Ann Thorac Surg 2008;86:466-471. doi:10.1016/j.athoracsur.2008.04.050
© 2008 The Society of Thoracic Surgeons
Original Articles: Adult Cardiac
Left Thoracotomy for Multiple-Time Redo Mitral Valve Surgery Using On-Pump Beating Heart Technique
Yoshikazu Suzuki, MD,
Francis D. Pagani, MD, PhD,
Steven F. Bolling, MD*
Section of Cardiac Surgery, Department of Surgery, Cardiovascular Center, University of Michigan Health System, Ann Arbor, Michigan
Accepted for publication April 14, 2008.
* Address correspondence to Dr Bolling, Section of Cardiac Surgery, Department of Surgery, Cardiovascular Center, University of Michigan Health System, 5144 Cardiovascular Center, SPC#5864, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5864 (Email: sbolling{at}med.umich.edu).
Presented at the Poster Session of the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2008.
 |
Abstract
|
|---|
Background: There are limited reports describing multiple-time redo mitral valve surgery using a left thoracotomy approach and on-pump beating heart technique.
Methods: A retrospective review of medical records for 16 patients from March 2002 to June 2007 was performed.
Results: Mean age was 54 ± 17 (mean ± SD) years (8 males). Preoperative mitral valve regurgitation was 3.6 ± 0.6 in 14, and 2 had severe mitral valve stenosis. New York Heart Association symptom class was 2.9 ± 1.0 and ejection fraction was 0.4 ± 0.15 (range, 0.2 to 0.6). Previous cardiac operations were performed twice in 14 and three times in 2 patients with an interval of 4.8 ± 5.5 years since the last. The procedures included repair (5), replacement (8), and re-replacement (3). All were performed through a fifth intercostal space, left posterolateral thoracotomy with the heart beating on cardiopulmonary bypass (32 to 37°C). Left femoral artery or descending thoracic aorta inflow and left femoral vein or left main pulmonary artery venous drainage with vacuum assist were used. Operation time was 221 ± 51 minutes and cardiopulmonary bypass time was 71 ± 27 minutes. Postoperative ventilation time was 10.0 ± 7.7 hours, intensive care unit stay was 2.9 ± 1.9 days, and hospital stay was 6.2 ± 2.4 days. There were two 30-day mortalities and two died late with a follow-up of 30 ± 22 months.
Conclusions: Left thoracotomy using the on-pump beating heart technique is safe, effective, and should be considered for multiple-time redo mitral valve surgery.
|
Introduction
|
|---|
Multiple-time redo cardiac valvular procedures are becoming more frequent as the population ages and cardiac valvular procedures continue to increase [1]. These complex cases, sometimes felt to have a prohibitive operative mortality, challenge surgeons not only because of advanced patient morbidity, but also because of technical issues including extensive dissection, bleeding, and injury to cardiac structures or previous coronary artery grafts. A right thoracotomy approach has been popularized for first-time redo mitral valve surgery as an alternative to the standard redo median sternotomy [2–10]. For the second time, or more, a left thoracotomy approach represents a possible option.
A left thoracotomy approach for minimally invasive mitral valve surgery, including 36 redo and 9 multiple-time redo cases, was reported by New York University [11]. However, we have found no reports of left thoracotomy using an on-pump beating heart technique. We describe a case series of 16 patients who underwent the left thoracotomy approach for multiple-time redo mitral valve surgery using the on-pump beating heart technique.
|
Material and Methods
|
|---|
Data were collected retrospectively from the medical records of 16 consecutive patients from March 2002 through June 2007 who underwent the left thoracotomy for multiple-time redo mitral valve surgery using the on-pump beating heart technique at the University of Michigan. Indications were previous median sternotomy and right thoracotomy, or any reasons that precluded both sternotomy and right thoracotomy for mitral valve surgery after second-time or more cardiac procedures. Comprehensive written informed consent was obtained prior to the operation, including for the purposes of data collection in our cardiovascular surgery database. The cardiovascular surgery database has been approved by the Institutional Review Board at the University of Michigan Medical School.
