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Prevention of residual ventricular septal defects with fibrin sealant
Prevention of Residual Ventricular Septal Defects With Fibrin Sealant Ludwig K. von Segesser, MD, Margrit S. Fasnacht, MD, Paul R. Vogt, MD, Michele Genoni, MD, Urs Arbenz, MD, and Marko I. Turina, MD Clinics for Cardiovascular Surgery and Pediatric Cardiology, University Hospital, Z6rich, Switzerland
Background. Modern echocardiography n o w allows for the detection of a substantial number of residual ventricular septal defects (VSDs) after surgical patch repair that remained h i d d e n in the past. Mostly without h e m o d y namic significance, residual V S D s may have clinical consequences (progressive dehiscence, hemolysis, prophylactic antibiotic treatment, endocarditis). To reduce the number and size of residual VSDs we performed an experimental and a clinical study. Methods. (1) In an experimental setup, burst pressure of 60 fibrin glue-sealed defects (calibrated between 1.0 and 5.0 m m in diameter) was determined using a computerized recording system and pressure loads up to 500 m m Hg. (2) In a prospective clinical trial with blinded postoperative echocardiographic controls V S D closure was performed in 36 consecutive patients (age, 37 ± 40 months; range, 4 to 134 months) using a polytetrafluoroethylene patch and running sutures reinforced with pledgets (22 of 36 patients) or sealed with fibrin glue (14 of 36 patients) in accordance to the surgeon's preference.
Results. (1) E x p e r i m e n t a l l y , m e a n pressure load achieved was more than 500 -+ 0 m m Hg for 1.0-mm defects, 413 + 52 m m Hg for 2.5-mm defects, 363 + 58 m m Hg for 4.0-mm defects, and 313 - 48 m m Hg for 5.0-mm defects (r 0.873, p < 0.001). (2) Clinically, all patients survived. Residual V S D s at echocardiography were observed in 16 of 22 patients (72%) for reinforced versus 5 of 14 patients (36~) for sealed with fibrin glue (p < 0.05). Diameter of residual V S D s accounted for 1.3 ± 1.2 m m for reinforced versus 0.3 ± 0.4 m m for sealed with fibrin glue (p < 0.01). HemodynamicaUy significant residual VSDs were found in 2 of 22 patients (9%) for reinforced versus 0 of 14 patients (0%) for sealed with fibrin glue (p = not significant). Conclusions. Small defects sealed with fibrin glue resist physiologic pressure load. Fibrin glue sealing of prosthetic patches during intracardiac V S D repair allows for significant reduction of number and size of residual VSDs. Improved long-term outcome can be expected.
urgical patch closure of ventricular septal defects (VSDs) is now well established. However, almost any larger series reports on some hemodynamically significant residual VSDs after surgical repair [1-3]. Furthermore m o d e r n echocardiography [4, 5] allows for detection of a substantial n u m b e r of residual VSDs that r e m a i n e d hidden in the past. Although most of these residual VSDs are without hemodynamic significance, this diagnosis may have clinical consequences, as in some series of infective endocarditis, a VSD was the main u n d e r l y i n g heart disease [6l. On the other hand, it is well accepted that surgical closure of VSDs lowers the risk of bacterial endocarditis [7]. Interestingly, the size of the VSD is not associated with the risk of bacterial endocarditis [7]. Hence, lifelong antibiotic prophylaxis of infective endocarditis remains indicated even in very small residual VSDs. Two types of problems can be considered responsible for residual VSDs. On one hand, there is the well-known friability of the myocardial tissue that does not always
allow for secure anchoring of the sutures. This is particularly evident for zones where superficial suturing is r e c o m m e n d e d to avoid disturbance of the atrioventricular conduction system. Of course, pull-through of sutures is particularly problematic with r u n n i n g sutures as it can result in a loose suture line. O n the other hand, the diagnosis of a loose patch can also be attributable to " u n s u t u r e d " segments of the patch circumference, which in turn may be due to incongruences between the prosthetic patch and the u n d e r l y i n g myocardial structures, inadequate exposure of the circumference of the VSD, or combinations. A n u m b e r of techniques to improve the strength of the sutures has been suggested in the past including Teflon pledgets, strips of Teflon felt, or strips of pericardium. Although these techniques help to reduce the n u m b e r of sutures pulled through the muscular septum they are not always suitable to occlude geometric incongruences between septum a n d patch. In an effort to reduce size and n u m b e r of residual VSD after surgical patch closure we evaluated the use of fibrin glue, which is well k n o w n for its occlusive properties from extracardiac [8, 9] as well as intracardiac applications [10, 11]. Before clinical application we evaluated the potential strength of fibrin glue in vitro.
S
Presented at the Thirty-firstAnnual Meetingol The Societx of lhoracic Surgeons, Palm Springs, CA, /an 3/}-Feb1, 1995. Address reprint requests to Dr xon Segesser, Clinic for Cardiovascular SurgeD', UniversityHospital, CH-g091 Z6rich, S~itzerland. © 1995 by The Society of "['h{~racic Surgeons
(Ann Thorac Surg 1995;60:511-6)
0003-4975/95/$9.50 0003-4975(95)00536-T
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Material and Methods Experimental Evaluation
To d e t e r m i n e the sealing potential of fibrin glue, we studied in vitro various defects occluded with fibrin glue. Sixty silicone r u b b e r tubing segments (outer diameter, 9.2 mm; inner diameter, 6.4 mm; wall thickness, 1.4 ram) were perforated laterally with an aortic punch. Four basic p u n c h sizes (diameters: 1.0, 2.5, 4.0, and 5.0 mm) were used to p r o d u c e circular defects. Fibrin glue (Tissucol, I m m u n o AG, Ziirich, Switzerland) was used as thermoinactivated preparation of the two main components, hum a n fibrinogen and h u m a n thrombin (the latter was previously provided from a bovine source), which are now available fully p r e p a r e d in frozen form. After thawing, the p r e m o u n t e d and filled double syringes are ready for use. Only the mixing connector and a blunt needle have to be added. Burst pressure of defects sealed with fibrin glue was d e t e r m i n e d in sequential fashion: (1) Calibration of the p u n c h e d defect with a probe. Only circular defects with k n o w n d i a m e t e r were included. (2) Sealing of the lateral defect with fibrin glue at room temperature. (3) Connection of the tubing s e g m e n t (with the sealed lateral defect) to a c o m p u t e r i z e d recording system on one side and a line providing c o m p r e s s e d air to the other. (4) Three minutes after sealing, progressive pressure load from 0 m m Hg up to 500 m m Hg was applied. (5) Analysis of the pressure loading curve. Loading pressures were read directly from a calibrated pressure transducer with digital r e a d out (Veri-Cal, Utah Medical Products, Midvale, UT), w h e r e a s burst pressures were d e t e r m i n e d by a microtip pressure transducer (Millar, Houston, TX) and transferred to a computerized recording system (Dasa, Gould lnc, Cleveland, OH) allowing for graphic and mathematic analyses. Clinical S h l d y Clinical application was studied in a prospective trial using for VSD closure a polytetrafluoroethylene patch and r u n n i n g sutures that were either reinforced with pledgets or sealed with fibrin glue and b l i n d e d postoperative echocardiographic controls. Thirty-six consecutive patients (mean age, 37 ~ 40 months; range, 4 to 134 months) u n d e r g o i n g VSD patch closure were studied. In accordance to the surgeon's preference, 22 patients had VSD patch repair with reinforced sutures a n d 14 patients with sealed patches. For the group o p e r a t e d on with reinforced sutures, the diagnoses included an isolated VSD in 8 of 22 patients (36%) as c o m p a r e d to a VSD in Fallot, double-outlet right ventricle, and more complex situations in 14 patients (64%). In contrast, for the group with sealed patches, there was only one isolated VSD (1 of 14 patients, 7",;,; p 0.05) as c o m p a r e d to VSDs in tetralogy of Fallot, doubleoutlet right ventricle, and more complex situations in 13 patients (93%; p - 0.05). Preoperative shunt fraction was 52 _+ 17% for reinforced sutures as c o m p a r e d to 72 - 16'I,, for sealed patches (p < 0.01). With exception of the type of VSD closure, all proce-
Fly. 1. Transatrial approach to the repair q]: a perimembranous ventricular septal defect demonstrating; the surgical technique. The borders of the ventricular septal defect patch art" sealed aqth fibrin glue in ta,,~ steps. The patch is seated on a layer of fibrin glue before the suture is ti~,,htened. An additional layer qf glue is added after (see inset). Caveat: region to be sealed must be dry to allow for acceptaide adhesion and soiling of left cavities and tricuspid valve with fibrin glue have to be avoided.
