The restrictive, preload-sensitive right ventricle

Chronic pressure overload in unrepaired tetralogy of Fallot drives concentric right ventricular hypertrophy, interstitial fibrosis, and progressive increases in myocardial stiffness. This structural remodelling impairs active relaxation and reduces diastolic compliance, creating a restrictive physiologic phenotype. ^{Reference Hoffman and Hoffman7,Reference Jost, Connolly and Burkhart8,Reference Munkhammar, Carlsson, Arheden and Pesonen14,Reference Ganni, Yen Ho and Reddy15,Reference Heinisch, Laetitia and Damian31} Consequently, the right ventricle becomes highly preload-dependent and operates along the steep portion of its diastolic pressure–volume relationship, rendering cardiac output exquisitely sensitive to even modest changes in loading conditions. ^{Reference Ganni, Yen Ho and Reddy15,Reference García and Santos20,Reference Naeije and Badagliacca22}

Clinically, restrictive right ventricular physiology is characterised by impaired relaxation, elevated right ventricular end-diastolic pressures, and antegrade diastolic pulmonary flow. ^{32,Reference Van den Eynde, Derdeyn and Schuermans33} Although this restrictive pattern may limit post-operative right ventricular dilation, it does so at the cost of elevated systemic venous pressures, reduced preload reserve, and heightened sensitivity to afterload changes. Perioperatively, this substrate predisposes patients to low cardiac output syndrome and prolonged ventilatory support, especially if pulmonary vascular resistance remains elevated. Importantly, right ventricular diastolic dysfunction persists long after surgical repair. ^{Reference Van den Eynde, Derdeyn and Schuermans33–Reference Sachdev, Bhagyavathy, Varghese, Coelho and Kumar35}

Pulmonary maladaptation

The pulmonary vasculature in late-presenting tetralogy of Fallot is shaped by two key insults: chronically reduced pulmonary blood flow (anatomic) and prolonged hypoxaemia (cyanosis). Together, these factors result in a vasculature that is underdeveloped, structurally remodelled, and functionally hyperreactive.

• • Chronic Low Flow: Inherent right ventricular outflow tract obstruction limits pulmonary arterial flow, which may lead to vascular hypoplasia and reduced effective cross-sectional area of the pulmonary vascular bed.

• • Chronic Hypoxaemia: Cyanosis induces secondary erythrocytosis, increasing blood viscosity and impairing microcirculatory flow. ^{Reference Corno, Milano, Samaja, Tozzi and Von Segesser12} Concurrently, it promotes endothelial dysfunction, reducing nitric oxide bioavailability and increasing basal and reactive pulmonary vascular tone. ^{Reference Zabala and Guzzetta11}

Collectively, these processes produce a pulmonary vascular bed characterised by elevated and labile resistance.

Following surgical correction, the abrupt increase in pulmonary blood flow confronts a vasculature that is poorly adapted to higher flow states and prone to exaggerated vasoconstrictive responses. This mismatch markedly increases right ventricular afterload, placing the already compromised right ventricle at high risk of failure during the early post-operative period.

Systemic vascular dysfunction and microcirculatory impairment

Beyond the pulmonary circulation, chronic cyanosis exerts widespread systemic effects. ^{Reference Zabala and Guzzetta11,Reference Corno, Milano, Samaja, Tozzi and Von Segesser12,Reference Oechslin, Kiowski, Schindler, Bernheim, Julius and Brunner-La Rocca16} Endothelial dysfunction impairs vasoregulation and organ perfusion, while increased blood viscosity contributes to microcirculatory sludging and end-organ hypoxia. These systemic alterations further reduce physiologic reserve, heighten sensitivity to haemodynamic perturbations, and contribute to the overall fragility of the post-operative state.

The fragile post-operative state: impaired coupling and ventricular interdependence

The interaction between a hypertrophied, restrictive right ventricle and a dysfunctional pulmonary vascular bed creates a precarious post-operative state. Two closely interrelated phenomena are central to this vulnerability:

1. 1. Compromised Ventriculo-arterial Coupling: The pressure-loaded right ventricle operates with limited contractile and diastolic reserve. Its performance is poorly matched to a reactive pulmonary vasculature, resulting in inefficient right ventricular–PA coupling. In this setting, even modest increases in pulmonary vascular resistance or decreases in right ventricular compliance can precipitate disproportionate declines in forward flow and cardiac output. ^{Reference Redington, Penny, Rigby and Hayes36}

2. 2. Ventricular Interdependence: Elevated right ventricular pressures and impaired right ventricular compliance adversely affect right ventricular performance. Right ventricular dilation or septal shift can distort LV geometry, impair diastolic filling, and reduce systemic output, further limiting cardiovascular reserve in the early post-operative period. ^{Reference Naeije and Badagliacca22,Reference Santamore and Dell’Italia37}

The burden of aortopulmonary collaterals

Aortopulmonary collateral arteries are prevalent in older cyanotic children and introduce distinct perioperative challenges. ^{Reference Fang, Xiong and Wang18,Reference Edraki, Naghshzan, Amoozgar, Keshavarz, Mehdizadegan and Mohammadi19} While they may augment pulmonary blood flow pre-operatively, collaterals impose a significant volume load on the left heart, increase pulmonary venous return, and complicate intraoperative haemostasis and post-operative fluid management. Following repair, the abrupt increase in pulmonary blood flow through both the reconstructed right ventricular outflow tract and persistent collaterals can overwhelm the non-compliant right ventricle, precipitating acute haemodynamic instability if loading conditions are not meticulously controlled.

