Pathophysiology

From 1958 to 2011, 13 studies were identified which addressed the pathophysiology of pulmonary vascular disease of infants and children undergoing ventricular septal defect repair (Table 1). The average study size was 32 patients (range from 1 to 85). The focus of these studies was most commonly the histologic changes to the pulmonary vasculature induced by increased pulmonary flow and/or pulmonary artery hypertension as the consequence of the ventricular septal defect. Less commonly, other studies investigated thromboxanes, prostaglandins, nitric oxide, endothelin, and matrix metalloproteinases. No study mentioned pharmacologic therapies targeted to any of these systems prior to, during, or after ventricular septal defect repair.

Table 1. Studies which address the pathophysiology of pulmonary vascular disease in infants and children undergoing repair of ventricular septal defect

MMP, matrix metalloproteinase; NO, nitric oxide; NOS, nitric oxide synthase; TXA, thromboxane A; PGI, prostaglandin I; TXB, thromboxane B

Pharmacologic management

As shown in Table 2, few studies documenting early or late outcomes after ventricular septal defect repair included details about pre-operative pharmacologic management or optimisation of congestive heart failure or pulmonary artery hypertension. Only two of 44 studies described pre-operative/post-operative pharmacologic management of pulmonary artery hypertension beyond those which discuss intra-operative considerations.^{Reference Aydemir, Harmandar and Karaci18,Reference Bhasin, Gogia, Nair and TK19} One of these is the study by Ademir et al in 2013. These authors compared 282 infants (median age 5 months) based on age at the time of surgery: Group 1, age 0–3 months; Group 2, age 3–6 months; and Group 3, age 6–12 months. The authors noted that the ratio of pulmonary-to-systemic blood pressure, the ratio of pulmonary vascular resistance to systemic vascular resistance, and the pulmonary vascular resistance remained higher post-operatively in both Groups 2 and 3 compared to Group 1 (p < 0.05 for both comparisons). This indicated a persistence of post-operative pulmonary hypertension in the older age groups. As there was also a greater frequency of mortality in the older age groups compared to Group 1, the authors concluded that early surgical repair of infants with isolated ventricular septal defects and severe pulmonary hypertension should be pursued. In this report, Ademir et al also described their management of severe pulmonary hypertension as using fentanyl (0.5–1 mcg/kg/h), nitroglycerin (0.5 mcg/kg/min), and/or iloprost (0.5–1 mcg/kg/min) and nitric oxide inhalation after 2006 during the peri-operative period. Post-operatively these authors report their use of oral captopril (1 mg/kg/day) before 2006 and oral sildenafil (3 mg/kg twice daily) after 2006. However, Ademir et al did not mention how titration of the dosages was determined or if these therapies were effective.^{Reference Aydemir, Harmandar and Karaci18} In a later study, Bhasin et al randomised 60 patients to either pre-operative placebo and post-operative sildenafil (Group 1) or pre- and post-operative sildenafil (Group 2). The median age in Group 1 was 15.8 months, and the median age in Group 2 was 14.5 months at the time of ventricular septal defect repair. The authors found that those in Group 2 had lower pre- and post-operative pulmonary artery pressures (p < 0.05) as well as a decreased intensive care length of stay (mean 78.5 versus 98.4 hours; p = 0.001). They also report that one patient in Group 1 had three episodes of pulmonary hypertensive crisis, and that two patients in Group 2 each had two episodes of pulmonary artery hypertensive crisis. Though the authors do not document the actual number of mortalities (if any), they do indicate that there was no mortality difference between the groups.^{Reference Bhasin, Gogia, Nair and TK19} Unfortunately, there were no pulmonary vascular resistance indices reported, so these cannot be contrasted between groups. Nonetheless, this study demonstrated similar results of sildenafil to those of others with mixed groups of congenital heart lesions, though the long-term effects are unclear for all.^{Reference Sharma, Joshi, Joshi, Kumar, Arora and Gard20–Reference Kirklin and Dushane25} In total, there remain little data to indicate what effects the applicable pharmacologic therapies have on individual patient outcomes for those with pulmonary artery hypertension related to congenital ventricular septal defects.