dures were p e r f o r m e d in s t a n d a r d i z e d fashion using microporous hollow fiber oxygenators (Lilliput, Masterflow or Midiflow, Dideco Spa, Mirandola, Italy), clear priming (whenever possible), and m o d e r a t e h y p o t h e r m i a (24 ° to 28°C). Repair of the VSD and left-sided lesions of the heart were p e r f o r m e d with cold blood cardioplegiainduced cardiac arrest, whereas right-sided lesions were repaired during r e w a r m i n g with fibrillating heart and open aorta. Transatrial, transpulmonary, or transaortic approach for VSD closure was selected w h e n e v e r possible. Transventricular approach was only used in cases with double-outlet right ventricle or p u l m o n a r y atresia type right outflow tract. Transatrial VSD closure was performed in 16 of 22 patients (73%) for reinforced sutures as c o m p a r e d to 8 of 14 patients (57%) for sealed with glue (p - not significant INS]). T r a n s p u l m o n a r y a p p r o a c h was selected in 3 of 22 patients (14",/,) for reinforced sutures as c o m p a r e d to 2 of 14 patients (14%) for sealed with glue (p = NS). Transaortic a p p r o a c h was used in 1 of 22 patients (5%) for reinforced sutures as c o m p a r e d to 1 of 14 patients (7%) for sealed with glue (p :: NS). Transventricular route was selected in 2 of 22 patients (9%) for reinforced sutures as c o m p a r e d to 3 of 14 patients (21%) for sealed with glue (p NS). A p p l i c a t i o n o f Fibrin Sealant Fibrin glue is now available as deep frozen preparation (see Experimental Evaluation), which is t h a w e d during cannulation, cardioplegia application, and inspection of the VSD. As o u t l i n e d above, t r a n s a t r i a l a p p r o a c h through the tricuspid valve is preferred. Figure 1 shows the operative exposure and repair of a p e r i m e m b r a n o u s VSD using an e x p a n d e d polytetrafluoroethylene patch (0.4- or 0.6-mm thickness; W. L. Gore & Associates Inc, Flagstaff, AZ). The patch is attached with a loose r u n n i n g 6/0 e x p a n d e d p o l y t e t r a f l u o r o e t h y l e n e s u t u r e (W. L.
Ann [horac Surg 1995;60:511 6
Gore). The inset of Figure 1 shows that some fibrin glue is applied behind the patch before the suture is tightened (eg, with a hook) and the patch is seated on a bed of liquid glue. A second laver of glue is applied on the border of the patch, the sutures, and the ventricular septum nearby. A speedy technique is necessarw as the fibrin glue coagulates up to some degree within seconds. After 60 s the glue becomes reasonably solid. To achieve a d e q u a t e adherence, the surfaces to be sealed have to be dried before application of the glue. Hence, we use a vent on the left side of the heart (through the interatrial septum), a p u m p sucker on the right side, and swabs in the peripatch area to keep the blood out of the zone to be glued. Rubbing of the endothelial contact area with a sponge provides superior adherence. Care must be taken not to soil the tricuspid valve and its subvalvar apparatus as well as the cavities of the left heart w h e r e embolization could occur. F o l l o w - u p and A n a l y s e s All patients included in the study u n d e r w e n t blinded postoperative two-dimensional echocardiographic control with color-coded Doppler m a p p in g by i n d e p e n d e n t pediatric cardiologists to assess the n u m b e r and diameter of residual VSDs after surgical patch closure on at least two occasions: early postoperatively and before discharge. Besides the usual echocardiographic evaluation, n u m b e r and diameter ot residual VSDs were documented. Statistical A n a l y s e s In the experimental stud,,', mean - standard deviation was derived for all pressure loads as well as for the respective groups corresponding to the different defects. Systat statistical software package (Systat lnc, Evanston, IL) was used for calculation of linear regression. For the clinical study, mean * standard deviation was calculated for parametric data and Student's t test was used where applicable for comparison between groups. Fisher's exact test was used for comparison of nonparametric data (Solo, distributed bv BMDP Statistical Sortware, Los Angeles, CA). Statistical significance was confirmed by a p value of less than 0.05. Results
yon SEGESSERET AL PREVENTION OF RESIDUALVSD
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i
500 ] r 450i 400i 350{ :~_ 300 i E 250 E 200 150 100 i 50! 0~
L
2.5
r
4
5
mm iX 2, lApcrimental evaluation. Mean ~ standard deviation of pressmcs achieved in bursted seals. Linear regression analysis provided ,t mttltil&' r value off 0.890 (p < 0,001), All 1.0-ram defects sealed with fibrin glue resisted the selected maximal pressure load of 500 m m Hg. For bursted seals, the r e c o r d e d p r e s s u r e s w e r e 196 + 129 mm Hg for 2.5-mm defects, 113 -- 61 m m Hg for 4.0-mm defects, and 63 + 52 m m Hg for 5.0-ram defects (Fig 2). Linear regression analysis of the burst pressures estimates the intercept (constant) with 591 and the slope with ( 120).The correlation b et w een diameter and burst pressure (multiple R) is 0.890 (p < 0.001). Clinical S t u d y As outlined above, 22 of 36 patients u n d e r w e n t VSD repair with a patch using sutures r e i n f o r c e d with pledgets and 14 of 36 had their VSD patch sutured and sealed with fibrin glue. Aortic cross-clamp time was 31 ± 10 minutes for reinforced sutures as c o m p a r e d to 34 -- 8 minutes for sealed with fibrin glue (p = NS). P u m p time was 75 *~ 24 minutes for reinforced sutures as c o m p a r e d to 84 + 23 minutes for sealed with fibrin glue (p = NS). All patients survived the p r o ced u r e and were discharged from the hospital. Hence, hospital mortality for the study population was 0%. The postoperative results are s u m m a r i z e d in Figure 3. Residual VSDs at echocardiography were o b s e r v e d in 16
80
i
] residual VSDs I
E x p e r i m e n t a l Evaluation Compilation of all data points (n 60) resulted in a mean pressure load of 438 ~ 78 mm Hg. The n u m b e r of test runs per size of defect was 7 of 60 for 5.O-ram diameter, 8 of 60 for 4.O-ram diameter, 15 of 60 for 2.5-ram diameter, and 30 of 60 for 1.0-ram diameter. Pressure loads achieved per group were 313 I 48 m m Hg for 5.0-ram defects, 363 -_+ 58 m m Hg for 4.0-ram defects, 413 52 m m Hg f o r 2 . S - m m defects, and 500 * 0 mm Hg for 1.0-mm defects. Linear regression analysis of pressure loads achieved estimates the intercept (constant) with 543 and the slope with ( 47) and the correlation is (multiple r) 0.873 (t' < 0.01).
70 60
~
i•
significant VSDs H
50 ~ /1
840
10 O"
# reinforced sutures
sealed with glue
Fi,,,, 3. Clinical study. Postoperah've results are given as percent per ,2nmp mmlvzed. There are siRn(ficantlg fewer residual ventricular septal detects (VSDs,' in the ,Woup with sealed patches (p < 0.05).
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vox SEGESSER ET AL PREVENTION OF RESIDUAL VSD
of 22 patients (72%) for reinforced sutures as c o m p a r e d to 5 of 14 (36%) for sealed with fibrin glue (p < 0.05). D i a m e t e r of residual VSDs accounted for 1.3 ÷ 1.2 m m (range, 0 to 4 ram) for reinforced sutures as c o m p a r e d to 0.3 _+ 0.4 m m (range, 0 to I ram) for sealed with fibrin glue (p < 0.01). H e m o d y n a m i c a l l y significant residual VSDs were found in 2 of 22 patients (9%) for reinforced sutures as c o m p a r e d to 0 (0%) for sealed with fibrin glue (p = NS).
