(Circulation. 1995;92:2252-2258.)
© 1995 American Heart Association, Inc.
Articles |
From the Division of Cardiothoracic Surgery, Division of Pulmonary Medicine, and Division of Cardiothoracic Anesthesiology, Washington University Medical Center at Barnes Hospital, St Louis, Mo.
Correspondence to Michael K. Pasque, MD, Division of Cardiothoracic Surgery, Washington University Medical School, One Barnes Hospital Plaza, Queeny Tower, Ste 3103, St Louis, MO 63110.
| Abstract |
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Methods and Results Thirty-four patients with pulmonary hypertension underwent evaluation, single lung transplantation, and follow-up assessment between November 1, 1989, and June 1, 1994. Operative survival for the entire group of patients was reasonable, with 91% (31 of 34 patients) surviving and being discharged from the hospital following transplantation. The actuarial survival for these 34 patients at 1-, 2-, and 3-year follow-up was 78%, 66%, and 61%, respectively. In the subgroup of 24 patients with primary pulmonary hypertension (PPH), 96% (23 of 24) were successfully discharged from the hospital after transplantation. The actuarial survival for this isolated PPH subgroup at 1-, 2-, and 3-year follow-up was 87%, 76%, and 68%, respectively. The uniform, early posttransplant normalization of pulmonary vascular resistance and right ventricular ejection fraction appears to persist throughout the 4-year follow-up period. Despite a high prevalence of bronchiolitis obliterans, the majority of survivors remain in New York Heart Association functional class I or II and are employed.
Conclusions Single lung transplantation can be performed in patients with end-stage pulmonary vascular disease with reasonable expectations for a relatively low operative mortality; immediate, complete, and durable amelioration of pulmonary hypertension and right ventricular failure; and optimal use of limited donor organ supply.
Key Words: lung transplantation hypertension pulmonary
| Introduction |
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Answers to the following questions were considered critical in the evaluation of single lung transplantation as a therapeutic option in this patient group: (1) Would single lung transplantation normalize pulmonary vascular resistance, and, if so, over what time frame could these ameliorative changes be expected to occur? (2) Would the anticipated drop in pulmonary vascular resistance normalize right ventricular function, and, if so, over what time frame would this improvement occur? (3) Would the anticipated improvement in right-side hemodynamics occur quickly enough to allow reasonable perioperative morbidity and mortality and therefore a reasonable hospital discharge rate compared with other treatment options? (4) If improvement in pulmonary vascular resistance and right ventricular function were documented in the early postoperative period, would this improvement persist at interval follow-up, and how would this durability affect interval survival? (5) Would functional status improve, and would these improvements be durable despite the ventilation-perfusion mismatch that results from the anticipated overperfusion of the transplanted lung? (6) How would bronchiolitis obliterans impact the long-term results in this patient population?
Several of these questions regarding early hemodynamic response and operative mortality have been sequentially answered as data have become available. Specifically, immediate posttransplant hemodynamics were characterized by an analysis of the hourly systemic arterial, pulmonary arterial, pulmonary capillary wedge, and central venous pressures measured in our first seven patients over the first 48 hours after transplantation.3 This analysis demonstrated almost immediate amelioration of markedly elevated pulmonary vascular resistance, with stabilization of hemodynamics and an immediate, gratifying improvement in right ventricular function.
In an attempt to further define the early response to single lung replacement in this critically ill patient subset, this same group of seven patients was more completely characterized at 3-month follow-up by right heart catheterization and radionuclide ventilation-perfusion scanning and ventriculography.4 This follow-up study confirmed the early stability of the hemodynamic improvement documented during the first 2 days after transplant, further characterized the ventilation-perfusion mismatch, and documented the marked improvement in right ventricular function.
In light of these early favorable results, single lung transplantation continued to be offered as a transplant option for patients with end-stage pulmonary vascular disease referred to the Barnes Hospital lung transplant program. The complete experience with single lung transplantation in 34 patients is reviewed, with specific attention to the therapeutic effectiveness of this treatment option as assessed at interval follow-up.
| Methods |
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Thoracic Donor Organ Utilization
Efficiency of thoracic organ
donor utilization was assessed by
documenting the total number of patients who were transplanted with the
opposite single lungs and the hearts of the donors used for the single
lung transplant procedures in our patient population. These data are
relevant in comparisons with other transplant options, such as
heart-lung and bilateral lung transplantation.
