The effects of monocusp valve implantation and transannular patch angioplasty on pulmonary regurgitation and right ventricular failure after total correction of tetralogy of fallot

1Department of Paediatric Cardiology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran 2Department of Anaesthesiology and Critical Care, Khatam-Al-Anbiya Hospital, Zahedan University of Medical Sciences, Zahedan, Iran 3Department of Nursing, School of Nursing and Midwifery, Mashhad University of Medical Sciences, Mashhad, Iran 4Department of Paediatrics, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran


BACKGROUND
Tetralogy of Fallot (TOF) is known as a congenital heart disease (CHD) impairing oxygen delivery to the tissues. It includes four types of defects that often occur together, i.e., overriding aorta, pulmonary stenosis, ventricular septal defect (VSD), and right ventricular hypertrophy (RVH) 1,2 . Former surgical procedures to correct this congenital anomaly have been thus far accompanied by a large right ventriculotomy to close ventricular septal defect (VSD) and pulmonary stenosis, resolved through transannular patch enlargement (TAPE) 3,4 . However, today, ventriculotomy is less commonly exercised to close VSD; other methods such as transarterial VSD closure and transarterial right ventricular outflow tract (RVOT) resection or patch plasty, together with transarterial transpulmonary repair, have been developed 5 . One of the important advantages of TAP is that it immediately leads to RV hypertension reduction as RVOT can usually grow proportionally with a child 6,7 . Nevertheless, TOF reconstruction with a TAP can induce post-surgery pulmonary regurgitation (PR). There-fore, reduction in cardiac output due to early RV dysfunction poses a myriad of problems for these patients. However, this is not the only cause of early morbidity and mortality after surgery. Indeed, other factors such as age and weight at the time of surgery, surgeons' skills, use of TAP, duration of surgery, and cardiopulmonary bypass (CPB) time may also have impact [8][9][10] . Despite advances and further developments of novel techniques in this field, long-term mortality and PR are still at high rates in patients undergoing TAP repair 11 . To diminish volume overload, even for a short time after surgery, some studies have recommended implanting a monocusp valve (MV) [12][13][14] . Theoretically, a monocusp patch can mitigate patch-related PR although long-term results might not be satisfactory, especially in younger children 15 . Accordingly, this work aimed to evaluate the results of two surgical approaches exercised for total repair of TOF, including MV implantation and TAP angioplasty on pulmonary artery (PA) insufficiency and RV failure.

METHODS
After review and approval from the Vice-Chancellor's Office for Research and Technology and the Ethics Committee of Tabriz University of Medical Sciences, Iran, as well as receival of the code of ethics (IR.TBZMED.REC.1397.311), this prospective randomized clinical trial (RCT) was performed. The study was conducted between March 2011 and March 2018, on a total number of 60 patients referred to Shahid Madani Hospital (city of Tabriz) for surgical repair of TOF. The patients were first visited by a pediatric cardiologist and a pediatric cardiac surgeon. Then, echocardiography and routine lab tests were performed to confirm the diagnosis and to determine the inclusion criteria. Upon obtaining informed consent from their parents, the patients who met the inclusion criteria were randomized into two groups. Regarding the informed consent, a written consent form was obtained after explaining the benefits and the complications of each surgical procedure. For the purpose of randomization of patient selection, corresponding to the estimated sample size, 60 cards with two different colors (30 green cards and 30 orange cards) were prepared and then respectively arranged in a black box. After referring the patients for surgery, a card was randomly selected from the box. Accordingly, the patients could be assigned to Group I if the card was green, or to Group II if the card was orange. As well, RVOT resection included reconstruction by TAP in Group I. In Group II, it entailed reconstruction by TAP plus monocusp ventricular outflow patch (MVOP) valve repair. The sample size was set at 60 in accordance with previous studies; it was determined to be 30 patients for each group based on the formula for calculating the sample size with 95% confidence interval (CI) and 80% test power 16 .

Inclusion criteria
The inclusion criteria were children aged 1-10 years, parental consent to perform elective surgical procedures, normal blood coagulation indices, and moderate pulmonary annular hypoplasia with z-score ranging from -2 to -3.