Data were presented as the proportions (%) and the mean and standard deviation (range) for categorical variables and numeric variables, respectively. The proportions (%) of ordinal categories for some numeric variables were also shown as appropriate. The SAS 9.1.3 for Windows (SAS Institute Inc, Cary, NC) was used for statistical analysis. As outcome variables, 30-day and total mortality were chosen. Evaluated predictor variables included age, gender, preoperative degree of mitral valve regurgitation (MR), New York Heart Association (NYHA) congestive heart failure (CHF) class, ejection fraction (EF), endocarditis, previous stroke, previous coronary artery bypass grafting (CABG), previous types of mitral valve surgery, number of previous cardiac operations, interval from the last cardiac operation, types of mitral valve procedure, operation time, and cardiopulmonary bypass (CPB) time. The Pearson 
2 exact test for categorical variables and Wilcoxon rank sum exact test for numeric variables were adopted. Variables were identified as significant if the p value was less than 0.05 (p < 0.05).
Surgical Technique
Anesthesia and monitoring
A double-lumen endotracheal tube was used for general anesthesia. Radial artery and pulmonary artery pressure monitoring lines and a transesophageal echocardiography (TEE) probe were placed while the patient was in the supine position. The correct position of the endotracheal tube was verified with bronchoscopy before and after positioning the patient. A prophylactic external defibrillator pad was placed on the side of the right chest prior to positioning.
Positioning and incision
The patient was placed in a right lateral decubitus position with a bean bag and the table flexed to facilitate exposure for a fifth intercostal space, posterolateral left thoracotomy incision. The neck was maintained in a neutral position with a pillow. All bony prominences were padded and the brachial plexus was protected with an axillary roll. The pelvis was half rotated to the back to allow access to the femoral vessels.
CPB and myocardial protection
After systemic heparinization, CPB was performed through the left femoral artery or descending thoracic aorta inflow and left femoral vein or left main pulmonary artery venous drainage with vacuum assist. A long venous cannula into the mid-right atrium was used through the left femoral vein with an open technique using a long wire under the TEE guidance. The heart was kept warm at 32°C to 37°C and beating on CPB.
Exposure of the mitral valve
The left lung was deflated and retracted posteriorly. The course of the phrenic nerve in the left thorax is more anterior to the hilum than in the right thorax so that the pericardium was incised either anterior or posterior to the phrenic nerve according to the specific anatomy. The surface of the left atrial and ventricular wall was dissected extending into both the cephalad and caudad directions to facilitate the anterior rotation and the exposure of the mitral valve (Fig 1). A longitudinal left atrial incision was made starting from the base of the left atrial appendage and going down below the left inferior pulmonary vein (Fig 2). Cardiotomy suctions and a vent through the left pulmonary vein were used to keep the operative field bloodless. Note that either one of the cardiotomy suctions or the vent cannula was kept positioned through the mitral valve to keep the mitral valve incompetent and avoid air being ejected into the ascending aorta during the entire mitral valve procedure while the left atrium was open. Traction sutures were put inside the left atrial wall close to the posterior mitral valve annulus. Standard mitral valve repair or replacement technique was used with excellent exposure (Fig 3). The left atriotomy was closed in two layers. After the patient was put in a steep Trendelenburg position, the air in the left cardiac chambers was evacuated with a vent through the valve. A small Foley balloon catheter was used through the valve in the cases of mechanical valve replacement to keep the mitral valve incompetent. Cardiac and mitral valve function and intracardiac air were monitored by TEE.
View larger version (126K):
[in this window]
[in a new window]
|
Fig 1. A cross-sectional computed tomographic image at the level of the left inferior pulmonary vein illustrates the location, dimensions, and orientation of the mitral valve in the left thorax. Note the point of a longitudinal left atrial incision and the counterclockwise rotation for the exposure of the valve (arrows).
|
|
View larger version (49K):
[in this window]
[in a new window]
|
Fig 2. A schematic drawing illustrates a surgeon's view of the "upside-down" mitral valve exposed through a fifth intercostal space, left posterolateral thoracotomy approach using the on-pump beating heart technique. Note the location of the longitudinal left atrial incision and the cardiotomy suction kept positioned through the valve.
|
|
View larger version (203K):
[in this window]
[in a new window]
|
Fig 3. Picture illustrates a shallow exposure of the mitral valve through a fifth intercostal space, left posterolateral thoracotomy approach using the on-pump beating heart technique.