Operative Technique
The technical aspects of single lung
transplantation in patients
with pulmonary hypertension have been described previously in
detail3 4 and have changed minimally. Previous
reports
described the routine use of femoral arterial cannulation
for cardiopulmonary bypass. Over the last several years,
the technique has evolved into the almost exclusive use of complete
intrathoracic cannulation. Right single lung transplantation has been
used exclusively if simultaneous repair of an associated
intracardiac defect is planned. Ascending aortic as well as right
atrial or bicaval cannulation is easily performed through a standard
right posterolateral thoracotomy. Likewise, cannulation of the
descending thoracic aorta, with pulmonary arterial
cannulation for venous return, is readily performed through a left
thoracotomy. We continue to stress the importance of careful donor lung
selection, as well as the routine use of intraoperative
transesophageal echocardiography,
postimplantation positive end-expiratory pressure, and 24 to 48
hours of postoperative sedation and mechanical ventilation.
Posttransplant Survival
Operative mortality was defined as
any death occurring within 30
days of transplantation or any death (even beyond 30 days) occurring
before discharge from the hospital. Actuarial survival was determined
as described below in "Statistical Analysis." Operative
mortality and actuarial survival were calculated for the entire group
of 34 patients with pulmonary vascular disease, as well
as for the subset of 24 patients with PPH.
PPH Survival Comparison
Actuarial survival data from the
isolated subset of PPH patients
was compared with the nontransplanted natural history predicted for the
same group of patients by the formula published by the Patient Registry
for the Characterization of Primary Pulmonary
Hypertension.5 This formula uses
hemodynamic data obtained at
catheterization to predict expected survival and was
generated and validated by the registry survival data. The formula
incorporates mean pulmonary artery pressure (x), mean right
atrial pressure (y), and cardiac index (z) and predicts a patient's
chances of survival [where P(t) indicates the patient's chances of
survival and t=1, 2, 3, 4, or 5 years] after diagnosis:
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To make this comparison more clinically relevant, survival data for the entire group of 42 patients with PPH who were evaluated and listed for single lung transplantation by the Washington University lung transplant program during the study period were examined. Of this group, 1 patient was excluded because of incomplete hemodynamic data for entry into the registry formula. In addition, 3 patients were excluded because they were selected during the later stages of the study period for bilateral lung replacement (all 3 were successfully transplanted and are still alive). The final study group therefore included 14 patients with PPH who were evaluated and listed but not transplanted in addition to the 24 PPH patients (out of the total transplant group of 34) who were transplanted. For the purposes of this comparison only, actuarial survival was calculated with the date of listing for transplantation being used as the entry point for all patients.
Therefore, we calculated both an actuarial and predicted (PPH registry formula) survival for all patients with PPH who were listed for lung transplantation during the study period. Comparison of these two survival curves, therefore, should reasonably compare single lung transplantation as a therapeutic modality with the natural history of the disease as predicted by the registry formula. This comparison was made from the time of listing for transplantation (not from the time of transplantation) and included all evaluated patients (not just those who were ultimately transplanted) in hopes of supplying efficacy information to the clinician who is faced with the clinical decision to refer for lung transplantation or continue with nontransplantation therapeutic options. This comparison more appropriately incorporates the influence of long waiting lists, donor organ shortages, and the very significant mortality accrued while waiting for a suitable donor organ.
Hemodynamics
Hemodynamic follow-up of our first 7
patients for the immediate 48 hours following
transplantation3 as well as the initial 3-month
follow-up4 has been reported previously. The
present study included a summary of pretransplant and follow-up
cardiac catheterization data for the entire group of 34
patients. In addition, pretransplant data were compared with the latest
available follow-up information for all patients who had at least
one posttransplant cardiac catheterization.
Ventricular Function
The pretransplant and 3-month
posttransplantation right and left
ventricular ejection fraction data (by radionuclide
ventriculography) for our first 7 patients has been reported previously
and the methodology described.4 The current report
includes a summary of right and left ventricular ejection
fraction data (pretransplant and at 3-month, 6-month, and yearly
intervals after transplantation) for the entire group of 34 patients.