Comment Small defects sealed with fibrin glue resist physiologic pressure load. In the experimental setup, sealed defects of 1.0 ram or less have consistently resisted the acute exposure to suprasystemic pressure load. However, resistance of larger sealed defects a p p e a r s primarily to be a function of its diameter. Linear regression analysis with defect d i a m e t e r as an i n d e p e n d e n t variable and burst pressure as a d e p e n d a n t variable showed good indirect correlation and a highly significant slope. Obviously, acceptable goodness of fit was d e m o n s t r a t e d for the defect diameters tested. C o m m o n sense, as well as extrapolation of the regression line make it clear that for larger defects (more than 5 mm) burst pressure is approaching zero. However, a n u m b e r of m e a s u r e s can be taken to increase the tolerable pressure load. These include a rough surface for better adherence, a conical defect with the larger orifice on the side with higher pressure load, production of a fibrin glue plug with rivet-like heads on both ends allowing for p r o p e r polymerization, and others. Translated into clinical practice, a textured patch is preferable and the contact area should be dried a n d p r e p a r e d with a sponge to achieve a rougher surface before sealing. Obviously the intact endothelial surface is not an ideal substrate for solid anchorage of the glue. Some excess glue has also to be d e p o s i t e d to form a plug that is of larger size than the potential orifice to be occluded, and the glue m u s t be allowed to polymerize properly. To monitor the p o l y m e r ization process intraoperatively, some excess glue can be d e p o s i t e d on a sponge just before the sealing of a specific area. Progress of polymerization can be evaluated optically (opacification) and digitally. In our hands, application of these techniques to the clinical setting (ie, fibrin glue sealing of prosthetic patches during intracardiac VSD repair) allowed for significant reduction of n u m b e r and size of residual VSDs despite more complex procedures p e r f o r m e d in the study group. As outlined before, the fibrin sealant can c o m p e n s a t e for small incongruences b e t w e e n cardiac structures a n d patch material. This function is similar to the naturally occurring clots sealing vascular anastomoses, which in this case are p r o v o k e d deliberately before the exposure to the bloodstream. Furthermore, if well placed, the fibrin glue can, due to its adherence, also contribute to better patch fixation (improved distribution of forces) a n d therefore, reduce the risk of suture pullthrough. This function is similar to the pledgets used in the control group. In contrast to additional stitches,
Ann Thorac Surg 1995;60:511-6
however, application of fibrin glue will not interfere with the conduction system. The a d e q u a t e resistance of glue d e p o s i t e d in the interventricular s e p t u m has also be d e m o n s t r a t e d b y Leca and colleagues [11] who r e p o r t e d on surgical t r e a t m e n t of multiple VSDs using biological glue. H e r group s t u d i e d the use of fibrin glue for repair of artificially created VSDs in sheep with sizes b e t w e e n 5 and 10 m m and achieved satisfactory results. Interestingly, n e c r o p s y studies s h o w e d that the glue was progressively r e p l a c e d with fibrous tissue. In the clinical study r e p o r t e d by the same group, fibrin glue was u s e d mainly for closure of apical VSDs a n d p r o v e d to be very reliable. T h r e e - y e a r follow-up further confirmed that repair of VSDs with fibrin glue r e m a i n e d intact over time as s u g g e s t e d by the previous experimental work. The r e c o m m e n d a t i o n to use fibrin glue for closure of m u s c u l a r VSDs with less than 8 m m of d i a m e t e r is in a g r e e m e n t with our finding that sealed defects of 5 m m or less in d i a m e t e r can hold considerable pressure. Potential drawbacks of glue application within the heart include soiling of structures that should not be included in the area to be sealed (eg, subvalvar a p p a r a t u s of the tricuspid valve) as well as embolization of glue particles d e p o s i t e d on areas with a blood film w h e r e p r o p e r adhesion is not possible. Both p r o b l e m s can be avoided if a d e q u a t e exposure a n d p r o p e r techniques are a p p l i e d as outlined above. Venting of the left-sided cavities should be nonocclusive during the sealing procedure to avoid aspiration of glue. Despite the application of fibrin glue on a large scale, there are only few reports on side effects. Even i m m u n i zation by bovine t h r o m b i n [12] u s e d in the mixture should not occur a n y m o r e as t h r o m b i n of h u m a n origin is now used in the frozen preparations. At this time, the only bovine c o m p o n e n t still necessary is aprotinin (3,000 KIU/mL). Routine application of fibrin glue a n d its potential side effects have to be balanced against the risk related to residual VSDs of m i n o r size on one side a n d the risk of reoperation in hernodynamically significant VSDs on the other. Traditionally, a VSD was mainly considered for surgical closure if p u l m o n a r y - t o - s y s t e m i c flow ratio was more than 2.0 and in general the s a m e criteria were a p p l i e d for closure of residual VSDs after surgical patch closure. Recently, Backer and colleagues [13] r e p o r t e d on closure of restrictive ventricular septal defects with pulm o n a r y - t o - s y s t e m i c flow ratio of less than 2.0. Despite excellent results in their series this issue r e m a i n s controversial as no real long-term results are available yet [14, 15]. However, it is a fact that a significant n u m b e r of reoperations have to be p e r f o r m e d after surgical patch closure of VSD even if only the so-called h e m o d y n a m i cally significant shunts are considered. C a s t a n e d a a n d colleagues [16] found two significant shunts after VSD closure in a series of 146 cases early after operation. Another three significant residual left-to-right shunts were found during late follow-up bringing the rate of significant residual VSDs up to 5 of 148 or 3.4%. A d m i t tedly there was also an u n k n o w n proportion of so-called
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trivial r e s i d u a l V S D s at c a r d i a c c a t h e t e r i z a t i o n . U n m e n t i o n e d is t h e p r o p o r t i o n of r e s i d u a l V S D s t h a t are o n l y detectable with modern echocardiographic techniques. The former and the latter may be without importance w i t h r e g a r d to t h e d e v e l o p m e n t of p u l m o n a ~ a r t e D, hypertension. However, lifelong antibiotic prophylaxis r e m a i n s i n d i c a t e d if t h e V S D w a s n o t c o m p l e t e l y c l o s e d d u r i n g o p e r a t i o n [7]. E v e n h i g h e r p r o p o r t i o n s of r e s i d u a l V S D s w e r e r e p o r t e d for p a t i e n t s w i t h m u l t i p l e V S D s . Kirklin a n d c o - w o r k e r s [17] o b s e r v e d a r e o p e r a t i o n r a t e of 28%. A g a i n o n l y h e m o d y n a m i c a l l y s i g n i f i c a n t V S D s w e r e r e o p e r a t e d a n d t h e r e is a n u n k n o w n p r o p o r t i o n of r e s i d u a l V S D s w i t h a s h u n t f r a c t i o n of less t h a n 2.0. F u r t h e r m o r e t h e p r o p o r t i o n of r e s i d u a l V S D s d e t e c t a b l e o n l y at e c h o c a r d i o g r a p h y is n o t a v a i l a b l e . In c o n t r a s t to t h e s e f i n d i n g s , t h e r e w a s n o r e o p e r a t i o n in t h e s e r i e s of Leca a n d c o l l e a g u e s [11] w h o u s e d f i b r i n g l u e to close s m a l l V S D s i n p a t i e n t s w i t h m u l t i p l e defects. C o n s i d e r i n g t h e i m p o r t a n c e of r e l i a b l e c o m p l e t e clos u r e of VSDs, w e b e l i e v e t h a t s e a l i n g of t h e p r o s t h e t i c p a t c h w i t h f i b r i n g l u e d u r i n g s u r g i c a l r e p a i r is a p r a c t i c a l w a y to r e d u c e t h e n u m b e r a n d size of r e s i d u a l V S D s . W i t h p r o p e r t e c h n i q u e t h e p o t e n t i a l risks of t h i s a p proach are minimal and improved long-term outcome can be expected.
References 1. Sairanen H, Leijala M, Louhimo 1. Surgery" for ventricular septal defect. Scand J Thorac Cardiovasc Surg 1991;25:1-5. 2. Vogt J, Wesselhoeft H, Luig H, et al. The pre- and postoperative findings in 627 patients with tetralogy of Fallot. Thorac Cardiovasc Surg 1984;32:234-43. 3. Bical O, Perrier P, Fermont L, et al. R6op6ration apr6s correction chirurgicale de tetralogie de Fallot. Arch Mal Coeur-Vaiss 1984;77:595-9.