Exclusion criteria
Patients with mental retardation, pulmonary failure, pulmonary infection or acute respiratory distress syndrome (ARDS), pulmonary atresia, discontinuous pulmonary arteries, as well as those undergoing previous palliative procedures and TOF with an atrioventricular septal defect (AVSD) were excluded from this study.
The sample selection process is shown in Figure 1.
In the operating room, the patients were examined by an anesthesiologist who was unaware of their placement in the study groups and who determined the amount of anesthetic drugs. The drugs were injected by the anesthetic nurse and the patients were intubated by the anesthesiologist. The arterial catheter was inserted accordingly into the radial artery by an anesthesiologist and the arterial pressure was monitored. The central venous catheter was also fixed through the internal jugular vein. Cardiac monitoring for all patients began and continued throughout the surgery. Subsequently, the surgical procedure started via midsternotomy incision. Soft tissue incision and bleeding control were further continued with an electrocauter until the heart was exposed and then percutaneous balloon pericardiotomy was done. Following heparin injection, 3 g/kg activated clotting time (ACT) increased up to 450 seconds. At this time, aorto-bicaval cannulation was conducted and CPB was connected to the patients. Cold blood cardioplegia was also completed and it was repeated every 25 min. After that, mild-tomoderate hypothermia induction was performed (28 -30 • C). Then, the band around the superior and inferior vena cava right atriotomy was tightened and RVOT obstruction was resolved by cutting the septal and parietal muscle bundles. Vertical pulmonary arteriotomy was also performed to ensure complete resection of the obstructing bundles. VCD closure was correspondingly fulfilled with a cortex patch using monofilament polypropylene (PP) 0.6 continuous sutures. Ultimately, the right ventricular outlet was reconstructed by two approaches: • Group I: TAP was created with a patch of autologous pericardium treated with 0.6% glutaraldehyde for 12 min (each side up in the solution for 6 min) and the main PA (MPA) angioplasty was performed with the prepared patch using 7-0 continuous PP sutures. • Group II: MV (i.e., one-way valve) with the cortex of 0.1 mm was created. Then, angioplasty was done with pericardial TAP via 7 -0 continuous sutures.
Both surgical procedures were fulfilled by the same surgical team. After stabilizing hemodynamic conditions and reversing the effects of heparin with protamine sulphate, the patients were weaned from CPB. Direct measurements of pressure were also used to rule out residual pressure gradients between RV and PA, and the ratio between RV and LV pressures (RVP/LVP ratio) of 30 -35 mmHg was accepted. The patients were then transferred to the PICU.

Post-operative critical care and follow-up
In the ICU, all the patients were visited twice daily by the anesthesiologist, pediatric cardiac surgeon, and pediatric cardiologist. Full monitoring and mechanical ventilation were also performed. Inotropic and sedative medications were additionally administered if needed. In the absence of hemorragia, and presence of good hemodynamic conditions, improved consciousness and respiratory status, based on the approval of an anesthesiologist, the sedation of the patients was discontinued. Patients were then hyperoxygenated for 2 min and the endotracheal tube was removed using suction. Oxygen administration was done with mask (7 L/min) until no further need was assured. After extubation, the patients were evaluated using Visual Analogue Scale (VAS) and a diclofenac suppository was used to alleviate pain if needed. Early post-operative echocardiography (24 h after surgery) was done to evaluate the outcome of surgery and cardiac function of the patients. The data were then recorded for comparisons between both groups. The early outcomes were duration of mechanical ventilation as well as length of PICU stay, mortality, and morbidity. Following the improvement of the general condition of the patients and approval by all three physicians, the patients were transferred to the cardiac surgery ward and discharged after two days. After discharge, all the patients received monthly followup twice by a pediatric cardiologist for clinical examinations, chest X-rays, echocardiography, and administration of medications if needed. At the end of the 6th month follow-up, an echocardiography was performed and data were recorded for comparisons between the two study groups.

Study outcomes
PR (none, mild, moderate, and severe), RV failure (fractional area change (FAC) less than 40% and tricuspid annular plane systolic excursion (TAPSE) lower than 10 mm were also considered as more than mild RV failure), ejection fraction (EF), and morbidity were evaluated after 6 months.

Statistical analysis
The data were analyzed using the IBM Statistical Package for Social Sciences (SPSS), version 22. Independent-sample t-test was also employed to compare the means of both quantitative variables. To compare proportions between two qualitative parameters, Chi-square (X 2 ) test was subsequently utilized.

RESULTS
The study population consisted of 39 male (65%) and 21 female (35%) patients. The basic patient characteristics showed no statistically significant differences between the two groups. These comparison data with reference to surgical approaches are shown in Table 1.
Furthermore, there was no statistically significant difference in pre-operative PVA z-score (p = 0.263) or PA index (PAI) (p = 0.220) between the two study groups. Additionally, no significant difference was observed in CPB time and aortic cross-clamp time between both groups. However, duration of mechanical ventilation was significantly different between the two groups (the mean number of days for PICU stay in Group I was significantly higher than that in Group II). In general, the mean duration of ICU stay was low in Group I and there was no significant difference between both groups ( Table 1).