Also reviewed is a comparison of the pretransplant and latest
follow-up ejection fraction data for all transplant survivors who
had at least one posttransplant scan.
Ventilation-Perfusion Imaging
The pretransplant and 3-month
posttransplant
ventilation-perfusion scan data for our first 7 patients has been
reported previously and the methodology described.4 The
current report includes a summary of ventilation-perfusion scan
data before and after transplantation for the entire group of 34
patients. Also reviewed is a comparison of the pretransplant and latest
follow-up ventilation-perfusion scan data for all transplant
survivors who had at least one complete posttransplant scan.
Functional Capacity
General functional capacity was assessed
for patients surviving
as of June 1, 1994, by characterization of pretransplant and latest
NYHA functional classification (I to IV) as well as their return to
partial or full employment (including housewife) or school.
Bronchiolitis Obliterans
Close surveillance for functional
(by pulmonary
function testing) or pathological (by transbronchial biopsy) evidence
of bronchiolitis obliterans is carried out at routine intervals in all
lung transplant patients. More than 4 months after transplantation, all
patients are considered to be at risk for development of bronchiolitis
obliterans. Classification is by the formula described by an ad hoc
working group established under the auspices of the International
Society for Heart and Lung Transplantation.6 This
classification system adopted the term "obliterative bronchiolitis
syndrome," which uses FEV1 as a clinical indicator of
the severity of the obstructive airway disease that is most commonly
associated with chronic lung allograft dysfunction. The severity of OBS
is categorized by four stages based on the percentage decrease in
FEV1 from the best posttransplant level: Stage 0 indicates
no significant abnormality, FEV1 80% or more of baseline
value; Stage 1, mild OBS, FEV1 66% to 80% of baseline
value; Stage 2, moderate OBS, FEV1 51% to 65% of baseline
value; and Stage 3, severe OBS, FEV1 50% or less of
baseline value. Each stage is further categorized as being with or
without pathological evidence of obliterative bronchiolitis.
Statistical Analysis
Statistical comparisons between data
groups were made by use of
Student's t test. Pretransplant and latest posttransplant
NYHA functional class data were compared by use of the Wilcoxon
signed rank test. Actuarial survival data were calculated by use of the
Kaplan-Meier estimator. The Mantel-Haenszel log rank test was used for
comparisons of actuarial survival between groups. All calculations were
done with SYSTAT: The System for Statistics7
on a personal computer. All results are expressed as mean±SD; a value
of P<.05 was considered statistically significant.
| Results |
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In the group of patients with secondary pulmonary hypertension, there were 7 with associated cardiac abnormalities and the presumed diagnosis of Eisenmenger's syndrome. The Eisenmenger group included 3 patients with large ostium secundum ASDs, 1 with a sinus venosus ASD with associated partial anomalous pulmonary venous return, and 1 with a VSD, all of which were repaired at the time of transplantation. Two other patients had previously undergone total correction of a VSD and a combination of patent ductus arteriosus, coarctation of the aorta, and VSD, respectively. The surgical correction of these abnormalities was performed early in childhood, with pulmonary hypertension becoming a problem later in life. Although it is not absolutely clear that their pulmonary hypertension resulted from the associated cardiac defects, they are categorized with the Eisenmenger group. Three other patients had severe secondary pulmonary hypertension associated with sarcoidosis, pulmonary fibrosis, andL-tryptophan poisoning, respectively.
Donor Thoracic Organ Utilization
Efficiency of donor thoracic
organ utilization was assessed by
documentation of the use of the opposite lung and heart in each of the
donors for the 34 transplant procedures. There were three instances in
which a single donor was utilized for simultaneous single
lung transplant procedures in 2 patients with pulmonary
hypertension at our institution. In addition, the heart and opposite
lung were utilized either at our institution or another transplant
center for an additional 28 and 20 transplant procedures, respectively.
The total was therefore 82 transplant procedures in 82 separate
patients from 31 donors. Since the lack of sufficient donor lungs is
the single most important factor limiting effectiveness of lung
transplantation in pulmonary hypertension, efficiency of donor
utilization is especially important in evaluating overall effectiveness
of single lung, bilateral lung, or heart-lung transplant
procedures.