|
|
|
Results
|
|---|
Demographics of 16 patients who underwent left thoracotomy for multiple-time redo mitral valve surgery using the on-pump beating heart technique are shown in Table 1. Previous cardiac operations included mitral valve repair or replacement, aortic or tricuspid valve surgery, CABG, tetralogy of Fallot repair, left ventricular aneurysm repair, and iatrogenic coronary sinus rupture repair. All patients underwent a right thoracotomy approach for the first-time redo mitral valve surgery except one patient who had a history of combined CABG and aortic valve surgery twice, and additional right pectoralis muscle flap operation for mediastinitis. Other preoperative critical comorbidities included inotropic infusion support (1; 6%), intraaortic balloon pumping (0; 0%), mechanical ventilation (0; 0%), diabetic chronic renal failure on hemodialysis (1; 6%), chronic obstructive pulmonary disease (1; 6%), and stroke (4; 25%) (rheumatic [1], endocarditis [1], carotid disease [2]).
View this table:
[in this window]
[in a new window]
|
Table 1 Demographics of Patients Undergoing Multiple-Time Redo Mitral Valve Surgery Using Left Thoracotomy and the On-Pump Beating Heart Technique (n = 16)
a
|
|
Operations performed included mitral valve re-repair (4; 25%), replacement (8; 50%), re-replacement (3; 19%), and suture repair of paravalvular leak (1; 6%); additionally CABG (descending aorta-obtuse marginal) (2; 13%), left-side maze (1; 6%), and left femoral artery plasty (1; 6%). Arterial inflow included the left femoral artery (14; 88%) and the descending thoracic aorta (2; 13%). Venous drainage included the left femoral vein (15; 94%) and the left main pulmonary artery (2; 13%). All patients underwent the surgery solely with the on-pump beating heart technique (32°C to 37°C) except 2 patients (13%) who had a short duration of ventricular fibrillation; one for a spontaneous ventricular fibrillation and one for a coronary artery anastomosis.
Perioperative and postoperative outcomes are shown in Table 2. No transfusion was required in 5 patients (31%). No inotropic or vasopressor infusions were required in 5 patients (31%). Complications included low cardiac output syndrome (1: 6%), sepsis, pneumonia, and multiple organ failure (1; 6%), prolonged CHF (2; 13%), mild hemolysis (1; 6%), and superficial wound infection 1 (6%). There was no inadvertent injury to coronary artery grafts or cardiac structures. There was no reexploration for bleeding. There were no postoperative stroke or delirium related to the surgery. There were 2 (13%) 30-day mortalities. The first was a 65-year-old female with diabetic chronic renal failure on hemodialysis and with severe peripheral vascular obstructive disease, who had previous history of a stroke and a carotid endarterectomy. Previous cardiac operations were a combined CABG and aortic and mitral valve replacement through median sternotomy and a redo mitral valve re-replacement through a right thoracotomy 5 months prior. Ejection fraction was 0.2. The patient underwent re-replacement for paravalvular leak and died from low cardiac output syndrome. The second was an 82-year-old female who had previous history of CABG twice through median sternotomy and mitral and tricuspid valve repair through a right thoracotomy two years prior. EF was 0.25. The patient presented with 4+ MR and 2+ aortic and tricuspid valve regurgitation, and severe CHF symptoms controlled on dobutamine infusion. The patient underwent re-repair for ring dehiscence and died from sepsis, pneumonia, and multiple organ failure. There were 2 (13%) deaths during a follow-up of 30 ± 22 months. The first had prolonged CHF symptoms and severe depression of bipolar disorders when discharged from hospital on postoperative day 7 and died suddenly at 6 weeks. The second had a left ventricular assist device for idiopathic dilated cardiomyopathy 33 months after the left thoracotomy multiple-time redo mitral valve surgery and died from stroke. All patients who died had EF less than 0.3.
View this table:
[in this window]
[in a new window]
|
Table 2 Perioperative and Postoperative Outcomes of Patients Undergoing Multiple-Time Redo Mitral Valve Surgery Using Left Thoracotomy and the On-Pump Beating Heart Technique (n = 16)
a
|
|
The statistical analysis showed that age (p = 0.0750) and EF (p = 0.0833) were associated with 30-day mortality, but none of them was significant. The EF (p < 0.0001) and CPB time (p = 0.0637) were associated with total mortality and only EF was significant.
|
Comment
|
|---|
In our initial experience of 16 patients who underwent the left thoracotomy approach for multiple-time redo mitral valve surgery using the on-pump beating heart technique, the exposure of the mitral valve was uniformly excellent (Figs 2; 3). The CPB time was short. There was no inadvertent injury to previous coronary artery grafts or cardiac structures. There was no reexploration for bleeding or postoperative stroke.
