The Fontan operation, the final stage of palliation for a univentricular circulation, places in series the systemic and pulmonary circulations without a subpulmonic pump. Studies performed in the 1940s and 1950s set the groundwork for the first Fontan operation in 1968 by revealing a critical finding: following the destruction of the right ventricle a near-normal stroke volume (SV) was maintained with little change in arterial and venous pressures (1). Nearly 50 years later, we are still dissecting the unique aspects of this circulation. In this issue of Pediatric Critical Care Medicine, the study by Adamson et al (2) reported the hemodynamic effects of arginine vasopressin (AVP) in the Fontan circulation. These findings and their interpretation provide further insight into the potential role of AVP in the acute management of Fontan patients.

Twenty-eight pediatric and adult Fontan patients (median age 13.5 yr) referred for cardiac catheterization for hemodynamic assessment and/or intervention were given a bolus of AVP followed by a continuous infusion (2). Twelve of these patients had met the criteria for “Fontan dysfunction” and three patients (11%) were fenestrated. Hemodynamic parameters were compared before and after initiation of the drug. Anesthesia was provided with propofol and ketamine, and spontaneous ventilation was maintained with a facemask, nasal cannula, or laryngeal mask airway. AVP caused a significant increase in systemic vascular resistance (SVR) and systemic arterial blood pressure, decrease in pulmonary vascular resistance (PVR) (1.8 to 1.4 Wood units), and increase in common atrial pressure. Both cardiac output (CO) and mean pulmonary artery pressure (i.e., Fontan pressure) did not show significant changes from baseline. In the subgroup analysis of patients with Fontan dysfunction, a similar response to AVP was noted.

In analyzing the findings of this study and properly placing the findings in context, an understanding of prior foundational work and integration with current validated hemodynamic models is helpful.

FONTAN CIRCULATION

In the normal two ventricular circulation, the pulmonary and systemic circuits are connected in series with each having a force-generating pump. The Fontan circulation connects the systemic veins directly to the pulmonary circulation without an intervening pump and relies on the pressure within the systemic venous system to drive not only systemic venous return but also pulmonary blood flow. For these reasons, the ability to maintain CO and the ability to increase CO is tightly linked to preload and preload reserve much more so than contractility and heart rate (3,4).

SYSTEMIC VENOUS RETURN AND THE FONTAN PATHWAY

In the Fontan circulation, the impedance provided by the cavopulmonary connection and pulmonary arterial tree is the principal determinant of ventricular preload and in turn SV and CO (3,5). Guyton’s model of circulation provides a construct to understand the vascular factors that determine systemic venous return to the heart. In brief, the mean systemic pressure (Pms) is the upstream pressure that drives systemic venous return, in both the normal and the Fontan circulations. In the Fontan circulation, the Pms is the primary factor necessary to overcome the impedance of the Fontan circuit and drive pulmonary blood flow (5–7). The Pms is a function of blood volume and vascular capacitance, where the vast majority of each resides within the systemic venous reservoirs. As blood volume increases, and/or venous capacitance decreases (vasoconstriction), Pms increases. For these reasons, alterations in intravascular volume or venous capacitance may have a significant impact on systemic venous return, SV, and ultimately CO (6).

VENTRICULAR FUNCTION IN THE FONTAN CIRCULATION

Systolic and diastolic function of the univentricular heart appears to follow differing trajectories during staged palliation. Contractility acutely and remotely from the time of the Fontan operation is typically adequate if not normal (4). The primary ventricular abnormality is diastolic dysfunction (8). Fontan patients arrive at the third stage of palliation after having been initially exposed to a parallel circulation necessitating the univentricular heart to manage upwards of twice the volume load of a normal heart. This volume load leads to eccentric hypertrophy and an increase in ventricular capacitance. Staged procedures convert this parallel circulation to an in-series circulation to reap the benefits of volume unloading, increasing circulatory efficiency, and improved arterial oxygen saturation. At the time of the Glenn operation, the volume load on the ventricle is reduced to about 90% for body surface area (BSA) and is further reduced following the Fontan operation to 50–80% for BSA (8). The ventricular preload when indexed to ventricular size is approximately 25–70% following the Fontan procedure (9). These changes reflect a high-ventricular mass-to-volume ratio. This alteration in ventricular geometry increases ventricular stiffness (10,11). Diastolic function is further compromised due to impaired ventricular relaxation (3,10,11).

BRINGING IT ALL TOGETHER

Assimilation of previous work with the findings from the current study enables us to comprehend the impact of AVP in this unique circulation. In doing so, we gain insight into the potential role of AVP in the acute management of the Fontan circulation. AVP vasoconstricts arterial resistance and venous capacitance vessels. AVP does not impact contractility or heart rate and has been demonstrated to have an equivocal effect on PVR. An increase in SVR and in turn aortic pressure and ventricular afterload will cause the SV to decrease. Without a change in heart rate, the increase in systemic arterial pressure occurs at the expense of SV and CO. In this study, AVP caused a statistically significant decrease in PVR. One may question the clinical relevance of this finding because the change in magnitude was minimal and occurred from a normal baseline. However, given the unique characteristics of the Fontan circulation, a small change in PVR can lead to substantial changes in pulmonary blood flow and, in turn, end-diastolic volume (EDV) and SV. It appears that the afterload-induced decrease in SV was offset by a decrease in PVR and an increase in pulmonary blood flow and EDV, allowing for the preservation of SV (and thus CO). The systemic arterial pressure increased significantly without compromising the SV. The increase in common atrial pressure resulted from an increase in afterload and end systolic volume (ESV) coupled with the increase in pulmonary blood flow.