Posttransplant Survival
Thirty-one (91%) of the 34 patients
with pulmonary
hypertension survived the transplant procedure and were discharged from
the hospital. Actuarial survival for this group of patients at 1-, 2-,
and 3-year follow-up was 78%, 66%, and 61%, respectively (Fig
1
). The originally reported4 first 7
consecutive patients are all still alive after more than 4 years of
follow-up.
|
In the isolated group of 24 patients with PPH, 23 (96%)
survived and
were discharged after transplantation. The actuarial survival for this
isolated PPH subgroup at 1-, 2-, and 3-year follow-up was 87%,
76%, and 68%, respectively (Fig 1
). A comparison of these
results
with the actuarial survival of the isolated group of 10 patients with
secondary pulmonary hypertension revealed no significant
difference between the two groups (P=.117), although the
study groups were small.
PPH Survival Comparison
As described in
"Methods," 42 patients with PPH were
evaluated and listed for transplantation during the study period. Four
patients were excluded from this total group (3 patients underwent
bilateral lung transplantation and 1 lacked complete data for entry
into the registry formula), leaving a total study population of 38
patients (24 of whom received transplants). The actuarial survival of
these 38 patients from the time of listing for transplantation was
compared with the survival rate predicted by the NIH Registry on
Primary Pulmonary Hypertension formula for that same group of
38 patients. The resulting survival curves are graphically
represented in Fig 2
.
|
Hemodynamics
A summary of pretransplant and posttransplant
(at 3 to 12 months
and at subsequent yearly intervals) cardiac
catheterization data for the entire group of 34
patients is presented in Table 1
. Pretransplant
data are also compared with the latest available follow-up
information for all patients who had at least one posttransplant
cardiac catheterization (n=28) in Table 1
.
|
Ventricular Function
A summary of pretransplant and
posttransplant (at 3-month,
6-month, and yearly intervals) right and left ventricular
ejection fraction data from the entire transplant group is
presented in Table 2
, with a comparison of
pretransplant and latest posttransplant right and left
ventricular ejection fraction data for all patients who had
at least one posttransplant scan (n=28).
|
Ventilation-Perfusion Imaging
A summary of pretransplant and
posttransplant (at 3 to 12 months
and at subsequent yearly intervals) ventilation-perfusion scan data
from the entire transplant group is presented in Table 3
, with
a comparison of pretransplantation and latest
posttransplantation ventilation-perfusion scan data for all
patients who had at least one complete posttransplant scan (n=30).
|
Functional Capacity
All patients were NYHA functional class
III or IV before
transplantation. Among currently surviving transplant recipients
(n=23), 20 were in functional class III and 3 were in functional class
IV before transplantation. At a mean of 2.42±1.50 years after
transplantation, the great majority of surviving patients (21 of 23,
91%) remain in NYHA functional class I or II, despite varying degrees
of bronchiolitis obliterans: NYHA I, 16 patients; NYHA II, 5; NYHA III,
2; and NYHA IV, 0. Currently, full- or part-time employment or
student status is enjoyed by 19 of 23 survivors (83%).
Bronchiolitis Obliterans
Latest bronchiolitis obliterans
status, as of June 1, 1994, is
classified according to the working formula established by an ad hoc
committee under the auspices of the International Society for Heart and
Lung Transplantation.6 This formula incorporates both
functional and pathological evidence for bronchiolitis obliterans in
determining status. All patients are now more than 4 months
posttransplant and are considered at risk for the development of
bronchiolitis obliterans.
Either functional or pathological evidence for bronchiolitis obliterans has been documented (to variable degrees) in 6 of 23 current survivors (26%). The bronchiolitis obliterans staging of these 6 current survivors includes 2 patients each with stage 0(b) and stage 2(a) and 1 each with stage 2(b) and 3(b). In addition, bronchiolitis obliterans was documented to some degree in 35% (11 of 31) of all operative survivors. In the first 7 transplanted patients, all of whom have survived more than 4 years since transplantation, 4 (57%) have some degree of bronchiolitis obliterans: 0(b)=1, 2(a)=2, and 2(b)=1. Five (45%) of the 11 deaths that have occurred in the 34 transplanted patients were due to bronchiolitis obliterans.
