Systematic surgical closure of patent foramen ovale in selected ...

European Journal of Cardio-thoracic Surgery 11 (1997) 824 – 827

Systematic surgical closure of patent foramen ovale in selected patients with cerebrovascular events due to paradoxical embolism. Early results of a preliminary study1,2 P. Ruchat a,*, J. Bogousslavsky b, M. Hurni a, A.P. Fischer a, X. Jeanrenaud c, L.K. von Segesser a a

Department of Cardio6ascular Surgery, Centre Hospitalier Uni6ersitaire Vaudois, CH-101 1 Lausanne, Switzerland b Department of Neurology, Centre Hospitalier Uni6ersitaire Vaudois, CH-101 1 Lausanne, Switzerland c Di6ision of Cardiology, Centre Hospitalier Uni6ersitaire Vaudois, CH-101 1 Lausanne, Switzerland Received 7 October 1996; accepted 22 January 1997

Abstract Objective: To define therapeutic strategy for management of patients with ischemic stroke due to a high probability of paradoxical embolism through a Patent Foramen Ovale (PFO). Methods: Since 1988 all consecutive patients with cerebrovascular events and PFO from the Stroke Registry of our population-based primary-care center are prospectively studied and followed. Since 1992, among 118 patients with cryptogenic embolic brain infarct or transient ischemic attack (TIA) and PFO, 32 consecutive patients younger than 60 years who presented at least two of the following criteria were admitted for surgery: history of Valsalva strain before stroke (11); multiple clinical events (13); multiple infarcts on brain Magnetic Resonnance Imaging (MRI) (15); atrial septal aneurysm (ASA) (16); large right-to-left shunt (\ 50 microbubbles) (12). Results: Operative time 135%9 33%. CPB time 34%9 14%. Aortic crossclamping time 16%9 6%. Post-operative bleeding 4859 170 ml. No homologous blood transfusion required. No neurological, cardiac or renal complications. All patients were followed-up corresponding to a cumulative time of 601 patient-months. This revealed no reccurent vascular events nor silent new brain lesions on brain MRI. Systematic simultaneous contrast Trans Esophageal Echocardiography (TEE)— Trans Cranial Doppler showed a small residual interatrial shunt in two patients. Conclusion: Surgical closure of a patent foramen ovale can be accomplished with very low morbidity and reduce efficently the risk of stroke recurrence. It seems to be the option of choice in selected patients with a higher (\ 1.5%/ year) risk of stroke recurrence. © 1997 Elsevier Science B.V. Keywords: Patent foramen ovale; Paradoxical embolism; Ischemic stroke; Surgical treatment

1. Introduction First described by Cohnheim in 1877 [7], Paradoxical Embolism (PE) remained a postmortem finding until 1930 [27]. Since that time, a number of cases have been * Corresponding author. Tel.: +41 21 3142280; fax: + 41 21 3142278. 1 Presented at the 10th Annual Meeting of the European Association for Cardio-thoracic Surgery, Prague, Czech Republic, 6–9 October 1996. 2 For the Lausanne Stroke with Paradoxical Embolism Study Group. 1010-7940/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved. PII S 1 0 1 0 - 7 9 4 0 ( 9 7 ) 0 1 1 7 5 - 5

diagnosed during life [19] and a few treated surgically [6]. Notwithstanding the fact that Patent Foramen Ovale (PFO) is found in 27–35% of the normal population, two independent case-control studies reported in 1988 an unusually high incidence of PFO (54 [20] and 50% [28]) in young cryptogenic-stroke patients. Direct evidence of PE is commonly lacking, but cerebral thromboembolism from a venous source through a right-to-left shunt is incriminating on young stroke and PFO patients, if all other known causes of cerebral emboli have been excluded. The natural history of patients with stroke and interatrial septum abnormality

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is not yet well known, so that preventive therapy is based only on a presumed risk of stroke recurrence. This can not be completely prevented by antiaggregation or anticoagulation [22,26] nor transcatheter closure [5]. In the present study we assessed systematic surgical closure in selected patients from the stroke registry of our population-based primary-care center, who had multiple episodes or were at high risk of stroke recurrence.

