repair of PPAS, and severe cases may require ECMO support. This included 150 patients who underwent surgical repair of PPAS, of whom 11 (7.3%) were placed on ECMO. Patients receiving ECMO had a 10-fold higher prevalence of death. Risk factors for ECMO included preoperative and postoperative RV/Ao pressure ratio, CPB time, and number of ostial stenoses.
Pulmonary artery reconstruction has been developed for the treatment of peripheral pulmonary artery stenosis (PPAS).
Presumably, acute lung injury is caused by an acute postoperative increase in pressure or flow to some portions of the lung that were previously protected by stenoses. Severe cases of lung injury may require support with extracorporeal membrane oxygenation (ECMO). ECMO support provides a window of time during which the lungs can rest and recover from the acute physiologic injury.
The majority of patients undergoing surgical repair of PPAS are able to recover from these lengthy procedures without developing acute lung injury or the need for ECMO. We hypothesized there may be certain factors that predispose to the development of acute lung injury. The purpose of this study was to evaluate the characteristics of patients requiring ECMO after pulmonary artery reconstruction.
Materials and Methods
This was a retrospective review of 150 consecutive patients who underwent surgical repair of PPAS at our institution from 2002 to the end of 2021.
All patients undergo a preoperative cardiac catheterization to measure hemodynamics including peak systolic right ventricle (RV) and aortic (Ao) pressures. The RV/Ao pressure ratios are calculated from these data and recorded as the preoperative values. The catheterizations also provide a visual road map for assessing the extent and degree of ostial stenoses.
A detailed description of our surgical approach has been put forth in several publications.
Because the focus of the current article is to evaluate the characteristics of patients requiring postoperative ECMO, the surgical details will not be repeated in this report. It should be pointed out that all patients undergoing CPB procedures at our institution receive intraoperative steroids (30 mg/kg methylprednisolone) per institutional protocol.
We use continuous ultrafiltration during CPB but do not use modified ultrafiltration after separation from CPB.
At the conclusion of the surgical procedure, pressure monitoring catheters are placed in the left atrium and RV. These values are placed in the context of the systemic pressure. The postoperative RV/Ao systolic pressures and pressure ratios are recorded in the operative record and reported in this article as the postoperative values.
Results are reported as the median and range for all descriptive data, and means and standard deviations when indicated. Characteristics of patients who required postoperative ECMO support were compared with patients who did not require ECMO using the Student nonpaired t test. Operative mortality was defined in accordance with the Society of Thoracic Surgeons database. Kaplan–Meier curves were constructed for survival, and 95% confidence intervals are shown in the shaded areas. A log-rank test was performed to compare the 2 Kaplan–Meier curves and the relative risk of mortality was calculated based on the data underlying the 2 curves. Linear regression analysis was performed for continuous variables, and receiver operating characteristic was performed for analysis of binomial variables.
The 150 patients with PPAS included 44 with Williams syndrome, 43 with Alagille syndrome, 21 with elastin arteriopathy, and 21 with tetralogy of Fallot and PPAS (Figure 1). Other diagnoses included truncus arteriosus (n = 5), transposition of the great arteries (n = 3), double outlet right ventricle (n = 2), arterial tortuosity syndrome (n = 3), hypoplastic left heart syndrome (n = 2), and 1 each with Noonan syndrome, chromosome 19 microdeletion, pulmonary artery calcinosis, scimitar syndrome, congenital rubella, and Leiden deficiency.
The mean age at PPAS surgery was 36 ± 12 months (range, 3-226 months, interquartile range [IQR], 24-90 months). Ninety-one patients had undergone previous cardiac surgical procedures, and 17 patients had undergone more than 1 previous sternotomy.
The mean preoperative RV/Ao pressure ratio was 1.01 ± 0.16 (median, 1.02, range, 0.60-1.60, IQR, 1.14-0.88). This was reduced to a mean postoperative value of 0.33 ± 0.09 (median, 0.31, range, 0.17-0.66, IQR, 0.25-0.37). The mean number of lobar, segmental, and subsegmental ostial stenosis repairs performed was 17 ± 9 (median, 17, range, 6-34, IQR, 12-22).
