Predictors of Protein Losing Enteropathy after Fontan completion, a retrospective study from eight years’ experience in a growing high volume cardiac surgery center.

doi:10.21203/rs.3.rs-2485535/v2

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Predictors of Protein Losing Enteropathy after Fontan completion, a retrospective study from eight years’ experience in a growing high volume cardiac surgery center.

https://doi.org/10.21203/rs.3.rs-2485535/v2

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Background:

Fontan procedure is the final stage of a three-stage palliation process in patients born with a univentricular heart as part of Hypoplastic Left Heart Syndrome (HLHS) or other types of Univentricular Heart. As essential as this procedure has proven to be for such cases, the Fontan physiology diminishes the cardiac output and expands systemic venous pressure which leads to venous congestion that can be complicated by Protein Losing Enteropathy (PLE). The aim of this retrospective research was to study the predictors of such complications in all patients who underwent completion of Fontan in our center in the past eight years. It involved the examination of medical records of patients who underwent completion of Fontan repair in our center since the inauguration of its cardiac surgery program. Exclusion criteria included the absence of any of the required predictors in a medical report. Included patients were divided into two groups: those who developed PLE and those who did not. For each group, the following data were collected: The degree of AV valve regurge, the ventricular functions, the invasive SVC, and pulmonary pressures before Fontan completion and the original cardiac diagnosis.

Results:

48 patients were included: only 13 developed PLE, accounting for 25% of the total patients. A multivariate regression analysis of the best predictors of the occurrence of PLE was the degree of AV valve regurge (P = 0.008), SVC mean pressure (P value = 0.01), and Ventricular functions (P value = 0.02). A ROC analysis was performed for each of the best predictors and showed that SVC pressure > 11 was 100% sensitive, moderate and severe regurge were 69% sensitive, and moderate to severe impairment of ventricular functions was 53% sensitive in predicting subsequent PLE.

Conclusion:

The unleashed findings might be game-changing in the decision-making of whether to complete the Fontan pathway or not in our growing cardiac surgery center, which is one of the largest in its respective region. The presence of moderate to severe AV valve regurge, moderate to severe ventricular dysfunction, and a Superior Vena caval pressure above 11 before Fontan completion should be regarded as contraindications to completion of the procedure.

Fontan

PLE

Predictors of Fontan failure

The "Fontan Circulation" was designed by Francis Fontan in 1971 to overcome the absence of two separate cardiac ventricles. This procedure was originally aimed at syndromes with a single left ventricle. However, after recent modifications, it is also applicable for cases born with a single right ventricle as those associated with HLHS. The recent decrease in perioperative mortality following the Fontan procedure can be attributed to its performance over two stages (superior Cavo-pulmonary anastomosis followed by later Fontan completion), the selection of younger candidates, and, undeniably, to improved perioperative management. ¹

Morbidity following Fontan is now only ≤ 5%, compared with 15–30% in earlier decades, with survival at 20 years being 85%. Although Atrio-pulmonary connection is now obsolete, adult survivors of earlier operations are currently experiencing an array of hemodynamic complications and sequelae of their abnormal circulatory status. This however should not be reflective of present-day Cavo-pulmonary Fontan outcomes, in which the vena cavae are directly connected to the pulmonary artery, bypassing the right atrium and ventricle. This procedure is usually performed over two stages to allow proper adaptation to the new hemodynamic conditions and performance of proper intermediate preparatory interventions. ²

However, due to the resulting systemic venous congestion and low cardiac output, complications following the Fontan Procedures are still not uncommon. ³

The primary outcome parameter of our retrospective study is to determine the prevalence of Fontan failure in our center for cardiac surgery and the secondary outcome parameter is to determine the best predictor of such failure among different risk factors, including, duration from Fontan surgery, gender, type of the original cardiac lesion, presence or absence of pulmonary overflow and the pressures' cut-offs in the SVC and pulmonary arteries that can predict Fontan failure.

