Download and Hanjörg Just Stavros Konstantinides, Annette

Patent Foramen Ovale Is an Important Predictor of Adverse Outcome in Patients With
Major Pulmonary Embolism
Stavros Konstantinides, Annette Geibel, Wolfgang Kasper, Manfred Olschewski, Liane Blümel
and Hanjörg Just
Circulation. 1998;97:1946-1951
doi: 10.1161/01.CIR.97.19.1946
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Patent Foramen Ovale Is an Important Predictor of Adverse
Outcome in Patients With Major Pulmonary Embolism
Stavros Konstantinides, MD; Annette Geibel, MD; Wolfgang Kasper, MD; Manfred Olschewski, MD;
Liane Blümel, MD; Hanjörg Just, MD
Background—Right-to-left shunt through a patent foramen ovale is frequently diagnosed by contrast echocardiography
and can be particularly prominent in the presence of elevated pressures in the right side of the heart. Its prognostic
significance in patients with pulmonary thromboembolism, however, is unknown.
Methods and Results—The present prospective study included 139 consecutive patients with major pulmonary embolism
diagnosed on the basis of clinical, echocardiographic, and cardiac catheterization criteria. All patients underwent
contrast echocardiography at presentation. The end points of the study were overall mortality and complicated clinical
course during the hospital stay defined as death, cerebral or peripheral arterial thromboembolism, major bleeding, or
need for endotracheal intubation or cardiopulmonary resuscitation. Patent foramen ovale was diagnosed in 48 patients
(35%). These patients had a death rate of 33% as opposed to 14% in patients with a negative echo-contrast examination
(P5.015). Logistic regression analysis demonstrated that the only independent predictors of mortality in the study
population were a patent foramen ovale (odds ratio [OR], 11.4; P,.001) and arterial hypotension at presentation (OR,
26.3; P,.001). Patients with a patent foramen ovale also had a significantly higher incidence of ischemic stroke (13%
versus 2.2%; P5.02) and peripheral arterial embolism (15 versus 0%; P,.001). Overall, the risk of a complicated
in-hospital course was 5.2 times higher in this patient group (P,.001).
Conclusions—In patients with major pulmonary embolism, echocardiographic detection of a patent foramen ovale
signifies a particularly high risk of death and arterial thromboembolic complications. (Circulation. 1998;97:1946-1951.)
Key Words: embolism n echocardiography n contrast media n shunts
T
he clinical relevance of a patent foramen ovale (PFO), a
relatively frequent remnant of fetal circulation,1 has
remained obscure for many decades. Before the development
of echocardiographic imaging techniques, detection of PFO
during life and clinical diagnosis of paradoxical embolism
were confined to isolated reports.2,3 During the past 15 years,
the initial studies reporting noninvasive detection of right-toleft atrial shunt by contrast echocardiography4,5 were followed by extensive clinical research on the association
between PFO and cryptogenic stroke.6 – 8 However, none of
the major series provided data on those patients who would
be expected to be at particularly high risk of paradoxical
embolism, namely patients with elevated pressures in the
right side of the heart caused by acute major pulmonary
embolism. In a previously published report, we observed that
the presence of a PFO in this patient group was associated
with a high incidence of cerebral and peripheral ischemic
events suggestive of paradoxical embolism.9 Therefore, the
aim of the present prospective study was to test the hypothesis that PFO detected by contrast echocardiography is an
important prognostic indicator, especially with regard to
mortality and the occurrence of cardiovascular complications
during the acute phase of pulmonary embolism.
Methods
Study Population
Between May 1988 and December 1994, 1343 consecutive patients
with clinically suspected acute pulmonary embolism either on
admission or during the hospital stay prospectively underwent
two-dimensional and Doppler echocardiographic evaluation at our
institution as part of the initial diagnostic workup. Of these, 139
patients who were found to have acute major pulmonary embolism
formed the population of the present study.