The mean duration of CPB was 437 ± 169 minutes (median, 398, range, 92-1016, IQR, 345-507 minutes). Fifty-three of the 150 patients required a period of aortic crossclamping with a mean of 56 ± 22 minutes (median, 60 minutes, range, 17-204 minutes, IQR, 28-85 minutes).
There were 3 (2.1%) in-hospital deaths, including 1 patient with Williams syndrome and 2 patients with Alagille syndrome. Mean length of hospital stay was 12 ± 3 days (median, 11 days, range, 4-118 days, IQR, 8-18 days). Mean duration of follow-up is 26 ± 4 months (median, 27 months, range, 1-220 months, IQR, 17-30 months). There have been 4 deaths (2.9%) since discharge from the hospital including 2 with Williams syndrome, 1 with Alagille syndrome, and 1 in the “other” category. These deaths occurred at 2, 9, 15, and 17 months postoperatively.
Eleven of the 150 patients (7.3%) undergoing pulmonary artery reconstruction required postoperative ECMO support. This included 10 patients who required ECMO for lung support and 1 for cardiac insufficiency. All 11 patients were initially placed on venoarterial ECMO due to severe hemodynamic instability. Eight of the 11 patients who required ECMO were cannulated in the operating room, and 3 patients were cannulated in the intensive care unit at intervals of 3,19, and 34 hours after arrival to the unit. To facilitate hemostasis, 10 of the 11 patients received protamine reversal and administration of platelets and fibrinogen before implementation of ECMO. Patients on ECMO are maintained on anticoagulation using bivalirudin (Angiomax, The Medicines Company, Parsippany, NJ) with an activated partial thromboplastin time between 60 and 80 seconds. Four patients were subsequently converted to veno-veno ECMO. The median duration of ECMO support was 13 days (range, 3-163 days).
Patients who went on ECMO accounted for 2 of the 3 postoperative deaths and 1 of the 4 late deaths. The Kaplan–Meier survival curve comparing patients who did and did not require ECMO is shown in Figure 2. The log-rank test demonstrated a P value less than .0001, and the relative risk of mortality was 9.5 (95% confidence interval, 2.4-37.1, P value < .001). For the 9 patients on ECMO who survived to discharge, the mean hospital stay was 62 ± 13 days compared with 10 ± 2 days for patients who did not require ECMO (P < .001).
Potential risk factors that could predispose to the need for ECMO are summarized in Table 1. The majority of these risk factors such as age, underlying diagnoses, and previous sternotomy were similar comparing patients with and without ECMO. However, there were 4 operative factors that revealed significant differences between patients receiving and not receiving ECMO and ECMO, including preoperative RV/Ao peak systolic (1.12 ± 0.18 vs 0.95 ± 0.26, P < .01), number of pulmonary artery ostial interventions (22 ± 11 vs 17 ± 9, P = .07), duration of CPB (655 ± 209 vs 418 ± 152, P < .001), and postoperative RV/Ao peak systolic pressure ratios (0.50 ± 0.12 vs 0.32 ± 0.10, P < .05). These data are shown in Figure 3, A-D.
Table 1Comparison of patients who did and did not require extracorporeal membrane oxygenation
Tetralogy of Fallot
Previous cardiac procedures
Concomitant cardiac procedures
Procedures requiring aortic crossclamp
Crossclamp time (min)
50 ± 27
61 ± 42
Age at surgery (y)
6.7 ± 1.4
3.9 ± 1.0
Preoperative RV/Ao ratio
1.12 ± 0.18
0.95 ± 0.26
22 ± 11
17 ± 9
CPB time (min)
655 ± 209
418 ± 152
Postbypass RV/Ao ratio
0.50 ± 0.12
0.32 ± 0.10
Hospital length of stay (d)
ECMO, Extracorporeal membrane oxygenation; CPB, cardiopulmonary bypass; RV/Ao, right ventricle to aortic.
Recognizing that the 4 risk factors summarized are closely interconnected, we sought to evaluate the “relative contribution” of each factor by looking at the number and prevalence of values that would be in the outlier category. Specifically, we calculated the mean and the mean value plus 1 standard deviation to define the upper 16% of values (or 24 patients). We then counted the number of patients receiving and not receiving ECMO who were within this upper 16%. The data demonstrate that 8.3% of the patients with a high preoperative RV/Ao pressure ratio required ECMO. The corresponding number for the number of ostial stenoses was 16.7%, CPB time was 25%, and postoperative RV/Ao pressure ratio was 29%. These data are shown in Figure 4.