Table 2. Studies of patients undergoing surgical closure of isolated ventricular septal defects with objective data on pulmonary artery hypertension and its relevant pre-operative pharmacologic management, peri-operative outcomes, and long-term outcomes

* Data unavailable on all patients

** Data limited, no mention of pulmonary arterial flow, or pressure measurements

*** Follow-up at one year

Peri-operative and long-term outcomes

Also shown in Table 2 are 44 studies containing data on outcomes (peri-operative and long-term) of infants and children undergoing isolated ventricular septal defect repair. These studies are from 1958 to 2019, of which the median study population was 53 patients (range from 4 to 767), with one undetermined. Repeat studies from the same institution were few and were usually published a decade apart. Of the 28 studies containing data on long-term outcomes (≥1 year), 20 had follow-up assessment of the pulmonary vasculature as indicated by objective measurements by catheterisation or imaging, or indirect measurement by exercise capacity. The majority of these reports indicated a measureable frequency of pulmonary artery hypertension or diminished exercise capacity late after ventricular septal defect repair, though the studies varied considerably in terms of decade published, age at the time of ventricular septal defect repair, means of pulmonary flow measurements, and time since surgery that follow-up measurements were performed. However, it is important to keep in mind that persistence of pulmonary hypertension is rare in the current era when ventricular septal defects are repaired in early infancy.

In their report from the 1960s, Halladie-Smith et al studied 36 patients with pulmonary vascular disease aged 3–12 years (mean 7.2 years) at the time of ventricular septal defect repair, of which 25 patients were investigated 1–8 years after operation. The authors report an overall mortality of 24% which is considerably greater than the 5% of their own patients with ventricular septal defects not complicated by pulmonary vascular disease. Of the deaths, three patients had pulmonary artery hypertension that did not resolve post-operatively. In this study, the greatest diameter of the ventricular septal defect ranged from 1.0 to 4.0 cm (mean 2.3 cm excluding one patient whose measurement was reported errantly in the report). Though overall “the results showed a fall in pulmonary artery pressure and in pulmonary vascular resistance, [t]he majority had some residual pulmonary vascular disease.”^{Reference Hallidie-Smith, Hollman, Cleland, Bentall and Goodwin28} Similarly, in their report from 1969, Gotsman et al studied 34 patients (age at ventricular septal defect repair not specified). According to their own classification scheme using defect size and the ratio of pulmonary systolic pressure to systemic systolic pressure, they found that 1-year post-surgery pulmonary artery pressures fell in all patients but that there was little change in pulmonary-to-systemic vascular resistance in patients with Type 1B (small defect, shunt 10–40%), Type 1C (“slightly larger” defect, shunt > 40%), or Type 2 (moderate-sized defect, shunt 40–80%), compared to a variable response in Type 3A patients (large defect, shunt > 40%).^{Reference Gotsman, Beck, Barnard and Schrire30} Soon thereafter, Maron et al studied 11 patients aged 11–40 years at the time of ventricular septal defect repair. These authors performed exercise studies 3–15 years after ventricular septal defect closure and found that during intense exercise, cardiac output was below normal in five patients and that two patients had an abnormally elevated mean pulmonary artery pressure.^{Reference Maron, Redwood, Hirshfeld, Goldstein, Morrow and Epstein32} In another study, Friedli et al described the results of 57 children who had undergone ventricular septal defect repair at ages 11 months to 17 years (mean 4.8 years), of whom 18 (32%) died at or immediately after operation. Of 32 long-term survivors who underwent cardiac catheterisation 1–11 years after ventricular septal defect closure, five had “evidence of progressive pulmonary vascular disease by both clinical and hemodynamic criteria, and [three] more [had] increased pulmonary vascular disease not suspected clinically.”^{Reference Friedli, Kidd, Mustard and Keith33} During the latter part of the same decade, Hallidie-Smith et al studied 27 patients 6–16 years after they underwent ventricular septal defect closure at ages 3–12 years. Of these patients, 15 underwent supine exercise recording of their pulmonary artery pressure. These authors found that five had pulmonary artery pressures which closely approximated systemic pressures, and in all except three, the systolic pulmonary artery pressure rose 30 mmHg or more.^{Reference Hallidie-Smith, Wilson, Hart and Zeidifard36}