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4. Andrade JL, Serino W, de Leval M, Somerville J. Two dimensional echocardiographic assessment of surgically closed ventricular septal defects. Am J Cardio11983;52:325-9. 5. Roberson DA, M u h i u d e e n IA, Cahalan MK, et al. Intraoperative transesophageal echocardiography of ventricular septal defect. Echocardiography 1991;8:687-97. 6. Fukushige J, Igarashi H, Ueda K. Spectrum of infective endocarditis during infancy and childhood: 20 year review. Pediatr Cardiol 1994;15:127-31. 7. Gersony WM, Hayes CJ, Driscoll DJ, et al. Bacterial endocarditis in patients with aortic stenosis, pulmonary stenosis, or ventricular septal defect. Circulation 1993;87(Suppl 1): 121-6. 8. Seelich T. Tissucol (Immuno Vienna): biochemistry and methods of application. J Head Neck Pathol 1982;3:65-9. 9. Rousou J, Levitsky S, Gonzales-Lavin L, et al. Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. J Thorac Cardiovasc Surg 1989;97:194-203. 10. Von Segesser LK, Oechslin E, Jenni R, Turina MI. Use of glue to avoid formation of perfused recesses in aortic homograft implantation. A n n Thorac Surg 1994;57:494-5. 11. Leca F, Karam J, Vouh6 P, et al. Surgical treatment of multiple ventricular septal defects using biologic glue. J Thorac Cardiovasc Surg 1994;107:96-102. 12. Berruyer M, Amiral J, French P, et al. Immunization by bovine thrombin used with fibrin glue during cardiovascular operations. J Thorac Cardiovasc Surg 1993;105:892-7. 13. Backer CL, Winters RC, Zales VR, et al. Restrictive ventricular septal defect: how small is too small to close. Ann Thorac Surg 1993;56:1014-9. 14. Malm JR. A reason to close ventricular septal defect? Ann Thorac Surg 1993;56:1013. 15. Waldman JD. Why not to close a small ventricular septal defect? Ann Thorac Surg 1993;56:1011-2. 16. Castaneda A, Jonas RA, Mayer JE, Hanley FL. Cardiac surgery of the neonate and infant. Philadelphia: Saunders, 1994:187-201. 17. Kirklin JK, Castaneda AR, Keane JF, Fellows KE, Norwood WI. Surgical m a n a g e m e n t of multiple ventricular septal defects. J Thorac Cardiovasc Surg 1980;80:485-93.
DISCUSSION DR PEDRO J. DEL NIDO (Pittsburgh, PA): Did you see any evidence or incidence of neurologic problems? Obviously, one of the concerns would be if you accidentally dropped some of the glue into the left side of the heart. DR VON SEGESSER: We did not see any of these problems. However, it is true that one has to use a proper technique. And as I said, it is useful to rub the surface to get better adhesion and, of course, no glue should drop on blood because it would not stay there and could be embolized. Until now we have not had that problem. DR CHARLES B. HUDDLESTON (St. Louis, MO): At what stage after the operation was the echocardiogram performed? Also, 1 presume by the hemodynamic significance those 2 patients had to return to the operating room for closure. DR voN SEGESSER: Yes. DR HUDD/ESTON: I would agree with concerns with embolization as Dr del Nido pointed out. It seemed like that would
produce a thrombogenic surface over and above what the patch produces itself on the left side of the heart. DR VON SEGESSER: With regard to the thrombogenic surface I think one can say that in adult cardiac operations we often have clots in the aorta and aneurysms that stay there for years without embolization. 1 think it is not necessarily a problem to have a clot there. l also believe that if the patch reaches the surface with a small angle, this region would clot off anyway, and if you have no flow in a place, you will have a clot there also. And there are some technical aspects to improve the resistance of the glue. I think it is helpful to produce a plug that has larger ends on both sides. And here in this application the glue is taken into the suture, therefore 1 think the risk of embolization is very low. DR RUEDIGER LANGE (Heidelberg, Germany): As far as I know fibrin glue is resorbed within approximately 3 days. Do you use a different glue or do you have any information on this issue? My second question is, at what time after the operation did you perform the echocardiographic examinations? If it was beyond 3 days after operation, there should not be any differ-
516
yon SEGESSER ET AL PREVENTION OF RESIDUAl VSD
ence b e c a u s e by that time t h e r e is no fibrin glue left. C o u l d y o u c o m m e n t on w h e t h e r y o u r o b s e r v e d difference in residual s h u n t i n g w a s m a y b e d u e to t h e difference in s u t u r e t e c h n i q u e , i n t e r r u p t e d v e r s u s c o n t i n u o u s , t h a n d u e to the application of fibrin glue? D R YON SEGESSER: W i t h r e g a r d to t h e r e s o r p t i o n of t h e glue, 1
can say t h a t t h e r e h a s b e e n a s t u d y d o n e by Leca a n d colleagues f r o m Paris w h e r e t h e y h a v e g l u e d m u l t i p l e v e n t r i c u l a r septal defects (VSDs) e x p e r i m e n t a l l y first a n d clinically thereafter, a n d t h e y f o u n d in the e x p e r i m e n t a l s e t u p that the glue w a s replaced b y scar tissue a n d t h e y h a d no r e c u r r e n c e a n d no r e o p e r a t i o n s in their group. W i t h r e g a r d to the e c h o c a r d i o g r a m , we did several echocard i o g r a m s : one early after operation, one before discharge, a n d one between 3 and 6 months. D R CARL L. B A C K E R (Chicago, IL): l a m c u r i o u s as to y o u r t h o u g h t s a b o u t t h e i n t e r r u p t e d s u t u r e t e c h n i q u e for closure of VSDs. We have published our results with interrupted p l e d g e t e d s u t u r e s a n d a n elastic D a c r o n patch, a t e c h n i q u e that w a s d e v e l o p e d by Farouk Idriss. W i t h b o t h small VSDs a n d with conal VSDs, we h a v e h a d essentially no residual VSDs u s i n g that t e c h n i q u e . I t h i n k t h e ideal o p e r a t i o n for a VSD, at least at our institution, is closure with i n t e r r u p t e d p l e d g e t e d s u t u r e s a n d a D a c r o n patch, a n d I w o n d e r if y o u could c o m m e n t on w h y you did n o t try t h a t t e c h n i q u e .
Ann Thorac Surg 1995;60:511-6
y o u w o u l d n o t detect a n y of these. So with r e g a r d to t h e i n t e r r u p t e d s u t u r e t e c h n i q u e , I believe that this w o u l d n o t h e l p in this application, b e c a u s e y o u still can h a v e i n c o n g r u e n c e s b e t w e e n the patch on o n e side a n d t h e m y o c a r d i u m on t h e other, w h i c h c a n n o t be o c c l u d e d with s u t u r e s e v e r y w h e r e . A n d if I u n d e r s t o o d correctly, y o u u s e d a D a c r o n patch. It w o u l d p r o b a b l y not e v e n be tight in t h e b e g i n n i n g b u t only later on, a n d w h a t m a k e s it tight finally is a clot all over t h e surface. D R M I C H A E L A. GREENE (Gainesville, FL): I w a s w o n d e r i n g if the s o u r c e of t h e f i b r i n o g e n e x p o s e s t h e p a t i e n t to a n y infectious risk. D R YON SEGESSER: 1 t h i n k that is a very i m p o r t a n t q u e s t i o n . T h e glue u s e d at this t i m e h a s n o t b e e n r e p o r t e d to be l i n k e d to t r a n s m i s s i o n of infectious diseases. T h e r e h a v e b e e n a n u m b e r of p r e c a u t i o n s taken. It is t h e r m a l l y inactivated m a t e r i a l on o n e side. A n d a l t h o u g h t h e r e h a s n e v e r b e e n a t r a n s m i s s i o n reported, t h e r e are PCR t e c h n i q u e s u s e d to avoid b a t c h e s that could be c o n t a m i n a t e d . Therefore, I believe t h e risk of t r a n s m i s sion of infectious d i s e a s e is e x t r e m e l y low. D R C O N S T A N T I N E E. A N A G N O S T O P O U L O S ( N e w York, NY): 1 h a v e b e e n f o r t u n a t e to u s e t h e fibrin glue in N e w York a n d t h e resorcinol glue w h e n I go to A t h e n s . If y o u really w a n t c o m p l e t e e l i m i n a t i o n of criticism from cardiology, are y o u willing to s p e n d 10 m i n u t e s so y o u can u s e t h e resorcinol glue? H a v e vou t h o u g h t of that? Or do y o u w a n t a little criticism?
D R VON SEGESSER: Well, I t h i n k we h a v e to state clearly that
h e r e we are n o t talking a b o u t residual VSDs that h a v e to be r e o p e r a t e d on. T h e s e are t h i n g s that you find in the r e p o r t s of t h e cardiologists that n o r m a l l y are called trivial VSDs, a n d you find t h e s e in all series that are p u b l i s h e d . You w o u l d not even s e e t h e s e VSDs at a n g i o g r a p h y or if you do o x y g e n saturations;
D R v o ~ SEGESSER: W e u s e t h e resorcin glue, or F r e n c h glue,
for aortic dissections. 1 a m n o t s u r e if h e r e it w o u l d be a g o o d application b e c a u s e of the c o n d u c t i o n tissue. A s y o u know, resorcin glue c o n t a i n s formalin, a n d I believe that fixation of t h e c o n d u c t i v e tissue m i g h t n o t be ideal.