Using the analysis in Figure 4, we then evaluated whether 1 or more of these risk factors would have any incremental effect on the prevalence of ECMO. Patients who had no risk factors had a 2.3% prevalence of ECMO, whereas patients with 1 risk factor had a 6% prevalence, patients with 2 risk factors had a 23% prevalence, patients with 3 risk factors had a 67% prevalence, and patients with 4 risk factors had a 100% prevalence. These data are shown in Figure 5.
The relationship between the preoperative RV/Ao pressure ratio and the CPB time is shown in Figure 6, A. This scatterplot demonstrates a trend from lower left to upper right, with the patients who required ECMO marked with black circles. The relationship between the number of ostial stenoses addressed and the CPB time is shown in Figure 6, B, and the relationship between the postoperative RV/Ao pressure ratio and the CPB time is shown in Figure 6, C.
Finally, to validate these data on a continuous variable basis, we performed logistic regression analysis for the 4 predisposing risk factors. This analysis demonstrated an area under the curve for preoperative RV/Ao pressure ratio of 0.80, number of ostial stenoses of 0.70, CPB time of 0.85, and postoperative RV/Ao pressure ratio of 0.91. The 4 logistic regression curves are available in the Figures E1-E4.
Follow-up cardiac catheterizations were performed in 83 of the 143 survivors. This included 77 patients who did not require ECMO and 6 patients who did require ECMO. The mean RV/Ao peak systolic pressure ratio for the 6 patients who required postoperative ECMO was 0.50 ± 0.15 (median, 0.55) compared with 0.33 ± 0.08 (median, 0.32) for patients who did not require ECMO.
The current study was performed to evaluate the characteristics of patients requiring ECMO after pulmonary artery reconstruction. The data demonstrate an overall prevalence of 7.3% of patients required postoperative ECMO. Patients who required ECMO had higher preoperative RV/Ao peak systolic pressure ratios, underwent more ostial interventions, had considerably longer periods of CPB, and had higher postoperative RV/Ao pressure ratios (Figure 7). These results suggest that the extent and complexity of peripheral disease may predispose to development of acute lung injury requiring ECMO support (Video 1).
The 4 predisposing risk factors identified are undoubtedly interlinked with one another. Specifically, higher preoperative RV/Ao pressure ratios are a physiologic measure of more extensive or complex ostial disease. It is then not surprising that patients with higher RV/Ao pressure ratios and more extensive disease require longer periods of CPB time to perform the repair. Finally, given this profile, it is not surprising that these same patients tended to have higher postoperative RV/Ao pressure ratios. The co-linearity of these 4 factors is evidenced by the statistical similarity from one risk factor to the other.
It might be anticipated that the underlying diagnoses of patients with PPAS would have an influence on the need for ECMO. There were 4 patients with Williams syndrome who required ECMO of a total of 44 patients for a prevalence of 9.1%. Three of the 43 patients (7.0%) with Alagille required ECMO, whereas zero of 21 patients with Elastin arteriopathy were placed on ECMO. However, in the subgroup of patients with tetralogy of Fallot and PPAS, 4 of 21 patients (19.0%) required ECMO. Thus, there were significant differences in the need for ECMO based on the underlying diagnoses.
Ten of the 11 patients who required ECMO received it for lung support. These patients developed an acute lung injury intraoperatively that was severe enough that they could not be managed with conventional ventilation alone. The 2 most common clinical indicators of acute lung injury are a decrease in lung compliance and bloody secretions coming from the endotracheal tube. The loss of lung compliance we interpret as an indicator of lung reperfusion, whereas bloody secretions are secondary to an intraparenchymal hemorrhage. Milder forms of lung reperfusion and intraparenchymal hemorrhage are frequently encountered and can be managed with a combination of 100% inspired oxygen and nitric oxide, increasing the positive end-expiratory pressure plus restoring the hemostatic process. However, severe cases are associated with an inability to oxygenate and ventilate, and the combination of hypoxemia and hypercapnia results in further pulmonary vasoconstriction. All 10 patients who ultimately required ECMO support for acute lung injury demonstrated poor lung mechanics after discontinuation from CPB, with 7 converted to ECMO in the operating room and the remaining 3 in the intensive care unit. Thus, the diagnosis of acute lung injury after pulmonary artery reconstruction can be made based on lung mechanics, assessment of endotracheal secretions, and arterial blood gas analysis at the conclusion of these procedures.
