Commentary based on Day RW. Improving guidance for the correctability of congenital cardiovascular shunts with increased pulmonary vascular resistance. IJC Congenital Heart Disease 2021;4:202.

Study Question
What is the accuracy of the current hemodynamic guidelines for correctability of congenital cardiovascular (CV) shunts in patients with elevated pulmonary vascular resistance (PVR)?

Methods
This study evaluated a subset of patients from the Inhaled Nitric Oxide as a Preoperative Test (INOP) study.¹ The original INOP study was a multicenter analysis of patients with heart disease and elevated PVR (n = 124; median age 28 months, range 1 – 569 months at time of catheterization) to evaluate if preoperative acute vasodilator testing with inhaled nitric oxide (iNO) in addition to oxygen identified patients who survived corrective surgery or transplantation without evidence of right heart failure from pulmonary hypertension (PH). Importantly, patients in INOP were excluded if they were considered inoperable (n = 46); these patients were significantly older, with higher PVR and PVR/systemic vascular resistance (SVR). Current guidelines from the World Symposium of PH (WSPH) and European Pediatric Pulmonary Vascular Disease Network (EPPVDN) are summarized in the Table 1,^2,3 which utilize pulmonary vascular resistance indexed (PVRi) to body surface area and PVR/SVR on baseline hemodynamic testing to identify shunts as either correctable or uncorrectable. In this study, Dr. Day evaluated the outcomes of a subset of patients with CV shunts in INOP who underwent surgical correction (n = 52) to determine the accuracy of these guidelines with and without acute vasodilator testing with oxygen and iNO.

Table 1: Accuracy of Current Guidelines to Identify Correctable/Uncorrectable Shunts at Baseline, with Oxygen and Inhaled Nitric Oxide

Guideline	Conditions	Correctable	Not Correctable
World Symposium of Pulmonary Hypertension (Rosenzweig et al., 2019)		PVRi < 4 WU*m2	PVRi >8 WU*m2
	Baseline	19%	46%
	Oxygen	56%	88%
	Inhaled NO	71%	88%
The European Pediatric Pulmonary Vascular Disease Network (Hansmann et al., 2019)		PVRi < 6 WU*m2	PVRi >8 WU*m2
	Baseline	29%	See above
	Oxygen	73%
	Inhaled NO	87%
		PVR/SVR < 0.3	PVR/SVR > 0.5
	Baseline	17%	48%
	Oxygen	72%	88%
	Inhaled NO	88%	88%

Results
Of the 52 patients with septal defects (n = 49) or patent ductus arteriosus (n = 3) who underwent shunt correction, there were 7 deaths and 2 patients with clinical right heart failure due to PH (median follow up 24 months, range 3-87 months), all in patients with PVRi of > 8 Wood Units (WU)*m². Utilizing the WSPH guidelines, the accuracy of baseline preoperative hemodynamic testing was 17% to identify patients with correctable shunts with PVRi < 4 WU*m². However, with the addition of oxygen this increased to 56%, and with oxygen and iNO this increased further to 71% (Table 1); identifying an additional 28 patients who ultimately underwent correction and had a good outcome, and falsely identifying only 1 of the 9 who died or suffered right heart failure as correctable. Applying the consensus guideline from EPPVDN, the accuracy of baseline preoperative hemodynamic testing was 19% for PVRi < 6 WU*m² and 17% for PVR/SVR < 0.3 (Table 1). With the addition of oxygen and then oxygen and iNO, the accuracy of PVRi < 6 WU*m² increased to 73% and 87%, respectively (Table 1); falsely identifying 3 of the 9 patients who died or suffered right heart failure. The accuracy of PVR/SVR < 0.3 increased to 72% with oxygen and 88% with oxygen and iNO (Table 1), with 2 of 9 patients falsely identified as correctable.

Conclusions
The accuracy of preoperative hemodynamic testing to identify patients with elevated PVR and correctable congenital CV shunts is increased with acute vasodilator testing using iNO.