Background. Modern echocardiography n o w allows for the detection of a substantial number of residual ventricular septal defects (VSDs) after surgical patch repair that remained h i d d e n in the past. Mostly without h e m o d y namic significance, residual V S D s may have clinical consequences (progressive dehiscence, hemolysis, prophylactic antibiotic treatment, endocarditis). To reduce the number and size of residual VSDs we performed an experimental and a clinical study. Methods. (1) In an experimental setup, burst pressure of 60 fibrin glue-sealed defects (calibrated between 1.0 and 5.0 m m in diameter) was determined using a computerized recording system and pressure loads up to 500 m m Hg. (2) In a prospective clinical trial with blinded postoperative echocardiographic controls V S D closure was performed in 36 consecutive patients (age, 37 ± 40 months; range, 4 to 134 months) using a polytetrafluoroethylene patch and running sutures reinforced with pledgets (22 of 36 patients) or sealed with fibrin glue (14 of 36 patients) in accordance to the surgeon's preference.
Results. (1) E x p e r i m e n t a l l y , m e a n pressure load achieved was more than 500 -+ 0 m m Hg for 1.0-mm defects, 413 + 52 m m Hg for 2.5-mm defects, 363 + 58 m m Hg for 4.0-mm defects, and 313 - 48 m m Hg for 5.0-mm defects (r 0.873, p < 0.001). (2) Clinically, all patients survived. Residual V S D s at echocardiography were observed in 16 of 22 patients (72%) for reinforced versus 5 of 14 patients (36~) for sealed with fibrin glue (p < 0.05). Diameter of residual V S D s accounted for 1.3 ± 1.2 m m for reinforced versus 0.3 ± 0.4 m m for sealed with fibrin glue (p < 0.01). HemodynamicaUy significant residual VSDs were found in 2 of 22 patients (9%) for reinforced versus 0 of 14 patients (0%) for sealed with fibrin glue (p = not significant). Conclusions. Small defects sealed with fibrin glue resist physiologic pressure load. Fibrin glue sealing of prosthetic patches during intracardiac V S D repair allows for significant reduction of number and size of residual VSDs. Improved long-term outcome can be expected.
urgical patch closure of ventricular septal defects (VSDs) is now well established. However, almost any larger series reports on some hemodynamically significant residual VSDs after surgical repair [1-3]. Furthermore m o d e r n echocardiography [4, 5] allows for detection of a substantial n u m b e r of residual VSDs that r e m a i n e d hidden in the past. Although most of these residual VSDs are without hemodynamic significance, this diagnosis may have clinical consequences, as in some series of infective endocarditis, a VSD was the main u n d e r l y i n g heart disease [6l. On the other hand, it is well accepted that surgical closure of VSDs lowers the risk of bacterial endocarditis [7]. Interestingly, the size of the VSD is not associated with the risk of bacterial endocarditis [7]. Hence, lifelong antibiotic prophylaxis of infective endocarditis remains indicated even in very small residual VSDs. Two types of problems can be considered responsible for residual VSDs. On one hand, there is the well-known friability of the myocardial tissue that does not always
allow for secure anchoring of the sutures. This is particularly evident for zones where superficial suturing is r e c o m m e n d e d to avoid disturbance of the atrioventricular conduction system. Of course, pull-through of sutures is particularly problematic with r u n n i n g sutures as it can result in a loose suture line. O n the other hand, the diagnosis of a loose patch can also be attributable to " u n s u t u r e d " segments of the patch circumference, which in turn may be due to incongruences between the prosthetic patch and the u n d e r l y i n g myocardial structures, inadequate exposure of the circumference of the VSD, or combinations. A n u m b e r of techniques to improve the strength of the sutures has been suggested in the past including Teflon pledgets, strips of Teflon felt, or strips of pericardium. Although these techniques help to reduce the n u m b e r of sutures pulled through the muscular septum they are not always suitable to occlude geometric incongruences between septum a n d patch. In an effort to reduce size and n u m b e r of residual VSD after surgical patch closure we evaluated the use of fibrin glue, which is well k n o w n for its occlusive properties from extracardiac [8, 9] as well as intracardiac applications [10, 11]. Before clinical application we evaluated the potential strength of fibrin glue in vitro.
S
Presented at the Thirty-firstAnnual Meetingol The Societx of lhoracic Surgeons, Palm Springs, CA, /an 3/}-Feb1, 1995. Address reprint requests to Dr xon Segesser, Clinic for Cardiovascular SurgeD', UniversityHospital, CH-g091 Z6rich, S~itzerland. © 1995 by The Society of "['h{~racic Surgeons
(Ann Thorac Surg 1995;60:511-6)
0003-4975/95/$9.50 0003-4975(95)00536-T
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yON SEGESSER E1 AL PREVENTION OF RESIDLAI \'%I)
Ann Thorac Surg 1995;60:511-6
Material and Methods Experimental Evaluation
To d e t e r m i n e the sealing potential of fibrin glue, we studied in vitro various defects occluded with fibrin glue. Sixty silicone r u b b e r tubing segments (outer diameter, 9.2 mm; inner diameter, 6.4 mm; wall thickness, 1.4 ram) were perforated laterally with an aortic punch. Four basic p u n c h sizes (diameters: 1.0, 2.5, 4.0, and 5.0 mm) were used to p r o d u c e circular defects. Fibrin glue (Tissucol, I m m u n o AG, Ziirich, Switzerland) was used as thermoinactivated preparation of the two main components, hum a n fibrinogen and h u m a n thrombin (the latter was previously provided from a bovine source), which are now available fully p r e p a r e d in frozen form. After thawing, the p r e m o u n t e d and filled double syringes are ready for use. Only the mixing connector and a blunt needle have to be added. Burst pressure of defects sealed with fibrin glue was d e t e r m i n e d in sequential fashion: (1) Calibration of the p u n c h e d defect with a probe. Only circular defects with k n o w n d i a m e t e r were included. (2) Sealing of the lateral defect with fibrin glue at room temperature. (3) Connection of the tubing s e g m e n t (with the sealed lateral defect) to a c o m p u t e r i z e d recording system on one side and a line providing c o m p r e s s e d air to the other. (4) Three minutes after sealing, progressive pressure load from 0 m m Hg up to 500 m m Hg was applied. (5) Analysis of the pressure loading curve. Loading pressures were read directly from a calibrated pressure transducer with digital r e a d out (Veri-Cal, Utah Medical Products, Midvale, UT), w h e r e a s burst pressures were d e t e r m i n e d by a microtip pressure transducer (Millar, Houston, TX) and transferred to a computerized recording system (Dasa, Gould lnc, Cleveland, OH) allowing for graphic and mathematic analyses. Clinical S h l d y Clinical application was studied in a prospective trial using for VSD closure a polytetrafluoroethylene patch and r u n n i n g sutures that were either reinforced with pledgets or sealed with fibrin glue and b l i n d e d postoperative echocardiographic controls. Thirty-six consecutive patients (mean age, 37 ~ 40 months; range, 4 to 134 months) u n d e r g o i n g VSD patch closure were studied. In accordance to the surgeon's preference, 22 patients had VSD patch repair with reinforced sutures a n d 14 patients with sealed patches. For the group o p e r a t e d on with reinforced sutures, the diagnoses included an isolated VSD in 8 of 22 patients (36%) as c o m p a r e d to a VSD in Fallot, double-outlet right ventricle, and more complex situations in 14 patients (64%). In contrast, for the group with sealed patches, there was only one isolated VSD (1 of 14 patients, 7",;,; p 0.05) as c o m p a r e d to VSDs in tetralogy of Fallot, doubleoutlet right ventricle, and more complex situations in 13 patients (93%; p - 0.05). Preoperative shunt fraction was 52 _+ 17% for reinforced sutures as c o m p a r e d to 72 - 16'I,, for sealed patches (p < 0.01). With exception of the type of VSD closure, all proce-
Fly. 1. Transatrial approach to the repair q]: a perimembranous ventricular septal defect demonstrating; the surgical technique. The borders of the ventricular septal defect patch art" sealed aqth fibrin glue in ta,,~ steps. The patch is seated on a layer of fibrin glue before the suture is ti~,,htened. An additional layer qf glue is added after (see inset). Caveat: region to be sealed must be dry to allow for acceptaide adhesion and soiling of left cavities and tricuspid valve with fibrin glue have to be avoided.