The diagnosis of acute major pulmonary embolism was based on
clinical suspicion of pulmonary embolism as defined below in
combination with at least one of the following criteria: (1) echocardiographic findings indicating acute pressure overload in the right
side of the heart in the absence of mitral valve or left ventricular
disease and/or (2) echocardiographic evidence of pulmonary hypertension or diagnosis of precapillary pulmonary hypertension on
catheterization of the right side of the heart. Nuclear imaging studies
(ventilation-perfusion lung scans) or pulmonary angiograms were
Received August 29, 1997; revision received November 21, 1997; accepted January 14, 1998.
From the Abteilung Innere Medizin III—Kardiologie (S.K., A.G., L.B., H.J.), the Abteilung Medizinische Biometrie und Informatik (M.O.),
Universitaetsklinik Freiburg, and the St. Josefs Hospital (W.K.), Wiesbaden—all in Germany.
Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10 –13, 1996, and previously published
in abstract form (Circulation. 1996;94[suppl I]:I-129).
Reprint requests to Dr S. Konstantinides, Universitaetsklinik Freiburg, Innere Medizin III—Kardiologie, Hugstetter Str 55, D-79106 Freiburg,
Germany.
E-mail [email protected]
© 1998 American Heart Association, Inc.
1946
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by guest on February 25, 2014
Konstantinides et al
performed in all patients whose condition was considered stable
enough to permit their transportation from the emergency room or
intensive care unit.
For clinical suspicion of acute pulmonary embolism, three or more
of the following findings had to be present: (1) syncope, (2)
tachycardia (heart rate .100 bpm), (3) dyspnea and/or tachypnea
(breathing rate over 24 breaths per minute or need for mechanical
ventilation), (4) arterial hypoxemia (partial pressure of oxygen
,70 mm Hg while breathing room air or ,80 mm Hg under
supplemental oxygen of $2 L/min) in the absence of pulmonary
infiltrates on chest x-ray, and (5) new-onset ECG signs of strain in
the right side of the heart (complete or incomplete right bundlebranch block, S waves in lead I combined with Q waves in lead III,
or T-wave inversion in the precordial leads V1 through V3).
Echocardiographic detection of acute right ventricular pressure
overload was based on the presence of (1) a dilated right ventricle
(end-diastolic diameter .30 mm measured from the parasternal
short-axis view or a right ventricle appearing larger than the left
ventricle from the apical or subcostal four-chamber view)10 or (2)
right ventricular hypertrophy (free wall thickness .5 mm as measured from the parasternal short-axis or the subcostal four-chamber
view) together with an elevation of right atrial pressure (absence of
inspiratory collapse of the inferior vena cava).
The presence of pulmonary hypertension had to be confirmed by
at least one of the following findings: (1) dilation of the right
pulmonary artery, defined as cross-sectional diameter .12 mm/m2
body surface area on the suprasternal echocardiogram,11 (2) tricuspid
regurgitant jet velocity of .2.5 m/s on Doppler echocardiography in
the absence of inspiratory collapse of the inferior vena cava,10 or (3)
diagnosis of precapillary pulmonary hypertension on catheterization
of the right side of the heart (systolic pulmonary arterial pressure
$35 mm Hg or mean pressure $20 mm Hg in the presence of
normal pulmonary artery occlusion pressure).
The tricuspid regurgitant jet velocity obtained by continuous-wave
Doppler echocardiography was used to estimate systolic right ventricular pressure by means of the simplified Bernoulli equation.12
Invasive measurement of right atrial, right ventricular, and pulmonary artery pressures was performed by means of a Swan-Ganz
thermodilution catheter. Finally, scintigraphic confirmation of pulmonary embolism (ie, definition of a diagnostic or high-probability
lung scan) was based on the criteria described by Selby et al.13
Contrast Echocardiography and the Diagnosis
of a PFO
All patients in the study population underwent contrast echocardiographic studies during the initial ultrasound examination for detection of right-to-left shunt through a PFO. During visualization of the
heart from the apical four-chamber view, echo-contrast opacification
of the right atrium was achieved by rapidly injecting 10 mL of
agitated 5.5% oxypolygelatine solution (Gelifundol, Biotest Pharma
Inc) through an antecubital vein as previously described.9 Every care
was taken to extrude all macroscopic air from the syringe before
injection. Echo-contrast was considered to be adequate if the entire
right atrium remained opacified for at least three cardiac cycles. The
detection of five or more microbubbles in the left heart cavities
within three cardiac cycles after their appearance in the right atrium
was considered diagnostic of a PFO.14 Informed consent was
obtained from all patients or their first-degree relatives before
administration of the echo-contrast agent. The procedure was well
tolerated in all cases, and no side effects were reported.