Perspective
Current guidelines on correctability of CV shunts in patients with elevated PVR are largely based on expert consensus. In this study population, the accuracy of these guidelines is low with baseline hemodynamic testing, and would inaccurately identify a large number of patients as uncorrectable. The accuracy increases with acute vasodilator testing utilizing oxygen and iNO, though this does falsely identify a small number of patients as correctable who had an adverse outcome. Age did not affect the outcome of patients who underwent surgery. However, exclusion of patients who were considered inoperable in the original INOP study may have biased this effect, as these significantly older patients with unrepaired shunts had more time to develop irreversible pulmonary vascular disease, causing hemodynamics which precluded repair. Given the exclusion of these patients, sample size is a major limitation of this study.

It is important to note the differences between acute vasodilator testing for patients with congenital cardiac shunts and PH compared to patients with idiopathic pulmonary arterial hypertension (iPAH). Guidelines for vasodilator testing in iPAH utilize only iNO, with the goal of identifying patients with a favorable hemodynamic response (defined as a reduction in the mean pulmonary artery pressure by more than 10 mmHg, to a value less than 40 mmHg, without reduction in cardiac output) who could be treated with an oral calcium channel blocker.⁴ However, for patients with congenital cardiac shunts, vasodilator testing is used to identify patients who could undergo shunt correction; in this case, the combination of oxygen and iNO is recommended to maximize pulmonary vasodilation.² Notably, when utilizing oxygen in vasodilator testing, dissolved oxygen must be taken into account;⁵ if dissolved oxygen is ignored, the arteriovenous oxygen difference may be underestimated, artificially increasing pulmonary blood flow and decreasing pulmonary vascular resistance based on the Fick equation. This may result in false identification of a patient with favorable hemodynamics. Therefore, catheterization for this population is recommended only in expert centers.^4,5

Recommendations for shunt correction based on acute vasodilator testing is not specifically addressed in the WSPH guidelines, and is used to direct targeted pulmonary vasodilator therapy or partial correction if baseline testing is not within the correctable range in the EPPVDN guidelines. The INOP study was performed when there were fewer options for pulmonary vasodilator therapy or partial correction with transcatheter fenestrated closure devices, therefore the outcomes may be improved with these therapies. In addition, this study included only patients in which there was a concern for high PVR and therefore underwent catheterization, thus the overall accuracy of baseline testing is likely higher than reported as many patients with normal PVR may undergo surgery based on assessment of the shunt by echocardiography, without invasive hemodynamic testing. With increasing data available on correctability of shunt lesions, less invasive options available for shunt correction, increased availability and usage of pulmonary vasodilator therapy,⁶ and potential for fenestrated shunt closures,⁷ this field is expected to evolve.

References

1. Balzer DT, Kort HW, Day RW, et al. Inhaled Nitric Oxide as a Preoperative Test (INOP Test I): the INOP Test Study Group. Circulation 2002;106:I76-81.
2. Hansmann G, Koestenberger M, Alastalo TP, et al. 2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: the European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT. J Heart Lung Transplant 2019;38:879-901.
3. Rosenzweig EB, Abman SH, Adatia I, et al. Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management. Eur Respir J 2019;53:1801916.
4. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67-119.
5. Apitz C, Hansmann G, Schranz D. Hemodynamic assessment and acute pulmonary vasoreactivity testing in the evaluation of children with pulmonary vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart 2016;102:ii23-29.
6. Bradley EA, Ammash N, Martinez SC, et al. "Treat-to-close": non-repairable ASD-PAH in the adult: results from the North American ASD-PAH (NAAP) Multicenter Registry. Int J Cardiol 2019;291:127-33.
7. Yan C, Pan X, Wan L, et al. Combination of F-ASO and targeted medical therapy in patients with secundum ASD and severe PAH. JACC Cardiovasc Interv 2020;13:2024-34.

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Congenital Heart Disease, CHD and Pediatrics and Imaging, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Acute Heart Failure, Pulmonary Hypertension, Echocardiography/Ultrasound, Hypertension

Keywords: Calcium Channel Blockers, Hypertension, Pulmonary, Nitric Oxide, Pulmonary Artery, Pulmonary Circulation, Vasodilation, Body Surface Area, Ductus Arteriosus, Patent, Familial Primary Pulmonary Hypertension, Follow-Up Studies, Vascular Resistance, Vasodilator Agents, Echocardiography, Oxygen, Heart Failure, Catheterization, Cardiac Output

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