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left shunting in all patients [24] (antebrachial venous contrast injection of 10 ml of 5% glucose with no more than 0.3 ml of air). Microbubbles test is positive if four microbubbles are seen in the left heart for a maximum of five heart cycles. A large shunt is defined as \50 microbubbles in the left heart [15]. Atrial septum aneurysm (ASA) is defined as a \ 1.5 cm bulging of the septum primum beyond the septal plane, when the width of the septum basis is at least 1.5 cm. [25]

2.2. Operation 2. Patients and methods

2.1. Patients We prospectively studied 340 patients aged B 60 years old with acute stroke or TIA admitted consecutively to our population-based primary-care center from 1988 to 1996. We used the standard protocol of the Lausanne Stroke Registry [2]. A total of 140 patients (41%) had PFO. No coexisting cause of stroke was found after extensive investigations in 118 patients. These investigations consist of standard blood and coagulation tests with antithrombin III, Protein C and S, and antiphospholipid antibody levels; echocardiography; 12-lead ECG; 24 h three-lead electrocardiographic monitoring; extracranial and transcranial Doppler ultrasonography; brain Computed Tomography (CT); brain MRI and angiography. Catheter angiography was performed in selected cases. Between December 1992 and April 1996, 32 consecutive patients (19 male, 13 female) from 20 to 58 yearsold (mean age 39.597.8 years) with cryptogenic vascular events and PFO were selected for surgery. We defined five criteria, that are signs of recurrent cerebral embolism or, we think, represent elevated risk of recurrent stroke (Table 1). Preoperative transesophageal contrast echocardiography with Valsalva maneuver was positive for right-toTable 1 Patient selection criteria PFO proven by contrast TEE No alternative cause of stroke No alternative cause of TIA Age B60 years old

32 19 13 32

at least 2 of the following criteria History of Valsalva strain before stroke Multiple clinical events Multiple infarcts on brain MRI Atrial septal aneurysm Large right-to-left shunt

11 13 15 16 12

PFO, patent foramen ovale. TEE, transesophagealechocardiography; TIA, transient ischemic accident; MRI, magnetic resonnance imaging. a n =32.

Median sternotomy and cardiopulmonary bypass with aortic and bicaval canulation were the standard. Myocardial protection was performed with mild general hypothermia, infusion of 10 ml/kg of St-Thomas II cardioplegia into the aortic root and by topical epicardial cooling. The atrial septum was approached by a right parallel-to-the-AV-sulcus atriotomy. From the 12th patient, we standardized the foramen closure by a double continuous polypropylene 4-0 suture beginning at each commissure. In the patients with ASA we proceeded to a plicature in the suture line. Atriotomy was closed by continuous 4-0 polypropylene and after de-airing the aortic crossclamp was removed. CPB was weaned after rewarming higher than 35°C and hemodynamic stability was obtained. Before protamine administration, contrast TEE was performed to exclude a residual shunt. The chest was closed in the usual manner.

2.3. Postoperati6e follow-up 3-Lead ECG monitoring was used during the first 48–72 postoperative hours. Chest X-ray, 12-lead ECG and transthoracic echocardiography were repeated before hospital discharge. All patients are followed regularly in the stroke clinic for clinical examination and history taking. They underwent systematically at 8 93 months a simultaneous TEE [24] and TC Doppler combined with a microbubbles test. Brain MRI was performed routinely to detect silent new infarcts that might have occured during follow-up.