Definition of Clinical End Points
Statistical evaluation of the patients’ outcome during the in-hospital
period focused on two major clinical end points: overall mortality
and complicated in-hospital course, defined as the occurrence of one
of the following events: death, ischemic stroke, peripheral arterial
embolism, major bleeding, or the need for endotracheal intubation or
cardiopulmonary resuscitation. The diagnosis of ischemic stroke was
confirmed by CT or autopsy in all cases. The diagnosis of peripheral
arterial embolism was based on clinical, laboratory, and radiological
TABLE 1.
May 19, 1998
1947
Clinical Characteristics at Diagnosis
Characteristic
n (%)
Acute symptom onset (within 4 d)
97 (70)
Syncope
35 (25)
Focal neurological deficit(s)
7 (5.0)
Peripheral arterial occlusion*
7 (5.0)
Arterial hypotension (systolic blood pressure ,90 mm Hg)
Cardiogenic shock
118 (85)
21 (15)
Cardiac arrest
8 (5.7)
Recent major surgery (within 14 d)
Recent major trauma or fracture (within 14 d)
History of venous thrombosis
28 (20)
8 (5.8)
45 (32)
History of pulmonary embolism
7 (5.0)
Congestive heart failure
21 (15)
Chronic pulmonary disease
7 (5.0)
Cancer
16 (12)
Gestation
2 (1.4)
Stroke
3 (2.1)
n5139.
*Clinical and laboratory findings signifying renal, intestinal, or limb ischemia.
findings signifying vascular occlusion with renal, intestinal, or limb
ischemia. Finally, major bleeding was defined as hemorrhagic stroke
confirmed by CT or autopsy or as a bleeding episode that fulfilled at
least one of the following criteria: a decrease in hemoglobin levels of
$2 g/dL, requirement for a blood transfusion of two units or more,
retroperitoneal bleeding, or bleeding that required surgical intervention or discontinuation of heparin anticoagulation or thrombolytic
treatment.
Statistical Analysis
For descriptive purposes, quantitative variables are presented as
mean6SD; qualitative variables, as absolute and relative frequencies. The prognostic relevance of PFO and other clinically important
variables with respect to mortality and major in-hospital events was
analyzed univariately by Fisher’s exact test. To investigate whether
the prognostic effect of PFO is independent of other clinical
variables, a multiple logistic regression model was additionally
applied to the two major end points (mortality and complicated
in-hospital course). The results of the logistic regression models are
presented as estimated odds ratios (ORs) with the corresponding
95% confidence intervals. All significance tests were two-sided, with
a value of P,.05 considered to indicate clinical significance. Data
processing and analysis were performed with the Statistical Analysis
System.
Results
Clinical and Echocardiographic Findings
at Diagnosis
The study population consisted of 69 women and 70 men
with a mean age of 59617 years (range, 17 to 89 years); their
clinical characteristics at the time of diagnosis are shown in
Table 1. Twenty-three patients (17%) had no known risk
factors for venous thromboembolic disease in their histories.
Most patients (70%) presented with an acute onset of symptoms, ie, ,5 days before the diagnosis of pulmonary embolism. All patients had evidence of pulmonary hypertension
and/or right ventricular pressure overload according to the
aforementioned criteria. Right ventricular dilation was present in the vast majority of the patients (134, or 96% of the
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1948
Patent Foramen Ovale in Major Pulmonary Embolism
study population). In addition, echocardiography detected the
presence of thrombi in the right chambers or in the proximal
portions of the right pulmonary artery in 25 patients (18%).