dures were p e r f o r m e d in s t a n d a r d i z e d fashion using microporous hollow fiber oxygenators (Lilliput, Masterflow or Midiflow, Dideco Spa, Mirandola, Italy), clear priming (whenever possible), and m o d e r a t e h y p o t h e r m i a (24 ° to 28°C). Repair of the VSD and left-sided lesions of the heart were p e r f o r m e d with cold blood cardioplegiainduced cardiac arrest, whereas right-sided lesions were repaired during r e w a r m i n g with fibrillating heart and open aorta. Transatrial, transpulmonary, or transaortic approach for VSD closure was selected w h e n e v e r possible. Transventricular approach was only used in cases with double-outlet right ventricle or p u l m o n a r y atresia type right outflow tract. Transatrial VSD closure was performed in 16 of 22 patients (73%) for reinforced sutures as c o m p a r e d to 8 of 14 patients (57%) for sealed with glue (p - not significant INS]). T r a n s p u l m o n a r y a p p r o a c h was selected in 3 of 22 patients (14",/,) for reinforced sutures as c o m p a r e d to 2 of 14 patients (14%) for sealed with glue (p = NS). Transaortic a p p r o a c h was used in 1 of 22 patients (5%) for reinforced sutures as c o m p a r e d to 1 of 14 patients (7%) for sealed with glue (p :: NS). Transventricular route was selected in 2 of 22 patients (9%) for reinforced sutures as c o m p a r e d to 3 of 14 patients (21%) for sealed with glue (p NS). A p p l i c a t i o n o f Fibrin Sealant Fibrin glue is now available as deep frozen preparation (see Experimental Evaluation), which is t h a w e d during cannulation, cardioplegia application, and inspection of the VSD. As o u t l i n e d above, t r a n s a t r i a l a p p r o a c h through the tricuspid valve is preferred. Figure 1 shows the operative exposure and repair of a p e r i m e m b r a n o u s VSD using an e x p a n d e d polytetrafluoroethylene patch (0.4- or 0.6-mm thickness; W. L. Gore & Associates Inc, Flagstaff, AZ). The patch is attached with a loose r u n n i n g 6/0 e x p a n d e d p o l y t e t r a f l u o r o e t h y l e n e s u t u r e (W. L.
Ann [horac Surg 1995;60:511 6
Gore). The inset of Figure 1 shows that some fibrin glue is applied behind the patch before the suture is tightened (eg, with a hook) and the patch is seated on a bed of liquid glue. A second laver of glue is applied on the border of the patch, the sutures, and the ventricular septum nearby. A speedy technique is necessarw as the fibrin glue coagulates up to some degree within seconds. After 60 s the glue becomes reasonably solid. To achieve a d e q u a t e adherence, the surfaces to be sealed have to be dried before application of the glue. Hence, we use a vent on the left side of the heart (through the interatrial septum), a p u m p sucker on the right side, and swabs in the peripatch area to keep the blood out of the zone to be glued. Rubbing of the endothelial contact area with a sponge provides superior adherence. Care must be taken not to soil the tricuspid valve and its subvalvar apparatus as well as the cavities of the left heart w h e r e embolization could occur. F o l l o w - u p and A n a l y s e s All patients included in the study u n d e r w e n t blinded postoperative two-dimensional echocardiographic control with color-coded Doppler m a p p in g by i n d e p e n d e n t pediatric cardiologists to assess the n u m b e r and diameter of residual VSDs after surgical patch closure on at least two occasions: early postoperatively and before discharge. Besides the usual echocardiographic evaluation, n u m b e r and diameter ot residual VSDs were documented. Statistical A n a l y s e s In the experimental stud,,', mean - standard deviation was derived for all pressure loads as well as for the respective groups corresponding to the different defects. Systat statistical software package (Systat lnc, Evanston, IL) was used for calculation of linear regression. For the clinical study, mean * standard deviation was calculated for parametric data and Student's t test was used where applicable for comparison between groups. Fisher's exact test was used for comparison of nonparametric data (Solo, distributed bv BMDP Statistical Sortware, Los Angeles, CA). Statistical significance was confirmed by a p value of less than 0.05. Results
yon SEGESSERET AL PREVENTION OF RESIDUALVSD
513
i
500 ] r 450i 400i 350{ :~_ 300 i E 250 E 200 150 100 i 50! 0~
L
2.5
r
4
5
mm iX 2, lApcrimental evaluation. Mean ~ standard deviation of pressmcs achieved in bursted seals. Linear regression analysis provided ,t mttltil&' r value off 0.890 (p < 0,001), All 1.0-ram defects sealed with fibrin glue resisted the selected maximal pressure load of 500 m m Hg. For bursted seals, the r e c o r d e d p r e s s u r e s w e r e 196 + 129 mm Hg for 2.5-mm defects, 113 -- 61 m m Hg for 4.0-mm defects, and 63 + 52 m m Hg for 5.0-ram defects (Fig 2). Linear regression analysis of the burst pressures estimates the intercept (constant) with 591 and the slope with ( 120).The correlation b et w een diameter and burst pressure (multiple R) is 0.890 (p < 0.001). Clinical S t u d y As outlined above, 22 of 36 patients u n d e r w e n t VSD repair with a patch using sutures r e i n f o r c e d with pledgets and 14 of 36 had their VSD patch sutured and sealed with fibrin glue. Aortic cross-clamp time was 31 ± 10 minutes for reinforced sutures as c o m p a r e d to 34 -- 8 minutes for sealed with fibrin glue (p = NS). P u m p time was 75 *~ 24 minutes for reinforced sutures as c o m p a r e d to 84 + 23 minutes for sealed with fibrin glue (p = NS). All patients survived the p r o ced u r e and were discharged from the hospital. Hence, hospital mortality for the study population was 0%. The postoperative results are s u m m a r i z e d in Figure 3. Residual VSDs at echocardiography were o b s e r v e d in 16
80
i
] residual VSDs I
E x p e r i m e n t a l Evaluation Compilation of all data points (n 60) resulted in a mean pressure load of 438 ~ 78 mm Hg. The n u m b e r of test runs per size of defect was 7 of 60 for 5.O-ram diameter, 8 of 60 for 4.O-ram diameter, 15 of 60 for 2.5-ram diameter, and 30 of 60 for 1.0-ram diameter. Pressure loads achieved per group were 313 I 48 m m Hg for 5.0-ram defects, 363 -_+ 58 m m Hg for 4.0-ram defects, 413 52 m m Hg f o r 2 . S - m m defects, and 500 * 0 mm Hg for 1.0-mm defects. Linear regression analysis of pressure loads achieved estimates the intercept (constant) with 543 and the slope with ( 47) and the correlation is (multiple r) 0.873 (t' < 0.01).
70 60
~
i•
significant VSDs H
50 ~ /1
840
10 O"
# reinforced sutures
sealed with glue
Fi,,,, 3. Clinical study. Postoperah've results are given as percent per ,2nmp mmlvzed. There are siRn(ficantlg fewer residual ventricular septal detects (VSDs,' in the ,Woup with sealed patches (p < 0.05).
514
vox SEGESSER ET AL PREVENTION OF RESIDUAL VSD
of 22 patients (72%) for reinforced sutures as c o m p a r e d to 5 of 14 (36%) for sealed with fibrin glue (p < 0.05). D i a m e t e r of residual VSDs accounted for 1.3 ÷ 1.2 m m (range, 0 to 4 ram) for reinforced sutures as c o m p a r e d to 0.3 _+ 0.4 m m (range, 0 to I ram) for sealed with fibrin glue (p < 0.01). H e m o d y n a m i c a l l y significant residual VSDs were found in 2 of 22 patients (9%) for reinforced sutures as c o m p a r e d to 0 (0%) for sealed with fibrin glue (p = NS).