3. Results All patients were operated on within 3 months after the last cerebrovascular events. Intermediate therapy was anticoagulation in 18 patients (56%) and antiaggregation in 14 (44%), 19 procedures were done by consultant surgeon and 13 by the residents alone or under supervision. Operative mean time: 133% 933% (median: 135; range 95%–220%). CPB mean time 34% 914% (median: 30%; range 19%-56%). Aortic crossclamping mean time: 16%9 6% (median: 15%; range 8%–32%) Mean occurrence of

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the five selection criteria was 2.1/patient. Valsalva strain before stroke 34%; multiple clinical events 41%; multiple brain infarcts 47%; PFO and ASA 50%; Large right-to left shunt 38%. In the perioperative period (intensive care unit) median time 17 h (range 5–26 h) no hemodynamic instability or major rythm disturbance was noticed. Mean total chest drainage: 4851 ml9 170 ml. No homologous blood transfusion was necessary. Six patients did a blood predonation of mean 2.1 blood units which were transfused during the post- operative days. There was no post-operative atrial fibrillation (AF) (our usual post- operative AF rate is 30%). There was no cardiac, no neurological, nor renal complications. One patient developped a chemical pancreatitis who did well with gastric suction. Another had a wound infection grade I with negative culture and delayed skin closure. Mean follow-up time was 18.8 months (range 6.9–46 months) on 100% of the patients included in our study. Cumulative follow-up is 601 patient-months. There was no death, no stroke, no TIA, nor new silent brain infarct on MRI done 8 9 3 months of follow-up. Contrast TEE-TC Doppler showed a small residual shunt in two patients (20 and 8 microbubbles). ECG and chest X-ray were normal in all patients.

4. Discussion Multiple studies emphasize the high prevalence of PFO in young patients with cryptogenic stroke [10,14,20,28] but De Belder showed that it is a risk factor for all age groups [8] We therefore decided to include in our study patients up to 59 years-old. After Johnson [16], diagnosis of PE is rarely proved but the most frequently presumed. The first of the four clinical diagnosis criteria defined by Meister [23], the source of thromboembolism, is scarcely found because the clinical diagnosis of deep venous thrombosis (DVT) is impossible in 50% of the cases and is missing in 20% of laboratory investigations [9]. Though we did not retain this criteria as many others [12,14,20,28]. This absence of a clear source of embolism and of an underlying thrombotic process is in contrast with the demonstration of an intracranial embolic occlusion in nearly 90% of our patients with PFO and stroke who underwent cerebral angiography in the acute phase of stroke [4]. The intracardiac right-to-left shunt as well as the young age of the patients is a prerequisite to be included in our study. To define the other selection criteria (Table 1) we assert that multiple clinical events or brain infarcts increase the risk of recurrent stroke. Yet, on the other hand, two studies dealing with recurrent stroke pointed out a 2.2% per year rate of recurrent infarct and death [4] and a recurrent rate of stroke of 4.4% per year on patients where PFO and ASA are present [22].

Currently, the most common treatment to reduce the frequency of recurrent cerebral paradoxical emboli is anticoagulation. However all the studies [3,11,22,26] mentioned recurrent stroke and that prognosis in long term treatment in young adults is compromised by a major risk of hemorrhagic cerebral complication of 1.5–11% [1,18,21]. Bridges [5] reported transcatheter closure on 36 patients with presumed paradoxical embolism without any procedural complication but 15% showed residual shunt necessitating anticoagulation with 4 TIA in the 8.4 months mean follow-up. Direct surgical closure under cardiopulmonary bypass is scarcely described in the literature. Harvey [12] on four patients and Di Tullio [13] on nine patients have described no peri-operative morbidity or mortality. There was no recurrent stroke or TIA in the 12 months follow-up but the absence of a systematic clinical evaluation and brain imaging impinge any conclusion. The procedures of that study were performed in a training environment where a balance between patients’ safety and the appropriate delegation of surgical reponsibility to trainees is required. This situation explained the large range in operative time and emphasized the feasibility of this procedure with very low hazards. The hospital mortality for repair of ASDs and related conditions has approached zero for many years in most cardiac surgical centers throughout the world [17]. We obtain a complete follow-up though we cannot demonstrate any death, stroke, TIA or silent brain infarct in a cumulate time of more than 50 patientyears. Surgical therapy obviates the need for an intracardiac prosthesis or for anticoagulation with its attendant problems of patient compliance and risk of cerebral hemorrhage. Stone [26] showed a positive correlation between the risk of recurrence and the size of the right-to-left shunt. Though the two patients of our series with small residual shunt are at low risk of having a new stroke. The quality of closure depends on the surgical technique and our experience of training centers emphasizes the need to cautiously manage the two commissures of the foramen and to avoid single stitches. In our experience, surgical closure of patent foramen ovale can be done safely. Although the recurrence rate generally remains low, our surgical results and the decision analysis model show that surgical therapy may be the option of choice in selected patients with a higher (\ 1.5%/year) risk of stroke recurrence.