After the initial clinical and echocardiographic evaluation,
nuclear imaging and pulmonary angiographic studies confirmed the diagnosis of pulmonary embolism in 86 (62%) and
32 (23%) patients, respectively. Overall, confirmation of the
thromboembolic event was provided by at least one of these
methods or by the autopsy findings in 110 patients of the
study group (79%). B-mode and/or Doppler ultrasonographic
or phlebographic studies were performed in 105 patients
(76%) and revealed the presence of deep vein thrombosis in
77 of these patients (73%).
Pulmonary artery pressure was measured during bedside
catheterization of the right side of the heart in 61 patients
(44%). In 93 patients (67%), systolic right ventricular pressure (approximately equal to pulmonary artery pressure) was
noninvasively estimated by Doppler echocardiography as
described in “Methods.” Overall, the severity of pulmonary
hypertension could be assessed at the bedside by either of
these two methods in 112 patients (81%). In these patients,
systolic pulmonary artery pressure ranged between 32 and
110 mm Hg (mean, 57618 mm Hg). The good correlation
between invasively and echocardiographically obtained pulmonary artery pressures as reported by other investigators12
has been confirmed in our laboratory for patients with
pulmonary embolism.10
Right-to-left shunt through a PFO was diagnosed by
contrast echocardiography in 48 patients of the study population (35%; see the Figure). There was no difference in
systolic pulmonary pressure between the patients with and
without PFO (58617 versus 57619 mm Hg; P5.60).
After diagnosis of acute pulmonary embolism, 57 patients
(41%) were treated with thrombolytic agents according to the
judgment of the clinicians in the emergency room or intensive
care unit. The remaining 82 patients (59%) received conventional heparin anticoagulation. Thrombolytic treatment was
given to 22 patients with and 35 patients without PFO (46%
versus 38%; P5.47).
Predictors of In-Hospital Mortality
The mean duration of hospitalization after the diagnosis of
acute pulmonary embolism was 22617 days. During this
period, 29 patients (21% of the study population) died. Death
was directly related to the acute thromboembolic event in the
vast majority of the cases (25 of the 29 patients; 86%). One
patient died of septic shock on the fourth postoperative day
after emergency pulmonary embolectomy. Another patient
recovered from the initial episode of pulmonary embolism
but died of recurrent major pulmonary embolism 3 days after
presentation. Finally, in-hospital death was due to the underlying disease in 2 patients who had Salmonella osteomyelitis
with sepsis and a malignant tumor, respectively.
Univariate analysis revealed that in-hospital mortality was
more than twice as high in the presence of PFO (33% versus
14% in patients without atrial communication; P5.015).
Death during the in-hospital phase was also significantly
more frequent in patients with an acute onset of symptoms
related to pulmonary embolism (27% versus 7.1%; P5.01)
Marked right ventricular (RV) and right atrial (RA) enlargement
could be detected by echocardiography in this patient with
acute, major pulmonary embolism (top, apical view). After echocontrast injection through a peripheral vein, the cavities of the
right side of the heart were adequately opacified (middle). Within
three cardiac cycles, however, complete opacification of the left
atrium and left ventricle (LV) also occurred, indicating massive
right-to-left shunt through a patent foramen ovale (bottom).
and in those presenting with cardiogenic shock caused by
failure of the right side of the heart (52% versus 15%;
P,.001). Logistic regression analysis demonstrated that after
adjustment for the baseline clinical characteristics listed in
Table 1 and for the echocardiographic detection of right-side
thrombi, PFO and arterial hypotension remained the only
independent predictors of in-hospital death (OR, 11.4 and
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Konstantinides et al
TABLE 2. Determinants of Outcome in Patients With Acute
Major Pulmonary Embolism
Patient Characteristic
Patent foramen ovale
Overall In-Hospital
Mortality
OR (95% CI)
Complicated
In-Hospital Course*
OR (95% CI)
11.35 (2.89–44.52)
P,.001
5.21 (2.32–11.71)
P,.001
Age .60 y
1.28 (0.45–3.66)
P5.64
1.46 (0.67–3.19)
P5.34
Acute symptom onset
(within 4 d)
3.72 (0.88–15.72)
P5.07
0.91 (0.40–2.09)
P5.82
Arterial hypotension
(systolic BP ,90 mm Hg)
26.29 (5.76–120)
P,.001
7.57 (2.10–27.26)
P,.002
Cardiac arrest
3.05 (0.46–19.83)
P5.24
6.09 (0.62–59.6)
P5.12
Malignant tumor
2.31 (0.53–10.17)
P5.27
1.52 (0.46–5.05)
P5.50
Right heart or proximal PA
thrombi (echocardiography)
1.70 (0.49–5.95)
P5.41
1.06 (0.36–3.05)
P5.93
OR indicates odds ratio; CI, confidence interval; BP, blood pressure; and PA,
pulmonary artery.