The latest available mean pulmonary artery pressure, pulmonary vascular resistance, right ventricular ejection fraction, transplanted lung perfusion, and transplanted lung ventilation data for all operative survivors with bronchiolitis obliterans were compared with similar data gathered from the operative survivors without bronchiolitis obliterans. There were no significant differences between these two groups of patients in any of these areas of testing.
| Discussion |
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Despite several obvious advantages in this high-risk patient population, the potential application of single lung transplantation was approached with legitimate concern with regard to the previously outlined questions concerning the immediacy, completeness, quality, and durability of the therapeutic response. Questions regarding the immediacy of reversal of pulmonary hypertension, immediacy of right ventricular recovery, and associated operative morbidity and mortality were addressed early in the course of our experience.3 4 The present review of our complete experience in 34 patients supplies further information regarding these questions but also supplies a 4-year interval response to questions concerning (1) the long-term durability of pulmonary hemodynamic and right ventricular recovery and the associated interval survival results; (2) functional status, including the significance of the obligate ventilation-perfusion mismatch; and (3) the impact of bronchiolitis obliterans.
The operative survival of 91% in our entire experience of 34 single lung transplants and the 96% operative survival in the isolated subset of PPH patients further support our previously published conclusions regarding the safety of this transplant procedure.3 4 Single lung transplantation is a relatively straightforward surgical procedure that can be carried out in this compromised group of patients with reasonable expectations of operative survival and discharge from the hospital.
Hemodynamic follow-up for up to 4 years after
transplantation (Table 1
) demonstrated satisfying durability of
the
complete pulmonary hemodynamic normalization
that we previously documented in the early posttransplant
period.3 4 Likewise, right ventricular
ejection fraction, which normalized early after
transplantation,4 has remained normal throughout 4 years
of follow-up (Table 2
). The durability of these responses is
responsible, at least in part, for the very reasonable
moderate-term survival in these patients (Figs 1
and
2
).
Significantly, in the transplanted group, there have been no late deaths secondary to cardiovascular events such as sudden death, heart failure, or arrhythmia. Such events are almost uniformly responsible for the dismal survival in nontransplanted patients with pulmonary hypertension. Clearly, single lung transplantation, at the follow-up intervals reported here, eliminates the primary cause of death in patients with end-stage pulmonary hypertension. Short-term survival after transplantation appears to be dependent on the absence of complications related to the operative procedure itself, while long-term survival is dependent on the absence of complications specific to lung transplantation and immunosuppression, such as infection, acute rejection, and bronchiolitis obliterans.
When survival after single lung transplantation in our isolated
subgroup of patients with PPH is compared with nontransplant survival
(PPH registry survival formula applied to the same group of patients),
there is a clear divergence of the survival curves at 1 year after
listing for transplantation (Fig 2
). Our comparison included
the entire
group of PPH patients who were listed for transplantation during the
study intervals (rather than just the 24 transplanted PPH patients) in
hopes of supplying clinically relevant information regarding the
effectiveness of referral for transplantation in improving the
otherwise dismal, nontransplant natural history of this disease
process. By evaluating these patients from the time of their listing
for transplantation rather than from the time of actual
transplantation, we incorporated into the comparison the possibility
that patients might die while awaiting transplantation. Comparison of
transplant outcome with the expected natural history of PPH (with
current medical therapy) must incorporate those patients who are
evaluated and listed but die before transplantation, because the often
long waiting list times are an indisputable obstacle to success with
this therapeutic option.
Pretransplant survival data of the 38 patients described in this report
further support the PPH registry formula. The actuarial survival curve
(Fig 2
) essentially follows the registry
formulapredicted curve
to a point that is nearly coincident with the average time on the
waiting list for the 24 patients who ultimately received transplants
(208±169 days). The actuarial survival curve diverges at this point
and remains widely divergent beyond the 4-year interval.
When functional status is considered, use of the single lung transplant
option appears well justified. The fear of dyspnea on exertion
secondary to the obligate ventilation-perfusion mismatch was a
reasonable concern before attempting single lung transplantation in
this group of patients. Indeed, the relative overperfusion of the
transplanted lung persisted to the 4-year follow-up and appears to
be uniform in our entire group of 34 patients (Table 3
).