Comment Small defects sealed with fibrin glue resist physiologic pressure load. In the experimental setup, sealed defects of 1.0 ram or less have consistently resisted the acute exposure to suprasystemic pressure load. However, resistance of larger sealed defects a p p e a r s primarily to be a function of its diameter. Linear regression analysis with defect d i a m e t e r as an i n d e p e n d e n t variable and burst pressure as a d e p e n d a n t variable showed good indirect correlation and a highly significant slope. Obviously, acceptable goodness of fit was d e m o n s t r a t e d for the defect diameters tested. C o m m o n sense, as well as extrapolation of the regression line make it clear that for larger defects (more than 5 mm) burst pressure is approaching zero. However, a n u m b e r of m e a s u r e s can be taken to increase the tolerable pressure load. These include a rough surface for better adherence, a conical defect with the larger orifice on the side with higher pressure load, production of a fibrin glue plug with rivet-like heads on both ends allowing for p r o p e r polymerization, and others. Translated into clinical practice, a textured patch is preferable and the contact area should be dried a n d p r e p a r e d with a sponge to achieve a rougher surface before sealing. Obviously the intact endothelial surface is not an ideal substrate for solid anchorage of the glue. Some excess glue has also to be d e p o s i t e d to form a plug that is of larger size than the potential orifice to be occluded, and the glue m u s t be allowed to polymerize properly. To monitor the p o l y m e r ization process intraoperatively, some excess glue can be d e p o s i t e d on a sponge just before the sealing of a specific area. Progress of polymerization can be evaluated optically (opacification) and digitally. In our hands, application of these techniques to the clinical setting (ie, fibrin glue sealing of prosthetic patches during intracardiac VSD repair) allowed for significant reduction of n u m b e r and size of residual VSDs despite more complex procedures p e r f o r m e d in the study group. As outlined before, the fibrin sealant can c o m p e n s a t e for small incongruences b e t w e e n cardiac structures a n d patch material. This function is similar to the naturally occurring clots sealing vascular anastomoses, which in this case are p r o v o k e d deliberately before the exposure to the bloodstream. Furthermore, if well placed, the fibrin glue can, due to its adherence, also contribute to better patch fixation (improved distribution of forces) a n d therefore, reduce the risk of suture pullthrough. This function is similar to the pledgets used in the control group. In contrast to additional stitches,
Ann Thorac Surg 1995;60:511-6
however, application of fibrin glue will not interfere with the conduction system. The a d e q u a t e resistance of glue d e p o s i t e d in the interventricular s e p t u m has also be d e m o n s t r a t e d b y Leca and colleagues [11] who r e p o r t e d on surgical t r e a t m e n t of multiple VSDs using biological glue. H e r group s t u d i e d the use of fibrin glue for repair of artificially created VSDs in sheep with sizes b e t w e e n 5 and 10 m m and achieved satisfactory results. Interestingly, n e c r o p s y studies s h o w e d that the glue was progressively r e p l a c e d with fibrous tissue. In the clinical study r e p o r t e d by the same group, fibrin glue was u s e d mainly for closure of apical VSDs a n d p r o v e d to be very reliable. T h r e e - y e a r follow-up further confirmed that repair of VSDs with fibrin glue r e m a i n e d intact over time as s u g g e s t e d by the previous experimental work. The r e c o m m e n d a t i o n to use fibrin glue for closure of m u s c u l a r VSDs with less than 8 m m of d i a m e t e r is in a g r e e m e n t with our finding that sealed defects of 5 m m or less in d i a m e t e r can hold considerable pressure. Potential drawbacks of glue application within the heart include soiling of structures that should not be included in the area to be sealed (eg, subvalvar a p p a r a t u s of the tricuspid valve) as well as embolization of glue particles d e p o s i t e d on areas with a blood film w h e r e p r o p e r adhesion is not possible. Both p r o b l e m s can be avoided if a d e q u a t e exposure a n d p r o p e r techniques are a p p l i e d as outlined above. Venting of the left-sided cavities should be nonocclusive during the sealing procedure to avoid aspiration of glue. Despite the application of fibrin glue on a large scale, there are only few reports on side effects. Even i m m u n i zation by bovine t h r o m b i n [12] u s e d in the mixture should not occur a n y m o r e as t h r o m b i n of h u m a n origin is now used in the frozen preparations. At this time, the only bovine c o m p o n e n t still necessary is aprotinin (3,000 KIU/mL). Routine application of fibrin glue a n d its potential side effects have to be balanced against the risk related to residual VSDs of m i n o r size on one side a n d the risk of reoperation in hernodynamically significant VSDs on the other. Traditionally, a VSD was mainly considered for surgical closure if p u l m o n a r y - t o - s y s t e m i c flow ratio was more than 2.0 and in general the s a m e criteria were a p p l i e d for closure of residual VSDs after surgical patch closure. Recently, Backer and colleagues [13] r e p o r t e d on closure of restrictive ventricular septal defects with pulm o n a r y - t o - s y s t e m i c flow ratio of less than 2.0. Despite excellent results in their series this issue r e m a i n s controversial as no real long-term results are available yet [14, 15]. However, it is a fact that a significant n u m b e r of reoperations have to be p e r f o r m e d after surgical patch closure of VSD even if only the so-called h e m o d y n a m i cally significant shunts are considered. C a s t a n e d a a n d colleagues [16] found two significant shunts after VSD closure in a series of 146 cases early after operation. Another three significant residual left-to-right shunts were found during late follow-up bringing the rate of significant residual VSDs up to 5 of 148 or 3.4%. A d m i t tedly there was also an u n k n o w n proportion of so-called
Ann Thorac Surg 1995;60:511-6
trivial r e s i d u a l V S D s at c a r d i a c c a t h e t e r i z a t i o n . U n m e n t i o n e d is t h e p r o p o r t i o n of r e s i d u a l V S D s t h a t are o n l y detectable with modern echocardiographic techniques. The former and the latter may be without importance w i t h r e g a r d to t h e d e v e l o p m e n t of p u l m o n a ~ a r t e D, hypertension. However, lifelong antibiotic prophylaxis r e m a i n s i n d i c a t e d if t h e V S D w a s n o t c o m p l e t e l y c l o s e d d u r i n g o p e r a t i o n [7]. E v e n h i g h e r p r o p o r t i o n s of r e s i d u a l V S D s w e r e r e p o r t e d for p a t i e n t s w i t h m u l t i p l e V S D s . Kirklin a n d c o - w o r k e r s [17] o b s e r v e d a r e o p e r a t i o n r a t e of 28%. A g a i n o n l y h e m o d y n a m i c a l l y s i g n i f i c a n t V S D s w e r e r e o p e r a t e d a n d t h e r e is a n u n k n o w n p r o p o r t i o n of r e s i d u a l V S D s w i t h a s h u n t f r a c t i o n of less t h a n 2.0. F u r t h e r m o r e t h e p r o p o r t i o n of r e s i d u a l V S D s d e t e c t a b l e o n l y at e c h o c a r d i o g r a p h y is n o t a v a i l a b l e . In c o n t r a s t to t h e s e f i n d i n g s , t h e r e w a s n o r e o p e r a t i o n in t h e s e r i e s of Leca a n d c o l l e a g u e s [11] w h o u s e d f i b r i n g l u e to close s m a l l V S D s i n p a t i e n t s w i t h m u l t i p l e defects. C o n s i d e r i n g t h e i m p o r t a n c e of r e l i a b l e c o m p l e t e clos u r e of VSDs, w e b e l i e v e t h a t s e a l i n g of t h e p r o s t h e t i c p a t c h w i t h f i b r i n g l u e d u r i n g s u r g i c a l r e p a i r is a p r a c t i c a l w a y to r e d u c e t h e n u m b e r a n d size of r e s i d u a l V S D s . W i t h p r o p e r t e c h n i q u e t h e p o t e n t i a l risks of t h i s a p proach are minimal and improved long-term outcome can be expected.
References 1. Sairanen H, Leijala M, Louhimo 1. Surgery" for ventricular septal defect. Scand J Thorac Cardiovasc Surg 1991;25:1-5. 2. Vogt J, Wesselhoeft H, Luig H, et al. The pre- and postoperative findings in 627 patients with tetralogy of Fallot. Thorac Cardiovasc Surg 1984;32:234-43. 3. Bical O, Perrier P, Fermont L, et al. R6op6ration apr6s correction chirurgicale de tetralogie de Fallot. Arch Mal Coeur-Vaiss 1984;77:595-9.