*Complicated in-hospital course was defined as the occurrence of one of the
following events: death, ischemic stroke, peripheral arterial embolism, major
bleeding, or the need for endotracheal intubation or cardiopulmonary resuscitation.
26.3, respectively; Table 2). PFO remained a significant
independent predictor of mortality even if only those patients
with definite confirmation of pulmonary embolism by lung
scan, pulmonary angiography, or autopsy were included in
the statistical analysis (OR, 8.58; 95% confidence interval,
1.92 to 38.4).
Patients with severe pulmonary hypertension (systolic
pressure .60 mm Hg) had a mortality rate of 10.3% compared with 23.3% in patients with mild or moderate pulmonary hypertension (systolic pressure, 32 to 60 mm Hg;
P5.13). On multivariate analysis, the association between
pulmonary artery pressure and the risk of in-hospital death
reached marginal statistical significance in the whole study
population (OR, 3.6:1 for mild to moderate hypertension;
P5.10). On the other hand, death risk was independent of the
severity of pulmonary hypertension in patients with right-toleft shunt through a PFO (P5.50).
Major Clinical Events and Determinants of a
Complicated In-Hospital Course
Following diagnosis of acute major pulmonary embolism, 62
patients (45%) suffered at least one of the major in-hospital
clinical events listed in Table 3. Ischemic stroke occurred in
8 patients (5.8%), and 7 patients (5%) suffered a peripheral
arterial thromboembolic event. Major bleeding was documented in 30 patients (22%), and the occurrence of cerebral
bleeding was 2.1%. The frequency of major bleeding episodes was 32% among 57 patients (41%) of the study group
who received thrombolytic treatment as opposed to 15% in
the remaining 82 patients who underwent conventional heparin anticoagulation (P5.02).
PFO was found to be significantly associated with the
occurrence of ischemic stroke, peripheral arterial embolism,
and the need for endotracheal intubation (Table 3). In fact, the
TABLE 3.
May 19, 1998
1949
In-Hospital Clinical Events
Patients With
Patent Foramen
Ovale
(n548), n (%)
Patients Without
Patent Foramen
Ovale
(n591), n (%)
P
Ischemic stroke
6 (13)
2 (2.2)
.02
Peripheral arterial
embolism
7 (15)
0
,.001
Cerebral bleeding
2 (4.2)
1 (1.1)
.27
Event
Other major bleeding
Endotracheal intubation
Cardiopulmonary
resuscitation
Death
8 (17)
19 (21)
.66
17 (35)
15 (16)
.02
9 (19)
10 (11)
.3
16 (33)
13 (14)
.015
presence of a PFO resulted in a more than fivefold increase in
the adjusted risk of major in-hospital complications (P,.001;
Table 2).
Discussion
Since its first description by Cohnheim15 in 1877, the entity of
paradoxical embolism through a PFO has remained a diagnostic challenge. Definite confirmation of paradoxical embolism essentially requires the detection of a right atrial thrombus crossing the foramen ovale.16,17 However, direct
observation of this phenomenon during life is rarely possible
and remains confined to isolated echocardiographic reports.18 –21 In clinical practice, the diagnosis of paradoxical
embolism is almost always presumptive and relies on (1) the
occurrence of an arterial thromboembolic event in the absence of atrial fibrillation, disease of the left side of the heart,
or severe atherosclerosis of the thoracic aorta; (2) the detection of right-to-left shunt, usually through a PFO or an atrial
septal defect; and (3) the presence of venous thrombosis or
pulmonary embolism.17,22
In recent years, contrast transthoracic or transesophageal
echocardiography was established as a simple, accurate, and
safe procedure for the diagnosis of interatrial communication.