Nonetheless,
our fear that significant dyspnea on exertion would be a uniform and
disabling problem in transplant survivors has not been substantiated by
our clinical experience with the uncomplicated posttransplant survivor.
Almost all patients with uncomplicated posttransplant courses have
described excellent exercise tolerance during vigorous outdoor
activities and exercise. Functional status after single lung
transplantation is not inherently compromised or limited by the
obligate ventilation-perfusion mismatch.
On the other hand, if surveillance is regimented and complete, functional and/or pathological changes consistent with bronchiolitis obliterans will be found in a large segment of any lung transplant population, especially as long-term follow-up is completed. The pulmonary hypertension lung transplantation group is no exception, as the early heart-lung transplantation experience demonstrated.12 13 14 It is intuitive that the functional debilitation associated with bronchiolitis obliterans would be compounded by the ventilation-perfusion mismatch that exists in single lung transplant patients. With the occurrence of bronchiolitis obliterans, the transplanted lung, which receives an average of 87±7% of the pulmonary blood flow at 1 year of follow-up, is subjected to a process that destroys its ventilatory capacity.
Despite the occurrence of some degree of bronchiolitis obliterans in a large portion of our patients, functional status, as assessed by NYHA functional class and employment status, appears quite reasonable in the entire group of current survivors at the reported average interval. This is especially notable in light of the very compromised functional status of the majority of pulmonary hypertensive patients before transplantation, which has almost uniformly prevented even monitored physical rehabilitation during the pretransplant waiting period.
In areas with limited donor supply, single lung transplantation may be specifically attractive with regard to optimizing efficiency of donor utilization. The 31 donors who supplied single lungs to the 34 patients reported in this series supplied thoracic organs to a total of 82 recipients. Because it is well recognized that the availability of suitable donor organs is the limiting factor in the therapeutic application of thoracic organ transplantation, efficient donor organ utilization is of paramount importance.
In summary, single lung transplantation appears to be a reasonable transplant option for patients with end-stage pulmonary hypertension. The relative simplicity of this surgical procedure makes it especially attractive in this critically ill group of patients because it can be done quickly with a short period of cardiopulmonary bypass, can be combined easily with simultaneous repair of intracardiac defects, can be performed with a very reasonable operative morbidity and mortality, and can serve the greatest number of patients in the shortest period of time by optimal donor organ utilization. Our experience has demonstrated an early and complete normalization of hemodynamics that persists for at least 4 years after transplantation. Single lung transplantation clearly represents a satisfactory therapeutic modality for completely preventing the predominant occurrence of cardiovascular death in this critically ill subset of patients. Functional status in the absence of bronchiolitis obliterans appears quite reasonable despite the obligate ventilation-perfusion mismatch. As is the case in all subgroups of lung transplant recipients, bronchiolitis obliterans limits long-term survival. These results support the further cautious application of single lung transplantation in patients with end-stage pulmonary vascular disease.
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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Received January 10, 1995; revision received March 23, 1995; accepted May 10, 1995.
| References |
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K. Yoshida, N. A. Flavahan, M. Horibe, N. G. Smedira, and P. A. Murray Endothelial defect mediates attenuated vasorelaxant response to isoproterenol after lung transplantation Am J Physiol Heart Circ Physiol, January 1, 1999; 276(1): H159 - H166. [Abstract] [Full Text] [PDF] |
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M. J. Ricciardi, B. P. Knight, F. J. Martinez, and M. Rubenfire Inhaled nitric oxide in primary pulmonary hypertension: A safe and effective agent for predicting response to nifedipine J. Am. Coll. Cardiol., October 1, 1998; 32(4): 1068 - 1073. [Abstract] [Full Text] [PDF] |
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J. Sandoval, J. Gaspar, T. Pulido, E. Bautista, M. L. Martinez-Guerra, M. Zeballos, A. Palomar, and A. Gomez Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension: A therapeutic alternative for patients nonresponsive to vasodilator treatment J. Am. Coll. Cardiol., August 1, 1998; 32(2): 297 - 304. [Abstract] [Full Text] [PDF] |
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