Study subjects:

Medical reports of all patients who underwent Fontan in the period between 01/01/2012 and 31/12/2020 in our center were retrieved from the CERNER enterprise system (Millennium: Cerner Corporation, Kansas City, Missouri). Exclusion criteria included all patients who have reverted their Fontan pathway to Biventricular repair or one and a half repair due to advances in the available surgical techniques and patients with incomplete medical records whose files did not include the required outcome parameters.

Study Methods:

The following data was retrieved from the system:

*Demographic and clinical data:

Age at development of PLE
Age at completion of Fontan and current age with subsequent deduction of duration from Fontan completion
Gender
Development of PLE or not

*Operative data

Conduit size
Presence of fenestration
Size of Fenestration

*Hemodynamic data: by invasive hemodynamics in last cardiac catheterization before completion of Fontan

SVC (Glenn) pressure
PA mean pressure

*Echocardiographic data:

Degree of AV (tricuspid) valve regurge
Degree of main ventricle dysfunction
Cardiac diagnosis (Pulmonary overflow or decreased pulmonary blood flow prior to univentricular pathway)

Statistical analysis:

Data were analyzed using MedCalc and excel software. Patients were divided into two groups; Group 1 (G1): Fontan patients who developed PLE, Group 2 (G2): Fontan patients who did not develop PLE.

Normally distributed numerical variables were presented as mean and Standard Deviation and inter-group differences were compared using the unpaired t test. Categorical data were compared using Chi square test.

Multivariate analysis was performed to determine the best predictor of PLE in Fontan patients.

Receiver Operating characteristic was performed to determine the SVC cut-off pressure to predict PLE in Fontan patients

Table 1 shows a comparison of the collected variable between the two study groups (Group 1 patients who developed PLE, and group 2 who did not develop PLE.

Table 1

Comparison of the epidemiologic, echocardiographic, operative and hemodynamic parameters between the two study groups
Variable			Group 1 (N = 13)		Group 2 (N = 35)		P Value
Age (mean ± SD)			7.9231 ± 2.9000		8.6857 ± 4.0784		0.2
Sex N (/%)		Female	5(38)		11 (31)		0.4
Sex N (/%)		Male	8 (62)		24 (69)		0.4
Age at completion of Fontan (mean ± SD)			3.9 ± 2.0108		3.9371±	2.1365	0.9
Duration From Fontan (mean ± SD)			3.9308±	2.6088	4.7486±	3.6733	0.2
Oxygen saturation before completion of Fontan (mean ± SD)			81 ± 10		85 ± 5		0.004
SVC mean pressure (mean ± SD)			13.7 ± 1.4		9.7 ± 3.4		0.002
PA mean pressure (mean ± SD)			11.5 ± 3.4		9 ± 3.7		0.7
Size of Fontan Conduit (mean ± SD)			18.7 ± 1		18 ± 0.9		0.4
Size Fontan Fenestration (mean ± SD)			2.8 ± 1.7		3.4 ± 1.4		0.39
Underlying cardiac lesion N (/%)	Pulmonary Overflow lesions		11 (85)		15 (43)		< 0.001
Underlying cardiac lesion N (/%)	Decreased Pulmonary blood flow lesions		2 (15)		20 (57)		< 0.001
Degree of AV regurge N (/%)	None or mild AV valve regurge		4 (31)		28 (80)		< 0.001
	Moderate AV valve regurge		7 (54)		7 (20)
	Severe AV valve regurge		2 (15)		0 (0)
Degree of ventricular dysfunction N (/%)	Normal functions and mild ventricular dysfunction		6 (46)		32 (91)		< 0.001
	Moderate Ventricular dysfunction		6 (46)		3 (9)
	Severe Ventricular dysfunction		1 (8)		0 (0)
Abbreviations:
AV: Atrioventricular, N: Number, PA: Pulmonary Artery, SD: standard deviation, SVC: Superior vena cava

The age was comparable between both groups, 7.9 ± 2 for G1 and 8 ± 4 for G2. The duration since Fontan surgery is seemingly unrelated to the development of PLE, as it was similar between the two groups with an insignificant P value of 0.2. Neither the size of the Fontan conduit nor the size of fenestrations impacted the outcome of TCPC, with P values of 0.4 and 0.39 respectively between the two study groups.