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4. Andrade JL, Serino W, de Leval M, Somerville J. Two dimensional echocardiographic assessment of surgically closed ventricular septal defects. Am J Cardio11983;52:325-9. 5. Roberson DA, M u h i u d e e n IA, Cahalan MK, et al. Intraoperative transesophageal echocardiography of ventricular septal defect. Echocardiography 1991;8:687-97. 6. Fukushige J, Igarashi H, Ueda K. Spectrum of infective endocarditis during infancy and childhood: 20 year review. Pediatr Cardiol 1994;15:127-31. 7. Gersony WM, Hayes CJ, Driscoll DJ, et al. Bacterial endocarditis in patients with aortic stenosis, pulmonary stenosis, or ventricular septal defect. Circulation 1993;87(Suppl 1): 121-6. 8. Seelich T. Tissucol (Immuno Vienna): biochemistry and methods of application. J Head Neck Pathol 1982;3:65-9. 9. Rousou J, Levitsky S, Gonzales-Lavin L, et al. Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations. J Thorac Cardiovasc Surg 1989;97:194-203. 10. Von Segesser LK, Oechslin E, Jenni R, Turina MI. Use of glue to avoid formation of perfused recesses in aortic homograft implantation. A n n Thorac Surg 1994;57:494-5. 11. Leca F, Karam J, Vouh6 P, et al. Surgical treatment of multiple ventricular septal defects using biologic glue. J Thorac Cardiovasc Surg 1994;107:96-102. 12. Berruyer M, Amiral J, French P, et al. Immunization by bovine thrombin used with fibrin glue during cardiovascular operations. J Thorac Cardiovasc Surg 1993;105:892-7. 13. Backer CL, Winters RC, Zales VR, et al. Restrictive ventricular septal defect: how small is too small to close. Ann Thorac Surg 1993;56:1014-9. 14. Malm JR. A reason to close ventricular septal defect? Ann Thorac Surg 1993;56:1013. 15. Waldman JD. Why not to close a small ventricular septal defect? Ann Thorac Surg 1993;56:1011-2. 16. Castaneda A, Jonas RA, Mayer JE, Hanley FL. Cardiac surgery of the neonate and infant. Philadelphia: Saunders, 1994:187-201. 17. Kirklin JK, Castaneda AR, Keane JF, Fellows KE, Norwood WI. Surgical m a n a g e m e n t of multiple ventricular septal defects. J Thorac Cardiovasc Surg 1980;80:485-93.
DISCUSSION DR PEDRO J. DEL NIDO (Pittsburgh, PA): Did you see any evidence or incidence of neurologic problems? Obviously, one of the concerns would be if you accidentally dropped some of the glue into the left side of the heart. DR VON SEGESSER: We did not see any of these problems. However, it is true that one has to use a proper technique. And as I said, it is useful to rub the surface to get better adhesion and, of course, no glue should drop on blood because it would not stay there and could be embolized. Until now we have not had that problem. DR CHARLES B. HUDDLESTON (St. Louis, MO): At what stage after the operation was the echocardiogram performed? Also, 1 presume by the hemodynamic significance those 2 patients had to return to the operating room for closure. DR voN SEGESSER: Yes. DR HUDD/ESTON: I would agree with concerns with embolization as Dr del Nido pointed out. It seemed like that would
produce a thrombogenic surface over and above what the patch produces itself on the left side of the heart. DR VON SEGESSER: With regard to the thrombogenic surface I think one can say that in adult cardiac operations we often have clots in the aorta and aneurysms that stay there for years without embolization. 1 think it is not necessarily a problem to have a clot there. l also believe that if the patch reaches the surface with a small angle, this region would clot off anyway, and if you have no flow in a place, you will have a clot there also. And there are some technical aspects to improve the resistance of the glue. I think it is helpful to produce a plug that has larger ends on both sides. And here in this application the glue is taken into the suture, therefore 1 think the risk of embolization is very low. DR RUEDIGER LANGE (Heidelberg, Germany): As far as I know fibrin glue is resorbed within approximately 3 days. Do you use a different glue or do you have any information on this issue? My second question is, at what time after the operation did you perform the echocardiographic examinations? If it was beyond 3 days after operation, there should not be any differ-
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yon SEGESSER ET AL PREVENTION OF RESIDUAl VSD
ence b e c a u s e by that time t h e r e is no fibrin glue left. C o u l d y o u c o m m e n t on w h e t h e r y o u r o b s e r v e d difference in residual s h u n t i n g w a s m a y b e d u e to t h e difference in s u t u r e t e c h n i q u e , i n t e r r u p t e d v e r s u s c o n t i n u o u s , t h a n d u e to the application of fibrin glue? D R YON SEGESSER: W i t h r e g a r d to t h e r e s o r p t i o n of t h e glue, 1
can say t h a t t h e r e h a s b e e n a s t u d y d o n e by Leca a n d colleagues f r o m Paris w h e r e t h e y h a v e g l u e d m u l t i p l e v e n t r i c u l a r septal defects (VSDs) e x p e r i m e n t a l l y first a n d clinically thereafter, a n d t h e y f o u n d in the e x p e r i m e n t a l s e t u p that the glue w a s replaced b y scar tissue a n d t h e y h a d no r e c u r r e n c e a n d no r e o p e r a t i o n s in their group. W i t h r e g a r d to the e c h o c a r d i o g r a m , we did several echocard i o g r a m s : one early after operation, one before discharge, a n d one between 3 and 6 months. D R CARL L. B A C K E R (Chicago, IL): l a m c u r i o u s as to y o u r t h o u g h t s a b o u t t h e i n t e r r u p t e d s u t u r e t e c h n i q u e for closure of VSDs. We have published our results with interrupted p l e d g e t e d s u t u r e s a n d a n elastic D a c r o n patch, a t e c h n i q u e that w a s d e v e l o p e d by Farouk Idriss. W i t h b o t h small VSDs a n d with conal VSDs, we h a v e h a d essentially no residual VSDs u s i n g that t e c h n i q u e . I t h i n k t h e ideal o p e r a t i o n for a VSD, at least at our institution, is closure with i n t e r r u p t e d p l e d g e t e d s u t u r e s a n d a D a c r o n patch, a n d I w o n d e r if y o u could c o m m e n t on w h y you did n o t try t h a t t e c h n i q u e .
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y o u w o u l d n o t detect a n y of these. So with r e g a r d to t h e i n t e r r u p t e d s u t u r e t e c h n i q u e , I believe that this w o u l d n o t h e l p in this application, b e c a u s e y o u still can h a v e i n c o n g r u e n c e s b e t w e e n the patch on o n e side a n d t h e m y o c a r d i u m on t h e other, w h i c h c a n n o t be o c c l u d e d with s u t u r e s e v e r y w h e r e . A n d if I u n d e r s t o o d correctly, y o u u s e d a D a c r o n patch. It w o u l d p r o b a b l y not e v e n be tight in t h e b e g i n n i n g b u t only later on, a n d w h a t m a k e s it tight finally is a clot all over t h e surface. D R M I C H A E L A. GREENE (Gainesville, FL): I w a s w o n d e r i n g if the s o u r c e of t h e f i b r i n o g e n e x p o s e s t h e p a t i e n t to a n y infectious risk. D R YON SEGESSER: 1 t h i n k that is a very i m p o r t a n t q u e s t i o n . T h e glue u s e d at this t i m e h a s n o t b e e n r e p o r t e d to be l i n k e d to t r a n s m i s s i o n of infectious diseases. T h e r e h a v e b e e n a n u m b e r of p r e c a u t i o n s taken. It is t h e r m a l l y inactivated m a t e r i a l on o n e side. A n d a l t h o u g h t h e r e h a s n e v e r b e e n a t r a n s m i s s i o n reported, t h e r e are PCR t e c h n i q u e s u s e d to avoid b a t c h e s that could be c o n t a m i n a t e d . Therefore, I believe t h e risk of t r a n s m i s sion of infectious d i s e a s e is e x t r e m e l y low. D R C O N S T A N T I N E E. A N A G N O S T O P O U L O S ( N e w York, NY): 1 h a v e b e e n f o r t u n a t e to u s e t h e fibrin glue in N e w York a n d t h e resorcinol glue w h e n I go to A t h e n s . If y o u really w a n t c o m p l e t e e l i m i n a t i o n of criticism from cardiology, are y o u willing to s p e n d 10 m i n u t e s so y o u can u s e t h e resorcinol glue? H a v e vou t h o u g h t of that? Or do y o u w a n t a little criticism?
D R VON SEGESSER: Well, I t h i n k we h a v e to state clearly that
h e r e we are n o t talking a b o u t residual VSDs that h a v e to be r e o p e r a t e d on. T h e s e are t h i n g s that you find in the r e p o r t s of t h e cardiologists that n o r m a l l y are called trivial VSDs, a n d you find t h e s e in all series that are p u b l i s h e d . You w o u l d not even s e e t h e s e VSDs at a n g i o g r a p h y or if you do o x y g e n saturations;
D R v o ~ SEGESSER: W e u s e t h e resorcin glue, or F r e n c h glue,
for aortic dissections. 1 a m n o t s u r e if h e r e it w o u l d be a g o o d application b e c a u s e of the c o n d u c t i o n tissue. A s y o u know, resorcin glue c o n t a i n s formalin, a n d I believe that fixation of t h e c o n d u c t i v e tissue m i g h t n o t be ideal.