Integrated right ventricular–pulmonary circulatory vulnerability

Taken together, a stiff hypertrophied right ventricle, a reactive pulmonary vascular bed, significant collateral burden, and adverse ventricular interdependence create a narrow physiologic window for maintaining adequate cardiac output. The right ventricular–pulmonary unit in late-presenting tetralogy of Fallot is functionally fragile and highly sensitive to perturbations in preload, afterload, and ventricular compliance. This integrated pathophysiologic state provides the foundational rationale for targeted inodilatory therapy, such as milrinone, which aims to simultaneously improve lusitropy, reduce pulmonary vascular resistance, and optimise ventriculo-arterial coupling during the high-risk post-operative period.

Targeting diastolic dysfunction: enhancement of right ventricular lusitropy

Augmentation of lusitropy is arguably milrinone’s most physiologically relevant effect in this setting. By increasing intracellular cyclic adenosine monophosphate, milrinone enhances phosphorylation of phospholamban, accelerates sarcoplasmic reticulum calcium reuptake via SERCA2a, and reduces diastolic calcium sensitivity, all of which promote earlier and more complete myocardial relaxation. ^{Reference Farah and Frangakis25} These cellular effects counteract the delayed relaxation and reduced compliance characteristic of the hypertrophied, fibrotic right ventricle in late tetralogy of Fallot. Clinically, improved lusitrophy translates into lower right ventricular filling pressures, improved early diastolic filling, and greater preload reserve, which are critical for maintaining forward flow in a preload-sensitive ventricle.

Reducing right ventricular afterload and improving right ventricular–PA arterial coupling

Milrinone reduces right ventricular afterload by promoting pulmonary vasodilation, addressing the elevated and labile pulmonary vascular resistance commonly present in delayed tetralogy of Fallot repair. Pulmonary vasodilation via phosphodiesterase-3 inhibition is largely independent of the nitric oxide pathway, which may be impaired in chronic cyanosis, a practical advantage in settings where inhaled nitric oxide is unavailable. ^{Reference Allbritton-King and García-Cardeña17,Reference Wessel38–Reference Bailey, Miller, Lu, Tosone, Kanter and Tam40}

By lowering pulmonary vascular impedance and improving ventricular relaxation, milrinone favourably shifts right ventricular–PA coupling towards a more efficient operating point. ^{Reference García and Santos20,Reference Kozlik-Feldmann, Hansmann, Bonnet, Schranz, Apitz and Michel-Behnke41} The combined effect enhances stroke volume at a lower metabolic cost, which is critical for the stiff, pressure-loaded right ventricle in the early post-operative period.

Inotropic support and arrhythmogenic potential

Milrinone provides mild inotropic support via improved intracellular calcium handling without β-adrenergic stimulation. ^{Reference Bailey, Miller, Lu, Tosone, Kanter and Tam40} This mechanism avoids the pronounced tachycardia and increased myocardial oxygen demand associated with catecholamines. However, milrinone is not without electrophysiologic effects; phosphodiesterase inhibition may predispose to arrhythmias, ^{Reference King, Thompson and Foote42,Reference Öztürk, Kafalı and Tanıdır43} particularly in the presence of electrolyte imbalance, atrial dilation, or surgical scarring. Some observational data suggest an association between post-operative milrinone use and increased tachyarrhythmia risk in congenital heart surgery cohorts, although causality is difficult to establish and many confounders exist. ^{Reference Burkhardt, Hummel, Rücker and Stiller27,Reference Saengsin, Sperotto and Lu28} However, in the specific context of late tetralogy of Fallot—where the substrate is dominated by diastolic dysfunction, elevated afterload, and catecholamine sensitivity—the net electrophysiologic profile of milrinone may still be favourable compared to pure β-agonists. Careful monitoring and maintenance of normal electrolyte concentrations remain essential.

Potential effects on microcirculatory and endothelial dysfunction

Beyond its macrohaemodynamic actions, milrinone may influence endothelial and microcirculatory function. Experimental and clinical evidence in other paediatric contexts suggests that phosphodiesterase-3 inhibition can preserve microvascular perfusion, maintain capillary density, and mitigate endothelial glycocalyx degradation, potentially facilitating tissue oxygen delivery and capillary recruitment. ^{Reference Sarta-Mantilla, Fernández-Sarmiento and Acevedo44} While direct evidence in late tetralogy of Fallot is limited, these effects are physiologically plausible and may be particularly relevant in erythrocytotic children, in whom increased blood viscosity and microcirculatory sluggishness contribute to post-operative organ dysfunction.