Several studies reported a significant association between
echocardiographically detected PFO and the occurrence of
cryptogenic stroke.6 – 8,23 On the other hand, it is not entirely
clear whether deep vein thrombosis or pulmonary embolism
was also present in the patients of those series. Thus, the
clinical importance of a PFO still continues to be the subject
of debate.24
Transient right-to-left shunt through a PFO can, indeed,
occur even in the presence of normal right-side hemodynamics.4,14,25 However, this phenomenon becomes especially
prominent in the setting of elevated right-side pressures.26 –28
We therefore hypothesized that patients with major pulmonary embolism and PFO might be particularly prone to suffer
paradoxical embolism with a substantial impact on their
in-hospital morbidity and mortality. In the present prospective study, we investigated the death rate and the incidence of
arterial thromboembolic events in a patient population presenting with acute major pulmonary embolism. All patients
underwent contrast echocardiographic imaging at diagnosis.
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1950
Patent Foramen Ovale in Major Pulmonary Embolism
The results of the study provide a clear confirmation of our
hypothesis. The death rate of patients with PFO was as high
as 33% and more than twice as high as that of patients without
evidence of right-to-left atrial shunt. According to multivariate analysis, PFO was associated with more than a 10-fold
increase in death risk and a 5-fold increase in the risk of major
adverse events during the hospital stay. The clinical relevance
of these findings is emphasized by the high frequency of PFO
in our study patients (35%), which is in accordance with the
results of autopsy series.1
The overall mortality rate of our patient population was
21%, and the frequency of serious in-hospital complications,
such as arterial thromboembolism, major bleeding, need for
endotracheal intubation, or cardiopulmonary resuscitation,
was also very high (45%). These figures are not surprising in
view of the fact that the present study focused on patients
with major pulmonary embolism. Our inclusion criteria
required echocardiographic evidence of acute right ventricular pressure overload and/or pulmonary hypertension diagnosed by echocardiography or catheterization of the right side
of the heart. Definite confirmation of acute pulmonary
embolism by scintigraphic or pulmonary angiographic studies
was recommended by the study protocol but not defined as an
inclusion criterion. Because clinical and hemodynamic instability precluded the performance of these procedures in 21%
of our patients, diagnostic uncertainty remains a possibility in
some cases. In particular, it cannot be excluded that preexisting pulmonary hypertension (resulting from recurrent
thromboembolism or chronic pulmonary disease) might have
led to right ventricular pressure overload in some patients.
The differential diagnosis of an enlarged right ventricle also
includes right ventricular myocardial infarction and congenital heart disease.29,30 These limitations notwithstanding, a
diagnostic strategy based on echocardiography not only is
safe and practicable in the intensive or emergency care setting
but also can lead to rapid identification31 and probably to
more effective treatment of high-risk patients with acute
pulmonary embolism.32
We found that systolic pulmonary pressure .60 mm Hg
was associated with a tendency toward decreased mortality
rates compared with mild or moderate pulmonary hypertension. The explanation for this finding probably lies in the fact
that severe pulmonary hypertension signifies the presence of
chronic right ventricular pressure overload as previously
demonstrated.33 In a recent study, we could show that patients
with a chronically “adapted,” hypertrophied right ventricle
resulting from recurrent thromboembolic events could better
tolerate the hemodynamic consequences of pulmonary embolism during the acute phase.34
Conclusions
The results of the present prospective study have, in our
opinion, important clinical implications. They demonstrate
that right-to-left shunt through a PFO is an independent
predictor of adverse outcome in patients with acute major
pulmonary embolism. Thus, detection of PFO by contrast
echocardiography should probably prompt consideration of
aggressive therapeutic options, such as thrombolytic treatment or catheter thrombus fragmentation, to restore pulmo-
nary vascular patency and normalize right-side hemodynamics as soon as possible. On the other hand, silent paradoxical
embolism might increase the risk of life-threatening hemorrhagic complications of thrombolysis. These crucial issues
need to be addressed by future controlled trials and will, it is
hoped, lead to a more sophisticated and effective strategy in
the treatment of acute pulmonary embolism.
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