Moderate and severe AV valve regurge was predominant in patients who developed PLE (69%), while no or mild AV valve regurge was most commonly seen in G2 accounting for 80% of the group. No patients in G2 displayed severe AV valve regurge. Similarly, moderate to severe ventricular dysfunction was most commonly seen in patients with PLE (G1), accounting for 54% of the total group members, while most of the patients in G2 had normal ventricular functions.

PA mean pressure was higher in G1 than in G2 without achieving statistical significance (11 ± 3 vs. 9 ± 3, P = 0.07), while SVC pressure was significantly higher in G1 than G2 (13 ± 1 vs. 9 ± 3, P = 0.002). An interactive dot diagram was performed to reflect ROC analysis and to determine the cut-off SVC pressure that can predict the development of PLE. SVC PRESSURE > 11 was 100% predictive of a negative outcome. (Fig. 1)

Multivariate analysis (Table 2) of the variables that achieved statistical significance by T-test and chi-square between study groups was performed to determine which of them was the best predictor of PLE and revealed that the degree of AV valve regurge achieved the highest statistical significance followed by SVC pressure, with ventricular dysfunction having the least significance.

Table 2

multivariate analysis for the best predictors of PLE in the study subjects:
Independent variables	Coefficient	Std. Error	t	P
Pulmonary Overflow	0.01663	0.1773	0.0938	0.9257
SVC mean pressure	0.05772	0.02231	2.587	0.0134
Ventricular functions	0.2697	0.1125	2.398	0.0213
Degree of AV valve regurge	0.2494	0.08933	2.792	0.0080
PA Mean pressure	-0.02099	0.01999	-1.050	0.3001
Abbreviations: AV: Atrioventricular, PA: Pulmonary Artery, SVC: Superior vena cava

PLE is one of the most serious postoperative complications that have a powerful predictor for morbidity and mortality in patients after the Fontan operation.

Recognizing the risk factors that might predict the occurrence of this complication is of utmost importance to eliminate them if possible or to avoid completion of Fontan in patients having one of these red flags. ⁴

Our research is the largest to date to study the predictors of PLE in Fontan patients, in the respective region of our center. An epidemiologic study, depicting the rate of short and long-term complications from a univentricular pathway, was published by Najashi and colleagues in 2021. The latter was only discussing the rate of complications rather than the respective predisposing factors. ⁵

There is no fixed duration between Fontan surgery and the development of PLE. However, most of the patients (30–50%) tend to develop this complication after five years of the procedure. In our study, 27% of the patients developed PLE following Fontan, with an average duration of 2.4 years between TCPC and the initial manifestations of PLE, which is shorter than the numbers previously reported. The duration between the collection of data and Fontan surgery was comparable between the two study groups, which signifies that the duration from Fontan is not a key factor in the development of PLE and that PLE might develop earlier if the risk factors needed for its development exist. ⁶

Fontan circulation is a low-energy system even during exercise. Larger conduits were proven to have redundant spaces with subsequent development of venous congestion due to loss of energy. Our study could not reveal a significant difference between the two study groups in the conduit size, as most of the used conduits were between 16–18 mm. However, patients developing PLE had a higher statistically insignificant conduit size of 18.7 mm which might confirm the hypothesis of loss of energy through larger conduits. ⁷