In the early 1980s, Richardson et al reported 32 patients who underwent ventricular septal defect repair at ages 1–24 months. Of these patients, 18 underwent cardiac catheterisation 12–33 months after operation, and only three had a mildly elevated pulmonary vascular resistance (5–7 units/m²).^{Reference Richardson, Schieken, Lauer, Stewart and Doty38} Later in this decade, Haneda et al described 43 patients who underwent surgical closure of ventricular septal defect in the first year of life.^{Reference Haneda, Ishizawa and Yamaki41} Not surprisingly, these authors found that the peak pulmonary to systemic pressure ratio (Pp/Ps) decreased from pre-operative indices for the majority of the cohort immediately after ventricular septal defect closure [0.79 ± 0.15 to 0.39 ± 0.11 (p < 0.01)]; however, there was no long-term follow-up described. Nonetheless, in the 1990s, this same group successfully described the late results after correction of ventricular septal defects with severe pulmonary artery hypertension.^{Reference Haneda, Sato, Togo, Miura, Hata and Mohri46} In their study of 58 patients with ventricular septal defect repair and severe pulmonary artery hypertension (Pp/Ps ≥ 0.90), 26 underwent cardiac catheterisation 1 month to 12 years (average 3.0  years) after the operation. Haneda et al found that Pp/Ps and pulmonary to systemic vascular resistance ratio (Rp/Rs) were significantly decreased post-operatively. However, there were significant differences between groups repaired prior to and after age 2, with the delayed repair group having a higher Rp/Rs [0.31 ± 0.19 versus 0.17 ± 0.06 (p < 0.05) and Rp [4.55 ± 1.88 versus 2.52 ± 0.65 units · m² (p < 0.05)]. Moreover, a greater frequency of those with delayed closures had Pp/Ps ≥ 0.40 (62.5% versus 20 %, p < 0.05); Rp/Rs > 0.30 (56.3% versus 0, p < 0.005); and Rp ≥ 4 units · m² (55.6% versus 0, p < 0.02). These authors suggested that their results indicated persistence of pulmonary vascular resistance and concluded that ventricular septal defect repair in those with severe pulmonary artery hypertension should occur before age 2.^{Reference Haneda, Sato, Togo, Miura, Hata and Mohri46}