The eleventh patient who required ECMO in this series received it secondary to cardiac insufficiency. This patient had Williams syndrome with PPAS, supravalvar aortic stenosis, aortic arch obstruction, and coronary artery ostial stenosis. This patient sustained a cardiac arrest on postoperative day 3, was placed on ECMO, and subsequently had the right coronary ostial stenosis repaired. This patient was successfully weaned from CPB and is a long-term survivor.
The majority of the current literature in both adult and pediatric patients would suggest that prolonged CPB is a risk factor for adverse outcomes.
This is based on the fact that in most types of cardiac procedures, prolonged CPB is a marker for a very complex case or one associated with intraoperative complications. In contrast, prolonged CPB is part of the norm for complex pulmonary artery reconstructions for PPAS. In a previous study aimed at evaluating the effects of prolonged CPB in patients undergoing complex pulmonary artery procedures, we demonstrated that CPB time was poorly correlated with the total number of postoperative complications or the hospital length of stay.
These results suggest that once patients were on bypass for greater than 5 hours, additional time on bypass had little or no adverse effects. In the context of the current study, it is likely that prolongation of CPB was linked to the severity or complexity of disease but probably is not an independent risk factor for requiring ECMO.
There are numerous articles about acute lung injury after CPB.
This literature would suggest that circulating mediators may be causal agents or associated markers for the development of acute lung injury. Gut endotoxins have been implicated as a mediator of acute lung injury through a pathway of ischemia and reperfusion.
Other agents that have been implicated as part of the systemic inflammatory pathway include activation of complement, cytokines, and metabolites of adenosine. Whether interventions directed at blocking the formation of these inflammatory agents can ameliorate the adverse effects is currently at an experimental level.
The first question is whether there are identifiable risk factors associated with the need for ECMO. Several risk factors have been identified including prolonged CPB, single ventricle physiology, and significant residual hemodynamic defects.
It should be noted that most patients in these studies were placed on ECMO for cardiac support; thus, the risk factors for ECMO will likely be different than for lung support. In the current series of patients undergoing pulmonary artery reconstruction, 10 of the 11 patients were placed on ECMO for lung support and the risk factors were related to the severity and complexity of the peripheral stenoses.
The second question the existing literature has addressed is whether there are factors associated with the likelihood of successfully weaning off ECMO. The literature has identified several factors, including prolonged ECMO runs, multiple ECMO runs, and development of neurologic injury or kidney failure.
In the current series of patients undergoing pulmonary artery reconstruction, 11 patients were placed on ECMO with 2 in-hospital mortalities. Both of these patients had extremely long ECMO runs (29 and 60 days) and ultimately died of the additional complications of multisystem organ failure in 1 and sepsis in 1. Remarkably, there was 1 patient in this series who was supported on ECMO for 163 days and survived. Thus, patients who are placed on ECMO for lung support may have different prognostic factors compared with patients who need ECMO for cardiac support.
The prevalence of requiring ECMO after pulmonary artery reconstruction was a modest 7.3%, and of those who required ECMO, 82% survived to discharge from the hospital. Risk factors for needing ECMO were related to the severity and complexity of peripheral stenoses as denoted by preoperative and postoperative RV/Ao pressure ratios and number of ostial interventions. Although the prognosis for patients who require ECMO for acute lung injury is generally favorable, it should also be recognized that the patients who received ECMO accounted for two-thirds of the in-hospital mortality and the survivors had hospital lengths of stay that were more than 2 months longer than for the patients who did not require ECMO. Thus, ECMO is major event that significantly contributes to morbidity and mortality in this patient population.
Conflict of Interest Statement
The authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
The study was approved by the Institutional Review Board at Stanford University: Protocol ID 48389 approved on October 16, 2018, and Protocol ID 42875 approved on August 24, 2018. The need for written consent was waived by the Institutional Review Board.
Abstract presented at the 49th annual meeting of the Congenital Heart Surgeons' Society, Chicago, Illinois, October 23-24, 2022.