Pre-Fontan assessment of SVC and pulmonary pressures is a routine procedure to determine if hemodynamics are suitable for TCPC. Pulmonary overflow and an incompetent tricuspid valve led to severe regurge and consequent pulmonary venous congestion, which, in turn, increases pulmonary vascular resistance. The latter mechanisms are invariably associated with Fontan failure as they impair venous return against elevated PA pressures. For this reason, HLHS is the commonest lesion associated with PLE following TCPC in our studies as well as in several other series. Cut-offs for SVC pressure risky for completion of TCPC were usually higher than 13 mmHg. In this study, an SVC pressure higher than 11 mmHg was 100% sensitive and 68% specific in predicting the occurrence of PLE post-Fontan. ⁸

Severe AV valve regurge and severe ventricular dysfunction were among the best predictors of PLE following TCPC, which is usually encountered when the systemic ventricular role is accounted for by the RV as in HLHS. ⁹

Our study is the first in the respective region of our center to sort out the hemodynamic, operative, and epidemiologic factors behind Fontan failure, in a large-volume center. Some of the illustrated risk factors went along previous studies, notably a dominant systemic right ventricle and a larger conduit size, others differed slightly such as the cut-off for SVC pressures and the insignificance of the time-lapse between Fontan and the development of complications. More studies should be conducted to elucidate if this cut-off for SVC pressure should replace the already settled cutoffs. In addition, more research is needed to craft new devices for mechanical support of a failing Fontan.

AV	Atrio-ventricular valve
G1	Group1
G2	Group2
HLHS	Hypoplastic Left heart syndrome
IVC	Inferior Vena Cava
PA	Pulmonary Artery
PLE	Protein Losing Enteropathy
SVC	superior Vena Cava
TCPC	Total Cavopulmonary connection

Ethics approval and consent to participate

The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant Egyptian guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008, and has been approved by the institutional committee of our institute. Ethical committee approval number is: REC-27.09.2022 [RS-770]. A written consent was fulfilled by each of the study participants.

Consent for publication

Not Applicable

Availability of data and material

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests

Funding

This research received no specific grant from any funding agency, commercial or notfor-profit sectors

Authors' contributions

AFA, AM: Conceptualization (lead); writing – original draft (lead); formal analysis (lead); writing – review and editing (equal).

LK, HEB, MK, BH, JT, AO, AZS, FTAJ, LAK, MT: Software (lead) and investigation; writing (equal).

NAH, OY, SI, ZA, NKJ, EMH, YO, MMA, AK, ZA, MA, MM, AAA, AM: Methodology (lead); writing – review and editing (equal).

All Authors read and approved the final manuscript

Acknowledgements

To our families, the small ones made by blood and the large ones made by genuine support.

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Barracano R, Merola A, Fusco F, et al. Protein-losing enteropathy in Fontan circulation: Pathophysiology, outcome and treatment options of a complex condition. Int J Cardiol Congenit Hear Dis. 2022;7:100322.
Kutty S, Jacobs ML, Thompson WR, et al. Fontan Circulation of the Next Generation: Why It’s Necessary, What it Might Look Like. J Am Heart Assoc. 2020;9:1–9.
Al Najashi K, Farouk S, Atiyah M, et al. Outcomes after the Fontan operation in the Middle East: A large Saudi Arabian single centre experience. Int J Cardiol. 2021;325:56–61.
Kramer P, Schleiger A, Schafstedde M, et al. A Multimodal Score Accurately Classifies Fontan Failure and Late Mortality in Adult Fontan Patients. Front Cardiovasc Med. 2022;9:1–14.
Itatani K, Miyaji K, Tomoyasu T, et al. Optimal Conduit Size of the Extracardiac Fontan Operation Based on Energy Loss and Flow Stagnation. Ann Thorac Surg. 2009;88:565–573.
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Predictors of Protein Losing Enteropathy after Fontan completion, a retrospective study from eight years’ experience in a growing high volume cardiac surgery center.

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Version 2

Abstract

Background:

Results:

Conclusion:

Figures

Background

Methodology

Study subjects:

Study Methods:

Statistical analysis:

Results

Discussion

Conclusion

List Of Abbreviations

Declarations

References

Status:

Version 2