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P. Ruchat et al. / European Journal of Cardio-thoracic Surgery 11 (1997) 824–827 [3] Bogousslavsky J, Cachin C, Regli F, Despland PA, Van Melle G, Kappennberger L, for the Lausanne Stroke Registry Group Cardiac sources of embolism and cerebral infarction — clinical consequences and vascular concomitants. The Lausanne Stroke Registry. Neurology 1991;41:855–859. [4] Bogousslavsky J, Garazi S, Jeanrenaud X, Aebischer N, van Melle G. Neurology 1996;46:1301–1305. [5] Bridges ND, Hellensbrand W, Catson L, Filliano J, Newsburger JW, Lock JE. Transcatheter closure of patent foramen ovale after presumed paradoxical embolism. Circulation 1992;86:1902 – 1908. [6] Caes FL, Van Belleghem YV, Missault LH, Coenye KE, Van Nooten GJ. Surgical treatment of impending paradoxical embolism through patent foramen ovale. Ann Thorac Surg 1995;59:1559 – 1561. [7] Cohnheim J. Thrombose und Embolie, Vorlesungen u¨ber allgemeine Pathologie; ein Handbuch fur Aertze und Studierende. Berlin, Hirschwald 1877;1,134,144–145. [8] De Belder MA, Tourikis L, Leech G, Camm AJ. Risk of patent foramen ovale for thromboembolic events in all age groups. Am J Cardiol 1992;69:1316–1320. [9] Devuyst G, Bogousslasky J, Despland PA, Ruchat P, Jeanrenaud X. Quel traitement pour les patients avec accident vasculaire cerebral et foramen ovale permeable. Rev Med Suisse Romande 1996;116:639–643. [10] Di Tullio M, Sacco RL, Gopal A, Mohr JP, Homma S. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 1992;117:461–465. [11] Hanna JP, Sun JP, Furlan AJ, Stewart WJ, Sila CA, Tan M. Patent foramen ovale and brain infarct: echocardiographic predictors, reccurrence, and prevention. Stroke 1994;25:782 – 786. [12] Harvey JR, Teague SM, Anderson JL, Voyles WV, Thadani U. Clinically silent atrial septal defects with evidence for cerebral embolization. Ann Intern Med 1986;105: 695–697. [13] Homma S, Di Tullio MR, Sacco RL, et al. Surgical closure of PFO in selected patients with cryptogenic stroke: a preliminary experience (abstract). Stroke 1995;26:172. [14] Jeanrenaud X, Bogousslavsky J, Payot M, Regli, Kappenberger L. Foramen ovale permeable et infarctus cerebral du sujet jeune. Schweiz Med Wochenschr 1990;120: 823–829. [15] Jeanrenaud X, Kappenberger L. Patent foramen ovale and stroke of unknown origin. Cerebrovasc Dis 1991;1:184 – 192. [16] Johnson BI. Paradoxical embolism. J Clin Pathol 1951;4:316 – 332. [17] Kirklin JW, Barratt-Boyes BG. Atrial septal defect and partial anomalous venous connection. In: Kirklin JW, Barratt-Boyes BG, editors. Cardiac surgery, 2nd ed, New York: Churchill Livingstone: 1993;634–635. [18] Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors know at the start of outpatient therapy. Am J Med 1989;87:144 – 152. [19] Laughlin RA, Mandel SR. Paradoxical embolization: Case report and review of the literature. Arch Surg 1977;112:648 – 650. [20] Lechat P, Mas JL, Lascault G, Loron Ph, Theart M, Klimczac M, Drobinski G, Thomas D, Grosgeat Y. Prevalence of patent foramen ovale in patients with stroke. N Eng J Med 1988);318: 1148 – 1152. [21] Levine NM, Hirsch J. Hemorrhagic complications of long-term anticoagulant therapy for ischemeic vascular disease. Stroke 1986;17:111 – 116.