Post-operative results and echocardiographic data
The findings revealed that no deaths had occurred during or after surgery until hospitalization. In primary post-operative echocardiography of the patients, PV velocity in Group I and Group II was 2.0 ± 0.5 m/sec and 1.5 ± 0.1 m/sec, respectively; this difference was not statistically significant (p = 0.249). In terms of echocardiography, 24 h after surgery, 18 patients in Group I had severe PR while 12 patients had moderate PR. In Group II, all the patients were also affected with mild PR. Besides, no statistically significant difference was observed in PR grades between the two groups (p = 0.781). Follow-up echocardiography, performed six months later, demonstrated that in the group with MV implantation, the severity of PA insufficiency was mild in 17 patients (56.7%), moderate in 8 patients (26.7%), and severe in 1 patient (3.3%). Moreover, 4 patients (13.3%) had no PR. In the group undergoing TAP angioplasty, the severity of PA insufficiency was mild in 7 patients (23.3%), moderate in 8 patients (26.7%), and severe in 9 patients (30%). In 6 patients (20%) of this group, no PR was observed. The difference between both groups in terms of severity of PV insufficiency was significant (p = 0.012) (Figure 2). No PV stenosis was reported in patients.
Accordingly, most of the patients with MV angioplasty had moderate PR, while severe PR was very high in the TAP group. In Group I, 6 patients had an EF of less than 50%, while EF was above 50% in 24 patients. In Group II, 7 patients had an EF of less than 50%, while it was above 50% in 23 patients. A comparison of left ventricular (LV) EF using the Chi-square (X 2 ) test did not show significant differences between both groups (p=0.912) (Figure 3). As illustrated in Figure 3, EF was low in a small number of patients in both groups; EF in other patients was acceptable. In Group I, 3 patients had moderate RV failure but 1 patient in Group II suffered from this dysfunction. Moreover, there was no significant difference between both groups (p = 0.510). Furthermore, 1 and 2 patients lost their lives in Groups I and II, respectively. No statistically significant differences were observed between the two groups (p = 0.312) (Figure 4). According to Figure 4, few patients in both groups died. There was also no difference between mortality rates in the two groups.

DISCUSSION
The results of this study demonstrated that TOF reconstruction via MV implantation could effectively mitigate PA insufficiency and severity. However, in the short term, it failed to affect RV functioning. Consistent with the results of the present study, other investigations have reported that the use of MV insertion could improve patient outcome by reducing early PR 17,18 . However, the major issue causing many complications in TOF patients is increased RV volume overload. If surgical procedures reduce the incidence rate of this complication, it will improve patient outcome. Different surgical procedures, such as MV reconstruction with autologous pericardium or polytetrafluoroethylene, have thus far been suggested to prevent complications. This corrective surgical technique can moderate RV workload by lowering the degree of PR 19,20 . In a study by Jang et al., using a method similar to that utilized in the present study, applying MV implantation with TAP angioplasty compared  with TAP alone could delay the grade 3-4 PR. Also, PV stenosis was not observed in patients 16 . Besides, no PV stenosis was reported at the 6-month followup echocardiography in the present study, although this was not a sufficient time for careful examinations and provision of definitive comments. However, the follow-up of the patients in the study by Jang et al. lasted nearly 10 years and, thus, the results from that study could be more reliable 16 .
Contrary to the results of the present study, other investigations have also revealed that classification and loss of mobility have been observed in a significant number of patients at one year post-surgery 16,21 . Additionally, the results of other studies have shown the significant incidence of valvular insufficiency and/or obstruction 16,17,21,22 . These studies found that MV insertion could cause significant complications and lead to poor patient outcomes. In the post-operative  echocardiographic studies, MVs have also exhibited various morphologies. Some have been further attached to PA wall and were non-functional; however, other MVs have been fixated to the middle of RVOT. It was hypothesized that the immobile MVs fixed to the middle of the RVOT might have acted as an antiregurgitation device, prolonging the interval between initial TOF repair and PR aggravation. However, this mechanism still needs to be elucidated 16  In this study, mortality rates were low in both groups. It should be noted that RV abnormality is a major element of morbidity and mortality following surgical repair of TOF 24 . This is justifiable since preserving RV functioning via preventing the right ventriculotomy reduces complications after TOF corrective surgery. The total correction of TOF through a transarterialtransventricular approach for patients aged greater than 6 months has also had a mortality rate of 0 -2% 24 .

CONCLUSION
It was concluded that MV reconstruction of TOF is effective in mitigating PR. However, long-term reviews are needed to evaluate the surgical effects on ventricular dysfunction and to confirm these findings. As limitations, long-term follow-up and surgical complications were not evaluated in this study.

AUTHOR'S CONTRIBUTIONS
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

FUNDING
The present study was financially supported by Tabriz University of Medical Sciences, Tabriz, Iran.

AVAILABILITY OF DATA AND MATERIALS
Data and materials used and/or analysed during the current study are available from the corresponding author on reasionable request.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE
This study was conducted in accordance with the amended Declaration of Helsinki. The institutional review board approved the study, and all participants provided written informed consent.