Figure 1A and B contains ventricular pressure–volume loops (PVLs) with superimposed elastance parameters generated by the Harvi cardiovascular simulator (PVLoops, LLC, New York, NY). These simulations provide a basis for interpreting the impact of AVP on the Fontan circulation and demonstrate that even small changes in pulmonary arterial impedance (in this case PVR) have a significant impact on systolic volume.

Figure 1.: The concepts of the ventricular pressure–volume relationship and the elastance model of the circulation are covered in detail elsewhere (12). In brief, the pressure–volume loops (PVLs) in A show the typical findings for the systemic ventricle of the Fontan circulation and a normal left ventricle (LV). Ventricular elastance (Ees), a load-insensitive indicator of ventricular contractility, is normal. Arterial elastance (Ea), a lumped parameter of systemic arterial impedance (systemic vascular resistance [SVR] is the primary determinant of Ea) is elevated at baseline (i.e., the slope of Ea is greater than for the normal circulation). The end-diastolic pressure–volume relationship (EDPVR), an index of ventricular stiffness (the inverse of compliance), is elevated as the EDPVR is shifted up and to the left (for a given diastolic volume, the ventricular pressure is elevated). The end-diastolic volume (EDV) and stroke volume (SV) (the width of PVL) are reduced. B, The impact of AVP. In this simulation, the baseline hemodynamic parameters from the study (“Fontan baseline”) were created by taking a biventricular circulation eliminating right ventricle Ees, and adjusting SVR, PVR, and LV Ees to align with baseline hemodynamic parameters. The resulting ventricular ejection fraction was 54%. In addition, the stressed blood volume (SBV) and ventricular stiffness were increased. The arterial blood pressure, Fontan pressure, common atrial pressure, transpulmonary pressure gradient, and cardiac output (CO) were nearly identical. Subsequently, PVR and SVR were adjusted to match the study findings while on AVP. Heart rate and contractility remained the same. With these changes alone; however, the CO and systemic arterial blood pressure were ~5–10% less than baseline. With an increase in the SBV by ~5% (AVP-induced vasoconstriction of the venous capacitance vessels), nearly identical parameters are generated. Of note, an increase in the SBV and, in turn, Pms increases the central venous pressure (Fontan pressure) by 1 mm Hg, which was not demonstrated in the study. The PVLs illustrate the increase in end systolic volume (ESV), an unchanged SV, and a significant increase in arterial blood pressure. The EDV and end-diastolic pressure have increased, reflecting an increase in the operating stiffness of the ventricle (the EDPVR is unchanged). The increase in EDV is due to the increase in ESV and increase in pulmonary blood flow, the latter resulting from the increase in SBV and decrease in PVR. The ejection fraction has decreased from 54 to 49% because of further uncoupling of the systemic ventricle from the systemic arterial circulation (i.e., Ea/Ees has increased further).

The current investigation complements preceding studies and provides an opportunity to enhance our clinical practice when managing this unique circulation. These findings also highlight the importance of considering the effects of the vasoactive agent on every aspect of the circulation, the hemodynamic substrate, and the goal of therapy on clinically discernable endpoints such as ventricular filling pressure, systemic arterial pressure, and CO.

REFERENCES 1. Kagan A: Dynamic responses of the right ventricle following extensive damage by cauterization. Circulation. 1952; 5:816–823 2. Adamson GT, Yu J, Ramamoorthy C, et al.: Acute Hemodynamics in the Fontan Circulation: Open Label Study of Vasopressin. Pediatr Crit Care Med. 2023; 24:952–960 3. Gewillig M, Brown SC, Eyskens B, et al.: The Fontan circulation: Who controls cardiac output? Interact Cardiovasc Thorac Surg. 2010; 10:428–433 4. Senzaki H, Masutani S, Ishido H, et al.: Cardiac rest and reserve function in patients with Fontan circulation. J Am Coll Cardiol. 2006; 47:2528–2535 5. Sundareswaran KS, Pekkan K, Dasi LP, et al.: The total cavopulmonary connection resistance: A significant impact on single ventricle hemodynamics at rest and exercise. Am J Physiol Heart Circ Physiol. 2008; 295:H2427–H2435 6. Jolley M, Colan SD, Rhodes J, et al.: Fontan physiology revisited. Anesth Analg. 2015; 121:172–182 7. Bronicki RA, Nick GA: Cardiopulmonary interaction. Pediatr Crit Care Med. 2009; 10:313–322 8. Gewillig M, Brown SC: The Fontan circulation after 45 years: Update in physiology. Heart. 2016; 102:1081–1086 9. Gewillig M: The Fontan circulation. Heart. 2005; 91:839–846 10. Redington A: The physiology of the Fontan circulation. Prog Pediatr Cardiol. 2006; 22:179–186 11. Penny DJ, Lincoln C, Shore DF, et al.: The early response of the systemic ventricle during transition to the Fontan circulation—an acute hypertrophic cardiomyopathy? Cardiol Young. 1992; 2:78–84 12. Bronicki RA, Tume SC, Flores S, et al.: The cardiovascular system in severe sepsis: Insight from a cardiovascular simulator. Pediatr Crit Care Med. 2022; 23:464–472