There are limited reports describing the outcomes of multiple-time redo mitral valve surgery. Saunders and colleagues [11] reported 40 minimally invasive isolated mitral valve cases including 9 multiple-time redo and 27 first-time redo. They used a left posterior mini-thoracotomy and cardioplegic ischemic arrest or hypothermic fibrillation. The CPB time was 117 ± 35 minutes. Hospital mortality occurred in 2 patients (5%), both octogenarians. Stroke occurred in 3 patients (7.5%). Magilligan and colleagues [12] reported in 1978 that 28 rheumatic patients underwent second-time redo mitral valve surgery through median sternotomy, and 26 patients (93%) were NYHA CHF class 3 or 4. There were 4 (14%) hospital mortalities. They concluded that deaths were related to poor ventricular function and not to the number of previous operations.
Svensson and colleagues [13] reported mitral valve reoperation through median sternotomy (n = 2,444) and through right thoracotomy (n = 80), including 2 or more previous operations in 619 (25%) and 40 (50%), respectively. For right thoracotomy, 73 (91%) used hypothermic ventricular fibrillation and the rest used cardioplegia. Preoperative left ventricular function was not reported. Concomitant CABG (955; 39%), aortic valve replacement (724; 30%), and tricuspid valve surgery (717; 29%) were frequent in sternotomy. The CPB time was 132 ± 58 minutes in sternotomy and 123 ± 43 minutes in right thoracotomy. Stroke occurred in 66 (2.7%) and in 6 (7.5%), no transfusion required in 652 (27%) and in 13 (16%), and hospital mortality was 163 (6.7%) and 5 (6.3%), respectively. Borger and colleagues [14] reported 1,521 cases of mitral valve replacement through median sternotomy, which included 398 first-time redo and 115 multiple-time redo. Among the 513 redo cases, 75 (15%) had EF less than 0.4. Cross-clamp time was 88 ± 38 minutes and CPB time was 123 ± 55 minutes. Hospital mortality was 46 (9.0%). Hospital mortality tended to increase with the number of prior operations (7% for first-time redo, 11% for second-time redo, 29% for third time redo, 8% for fourth-time redo, and 33% for fifth-time redo). Compared with these reports, our experience showed that the left thoracotomy approach using the on-pump beating heart technique can be performed with shorter CPB time and with an acceptable morbidity and mortality for multiple-time redo mitral valve surgery.
For the first-time redo operation, a right thoracotomy approach has been reported with less transfusion requirements [3, 4, 6, 10]. In our series, one third were transfusion free. The median transfusion requirements for packed red blood cell, fresh frozen plasma, and platelet were small and much less than the mean. This may imply that the left thoracotomy approach and the on-pump beating heart technique require less transfusion, but sick patients with multiple comorbidities may still require a considerable amount of transfusion.
Technically, exposure of the mitral valve is of paramount importance for mitral valve surgery. We chose to use a posterolateral incision in the fifth intercostal space for two reasons (Fig 1). First, the mitral valve faces to the right posteriorly. Second, the location of the longitudinal left atriotomy near the hilum is posterior and closest to this incision. The exposure of the mitral valve is upside-down, in contrast to that in sternotomy or right thoracotomy as discussed by Saunders and colleagues [11], because the mitral valve faces to the right posteriorly and the direction of rotating the heart for the exposure is opposite. The upside-down image of the mitral valve does not present any technical difficulties. The exposure of the mitral valve is excellent with a wider view angle and less depth in dimensions [15].
We did not have any problem when an assistant surgeon exposes the left femoral vessels at the same time as an operator exposes the left chest. We rotate the table toward the back of the patient for cannulation of the femoral vessels and toward the front of the patient in turn for the mitral valve procedure once cardiopulmonary bypass is commenced. The left main pulmonary artery is a good option for venous drainage but the tissue can be friable. We routinely use a pledgetted suture and cannulate the left main pulmonary artery abutted on the pleura. The mitral valve procedure is feasible even if the patient has mild aortic valve regurgitation. Cardiotomy suctions and a vent through the left pulmonary vein keep the operative field bloodless. In addition to the vacuum assist for the venous drainage, controlling the flow rate of CPB as low as tolerated by monitoring total venous blood oxygen saturation is useful.