Also in the 1990s, Ikawa et al assessed pulmonary artery pressure and resistance during exercise late after closure of a large ventricular septal defect with pulmonary hypertension.^{Reference Ikawa, Shimazaki, Nakano, Kobayashi, Matsuda and Kawashima47} The authors identified two groups with a pulmonary-to-systemic resistance ratio of 0.15–0.50 (Group 1) and 0.50–0.96 (Group 2). The age at operation was 0.9–13.0 years (mean 4.6 years) in Group 1 and 0.8–15.8 years (mean 4.3 years) in Group 2. These authors found that the mean pulmonary artery pressure increased in both groups during exercise (p < 0.05). Pulmonary vascular resistance also increased in both groups during exercise (p < 0.001). These results were also significantly different from the normal control group’s response to the same exercise stimulus. Ikawa et al employed their data to indicate that those with a higher pulmonary-to-systemic resistance ratio should be operated on at a younger age.^{Reference Ikawa, Shimazaki, Nakano, Kobayashi, Matsuda and Kawashima47} Furthermore, in their study of 176 patients who underwent isolated ventricular septal defect repair before the age of 15 years, Meijboom et al found in 109 participating patients that exercise capacity at a mean of 14.5 years following ventricular septal defect repair was better (p = 0.02) in those with lower pre-operative pulmonary vascular resistance (<400 dynes·s·cm⁻⁵). They further stated that elevated pre-operative pulmonary vascular resistance was the only independent predictor for decreased exercise capacity upon linear regression analysis.^{Reference Meijboom, Szatmari and Utens45} In addition, Roos-Hesselink et al noted a 4% prevalence of pulmonary artery hypertension in their more recent, longitudinal study of 176 consecutive patients undergoing isolated ventricular septal defect repair at a median age of 4 years (range 0–13 years).^{Reference Roos-Hesselink, Meijboom and Spitaels52} Unfortunately, the details of these 4% of the patients were not provided, other than that they did not differ from the rest of the cohort in terms of age at operation. In 2013, Aydemir et al reported their experience of 282 infants undergoing ventricular septal defect repair, with an emphasis on pulmonary hypertension.^{Reference Aydemir, Harmandar and Karaci18} These authors found that pre-operatively 89.4% had congestive heart failure or failure to thrive and that 87.6% had pulmonary hypertension (43.3% severe). All of the eight patients who died had severe pulmonary hypertension. In this study, there were higher values of post-operative Pp/Ps, pulmonary vascular resistance/systemic vascular resistance, and pulmonary vascular resistance in those repaired at 6–12 months compared to prior to 3 months, indicating persistence of post-operative pulmonary hypertension. The authors conclude that the relatively higher mortality in their study could be due to severe pulmonary hypertension, and “that early repair…of isolated ventricular septal defects in patients with severe pulmonary hypertension is strongly advised to achieve favorable results.”^{Reference Aydemir, Harmandar and Karaci18}

Among more recent studies, Heiberg et al compared 27 patients approximately 20 years following ventricular septal defect repair versus 30 control patients. Compared to controls, they found that those in the ventricular septal defect group had a significantly lower mean minute ventilation at peak exercise (1.4 ± 0.4 L/kg/min versus 1.8 ± 0.4 L/kg/min, p < 0.01) and mean oxygen uptake (38.0 ± 8.2 ml/kg/min versus 47.9 ± 6.5 ml/kg/min, p < 0.01).^{Reference Heiberg, Petersen, Laustsen and Hjortdal56} These results were soon thereafter replicated by Nederend et al.^{Reference Nederend, de Geus, Blom and Ten Harkel59} Also recently, Gabriels et al reported that 4 of 47 patients approximately 30 years following ventricular septal defect repair had pulmonary hypertension diagnosed by echocardiography.^{Reference Gabriels, Van De Bruaene and Helsen57} In a later study specifically measuring pulmonary vascular resistance late after ventricular septal defect repair, this same group reported a higher peak total pulmonary vascular resistance compared to controls (2.7 ± 0.8 versus 2.2 ± 0.3 mmHg/L/min, p = 0.005), and concluded that life-long follow-up is warranted.^{Reference Gabriels, Buys and Van de Bruaene60} Finally, in an age- and gender-matched control study, Rex et al compared 30 patients approximately 23 years after ventricular septal defect repair versus 30 healthy controls. These authors found that those in the ventricular septal defect repair group had lower expiratory volume in 1 second (99 ± 18% versus 118 ± 19%, p < 0.001), impaired forced vital capacity (106 ± 12% versus 118 ± 13%, p < 0.001), and lower alveolar volume (92 ± 10% versus 101 ± 11%, p < 0.001). Rex et al concluded that adults who had undergone ventricular septal defect repair as a child had reduced pulmonary function versus controls.^{Reference Rex, Eckerstrom and Heiberg61}