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[22] Mas LJ, Zuber M, for the French Study Group on Patent Foramen Ovale and Atrial Septal Aneurysm. Recurrent cerebrovascular events in patients with patent foramen ovale, atrial septal aneurysm, or both and cryptogenic stroke or transient ischemic attack. Am Heart J 1995;130:1083 – 1088. [23] Meister SG, Grossman W, Dexter L, Dalen JE. Paradoxical embolism: Diagnosis during life. Am J Med 1972;53:292–298. [24] Pearson AC, Labovitz AJ, Tatineri S, Gomez SR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am CoIl Cardiol 1991;17:66 – 72. [25] Pearson AC, Nagelhout D, Castello R, Gomez C, Labovitz A. Atrial septal aneurysm and stroke: a transesophageal echocardiographic study. J Am CoIl Cardiol 1991;18:1223 – 1229. [26] Stone DA, Godard J, Corretti MC, Kittner SJ, Sample C, Price TR, Plotnick GD. Patent foramen ovale: association between the degree of shunt by contrast trans esophageal echocardiography and the risk of future ischemic neurologic events. Am Heart J 1996;131:158 – 161. [27] Thompson T, Evans W. Paradoxical embolism. Q J Med 1930;23:135 – 150. [28] Webster MWI, Chancellor AM, Smith HJ, Swift DL, Sharpe DN, Bass NM, Glasgow GL. Patent foramen ovale in young stroke patients. Lancet 2: 1988;11 – 12.

Appendix A. Conference discussions Dr T. Carrel (Bern, Switzerland): In your decision-making analysis, do you think there is a place for interventional cardiological closure of these patent foramen ovale? Dr P. Ruchat: In fact there is one paper in the literature, Bridges, who closed 36 patients with an umbrella, and he had a recurrency rate of 15%, which is still too much. Dr T. Carrel: I think there is a need to emphazise this particular problem, because our cardiological colleagues are sometimes a little bit too enthusiastic. In our hospital we had about 30 patients who underwent closure of patent foramen ovale or ASD with umbrellas, and the rate of recurrence or of noncomplete closure of the patent foramen ovale was quite high (around 70%). We also had to operate emergency on patients with dislocation and embolation of the Sideris device on the left or on the right side. So I think it is our role to limit the enthusiasm of the cardiologists. Dr J. Vaage (Stockholm, Sweden): You have shown that you can close the ASD with low morbidity and good results, but you also had a control group of patients that did not get any surgery. What was their stroke rate? Dr. P. Ruchat: There is also a study that follows these patients, and in fact the recurrence rate is 2.2% each year, stroke and death rate, 2.2%, and this is a collective of patients from 1988 to 1994, actually. It was just published in Neurology. Dr E. Wolner (Vienna, Austria): Do you recommend closure of such an ASD if you have a patient with venous disease and patent foramen ovale but no stroke, tested by MRI and so on? Dr P. Ruchat: Actually not because we have proposed surgical therapy only on people who had a stroke and we have a subgroup of stroke patients, even where we take the patient evidently recurrent and one or two criteria who were demonstrated in the literature as a risk factor for recurrence. But this is a preliminary study and maybe we will have to change our minds in the next few years owing to the follow-up results.