Historically, the mitral valve has been approached through median sternotomy, transverse sternotomy, right thoracotomy, and left thoracotomy. It was left thoracotomy through which Bailey and Harken first successfully performed closed mitral valve commissurotomy in 1948 [16–19]. Bailey and Harken approached through a third to fifth intercostal space left "anterior" thoracotomy; then, this approach was abandoned in open procedures because of no versatility, initial difficulties with venous drainage access, and poor visibility of the mitral valve [16, 18–20]. This approach is not the first or second option when no versatility is a serious concern. However, long femoral venous cannula or pulmonary artery venous drainage with vacuum assist is enough for the beating heart technique. The exposure of the mitral valve is excellent through the fifth intercostal space, left posterolateral approach with the techniques stated above [11, 15].
A major disadvantage is that this approach is limited to the procedures of the left side of the heart, such as mitral valve surgery, CABG, and left ventricular procedures [20]. Other disadvantages related to the on-pump beating heart technique include a possible risk of air embolism, blood in the field, undue tension to the heart, and technical difficulties [10]. Contraindications of this approach include severe left pleural adhesion and poor pulmonary function [4]. Our statistical analysis showed that the outcomes and prognosis were only limited by the left ventricular function of the patients, similar to the median sternotomy approach [12, 14].
It has been controversial whether the right thoracotomy approach has higher incidence of stroke [4, 7, 8, 10, 13, 21]. First, stroke may be caused by femoral artery cannulation and reversed CPB flow in patients with a severely atherosclerotic aorta. Showering of atheromas from retrograde perfusion flow is a serious issue to be contemplated in those patients. Even though the second option of arterial inflow could be the descending thoracic aorta, redo sternotomy could be an option for those patients if the risk is still considered high. Second, stroke may also be caused by air embolism from incomplete removal of air from the left ventricle [4, 7, 8, 10]. The possibility of the left ventricle ejecting air during the mitral valve procedure, and particularly during the closure of the left atrium, is a paramount concern for the on-pump beating heart technique. We do not think the left ventricle ejects air into the ascending aorta against systemic mean blood pressure from CPB pump flow as long as the mitral valve is kept incompetent. Therefore, it is important to keep either one of the cardiotomy suctions or the vent positioned through the mitral valve and to keep the mitral valve incompetent during the entire mitral valve procedure while the left atrium is open. We routinely use TEE as a monitoring of the intracardiac air. We did not use additional techniques of carbon dioxide or fibrillation to prevent air embolism. There were no postoperative stroke or delirium related to the surgery in our series, but the number was small.
Note that the advantage of the left posterolateral thoracotomy approach with the on-pump beating heart technique compared with the right thoracotomy approach is that the aortic valve stays at the most dependent portion of the left ventricle, and that the lesser curvature of the aortic arch stays higher level than the arch vessels. Air can be removed from the left ventricle with a vent through the valve or a puncture needle in the apex during and after the closure of the left atrium. Therefore, we consider the left thoracotomy approach to be safer than the right thoracotomy approach regarding the risk of air embolism using the on-pump beating heart technique. Furthermore, the left thoracotomy approach is most advantageous in combination with the on-pump beating heart technique in multiple-time redo mitral valve surgery because the ascending aorta can be extremely difficult to dissect and expose for cross-clamping when approached from the left thorax. Avoiding this is a crucial advantage.
In conclusion, the left thoracotomy approach using the on-pump beating heart technique is a safe, effective, and valuable option and should be considered for multiple-time redo mitral valve surgery. This paper is a description of a case series of 16 patients and the results should be interpreted as such. To delineate the comparability among the three approaches for multiple-time redo mitral valve surgery, further accumulation of the cases and analytic studies are warranted.
|
References
|
|---|
- STS National Cardiac Surgery Database Annual first vs reoperative summary: U.S. data mitral valve replacement. STS Data Analysis – January 1999: Annual Trends and Summarieshttp://www.sts.org/graphics/sts/db/us98/gchart30.gifAccessed January 22, 2008.
- Berreklouw E, Alfieri O. Revival of right thoracotomy to approach atrio-ventricular valves in reoperations Thorac Cardiovasc Surg 1984;32:331-333.[Medline]
- Tribble CG, Killinger Jr WA, Harman PK, Crosby IK, Nolan SP, Kron IL. Anterolateral thoracotomy as an alternative to repeat median sternotomy for replacement of the mitral valve Ann Thorac Surg 1987;43:380-382.[Abstract]
- Braxton JH, Higgins RS, Schwann TA, et al. Reoperative mitral valve surgery via right thoracotomy: decreased blood loss and improved hemodynamics J Heart Valve Dis 1996;5:169-173.[Medline]
- Steimle CN, Bolling SF. Outcome of reoperative valve surgery via right thoracotomy Circulation 1996;94(9 suppl):II126-II128.[Medline]
- Vleissis AA, Bolling SF. Mini-reoperative mitral valve surgery J Card Surg 1998;13:468-470.[Medline]
- Holman WL, Goldberg SP, Early LJ, et al. Right thoracotomy for mitral reoperation: analysis of technique and outcome Ann Thorac Surg 2000;70:1970-1973.[Abstract/Free Full Text]
- Byrne JG, Aranki SF, Adams DH, Rizzo RJ, Couper GS, Cohn LH. Mitral valve surgery after previous CABG: with functioning IMA grafts Ann Thorac Surg 1999;68:2243-2247.[Abstract/Free Full Text]
- Burfeind WR, Glower DD, Davis RD, Landolfo KP, Lowe JE, Wolfe WG. Mitral surgery after prior cardiac operation: port-access versus sternotomy or thoracotomy Ann Thorac Surg 2002;74:S1323-S1325.[Abstract/Free Full Text]
- Thompson MJ, Behranwala A, Campanella C, Walker WS, Cameron EW. Immediate and long-term results of mitral prosthetic replacement using a right thoracotomy beating heart technique Eur J Cardiothorac Surg 2003;24:47-51.[Abstract/Free Full Text]
- Saunders PC, Grossi EA, Sharony R, et al. Minimally invasive technology for mitral valve surgery via left thoracotomy: experience with forty cases J Thorac Cardiovasc Surg 2004;127:1026-1031.[Abstract/Free Full Text]
- Magilligan Jr DJ, Lam CR, Lewis Jr JW, Davila JC. Mitral valve–the third time around Circulation 1978;58(3 Pt 2):I36-I38.[Medline]
- Svensson LG, Gillinov AM, Blackstone EH, et al. Does right thoracotomy increase the risk of mitral valve reoperation? J Thorac Cardiovasc Surg 2007;134:677-682.[Abstract/Free Full Text]
- Borger MA, Yau TM, Rao V, Scully HE, David TE. Reoperative mitral valve replacement: importance of preservation of the subvalvular apparatus Ann Thorac Surg 2002;74:1482-1487.[Abstract/Free Full Text]
- Repossini A, Kotelnikov IN, Parenzan L, Arena V. Left-side approach to the mitral valve J Heart Valve Dis 2001;10:591-595.[Medline]
- Balasundaram SG, Duran C. Surgical approaches to the mitral valve J Card Surg 1990;5:163-169.[Medline]
- Khan MN. The relief of mitral stenosis. An historic step in cardiac surgery. Tex Heart Inst J 1996;23:258-265.[Medline]
- Bailey CP. The surgical treatment of mitral stenosis (mitral commissurotomy) Dis Chest 1949;15:377-397.[Medline]
- Harken DE, Ellis LB, Ware PF, Norman LR. The surgical treatment of mitral stenosis. I. Valvuloplasty. N Engl J Med 1948;239:801-809.[Medline]
- Pratt JW, Williams TE, Michler RE, Brown DA. Current indications for left thoracotomy in coronary revascularization and valvular procedures Ann Thorac Surg 2000;70:1366-1370.[Abstract/Free Full Text]
- Glower DD, Clements FM, Debruijn NP, et al. Comparison of direct aortic and femoral cannulation for port-access cardiac operations Ann Thorac Surg 1999;68:1529-1531.[Abstract/Free Full Text]
Top
Abstract
Introduction