Potential influence on post-operative effusions

While no studies have directly evaluated milrinone’s effect on post-operative effusions, its capacity to reduce pulmonary vascular resistance and improve right ventricular diastolic function may lower right-sided filling pressures and systemic venous congestion, providing a plausible mechanistic link to altered pleural fluid formation and clearance. This potential effect remains speculative and warrants focused investigation. ^{Reference Gagliardi, Ceccherelli, Lovato and Gagliardi45}

Pharmacokinetic considerations in older cyanotic children

Children undergoing late tetralogy of Fallot repair exhibit altered pharmacokinetics due to polycythaemia, expanded plasma volume, chronic hypoxaemia, and variable renal perfusion, all of which influence milrinone clearance and volume of distribution. ^{Reference Bailey, Miller, Lu, Tosone, Kanter and Tam40,Reference Bailey, Hoffman and Wessel46} Dosing paradigms derived from infant cohorts may be unreliable in this population, and comorbid renal dysfunction may further prolong drug elimination. Consequently, milrinone exposure is often unpredictable, reinforcing the importance of careful clinical titration guided by perfusion indices, lactate trends, and serial echocardiography rather than fixed dosing alone.

Evidence from landmark trials and heterogeneous cohorts

The haemodynamic rationale for phosphodiesterase-3 inhibition in paediatric cardiac surgery was established through early physiologic studies conducted before the availability of randomised outcome trials. ^{Reference Hammett and Griksaitis47} Seminal investigations by Wernovsky, Chang, and colleagues demonstrated that milrinone increases cardiac output while reducing systemic and pulmonary vascular resistance, without a proportional rise in myocardial oxygen consumption or significant tachycardia in children following cardiopulmonary bypass. These studies highlighted the importance of enhancing lusitropy and reducing afterload in the post-operative congenital heart population and provided the mechanistic foundation for subsequent clinical trials.

The most influential clinical evidence supporting milrinone use derives from the landmark PRIMACORP trial, a multicentre, randomised, placebo-controlled study evaluating prophylactic milrinone after paediatric congenital heart surgery. ^{Reference Hoffman, Wemovsky and Atz29,Reference Hoffman, Wernovsky and Atz48} PRIMACORP demonstrated a significant reduction in the incidence of low cardiac output syndrome and shorter ICU stay in patients receiving milrinone compared with placebo. However, the trial population consisted predominantly of infants with mixed cardiac diagnoses, with minimal representation of older, cyanotic children or patients with chronically pressure-loaded right ventricles.

Following PRIMACORP, multiple observational studies and single-centre series evaluated milrinone in heterogeneous paediatric cardiac surgery cohorts, generally reporting associations with improved cardiac index, reduced catecholamine requirements, and shorter ICU duration. ^{Reference Burkhardt, Hummel, Rücker and Stiller27,Reference Cavigelli-Brunner, Hug and Dave30,Reference Feneck, Sherry, Withington and Oduro-Dominah49,Reference Bailey, Miller, Lu, Tosone, Kanter and Tam50} Subsequent systematic reviews and network meta-analyses have confirmed that milrinone reduces the incidence of low cardiac output syndrome compared with placebo or no inotrope, although effects on mortality remain inconsistent and highly context-dependent. ^{Reference Burkhardt, Hummel, Rücker and Stiller27,Reference Lechner, Hofer and Leitner-Peneder51} Collectively, these data support milrinone’s physiologic efficacy in paediatric cardiac surgery but offer limited insight into its effectiveness in specific lesion phenotypes such as late-presenting tetralogy of Fallot.

Lesion-specific evidence, current gaps, and evolving efficacy debate

Robust, lesion-specific evidence for milrinone in repaired tetralogy of Fallot is scarce. Existing data are largely derived from small observational series, retrospective analyses, and subgroup analyses. ^{Reference Hammett and Griksaitis47,Reference Gatzoulis, Clark, Cullen, Newman and Redington52,Reference Therrien, Marx and Gatzoulis53} These reports suggest potential benefits, including improved right ventricular diastolic indices, reduced filling pressures, and earlier extubation, particularly in patients with elevated pulmonary vascular resistance or significant restrictive physiology. Importantly, no randomised controlled trials have been designed specifically to evaluate milrinone in older children undergoing late tetralogy of Fallot repair, representing a critical evidence gap.

The limitations of existing evidence are most consequential in low- and middle-income countries, where delayed tetralogy of Fallot repair remains common and post-operative physiology differs substantially from early-repair cohorts in high-income settings. ^{Reference Jivanji, Qureshi, Reel and Lubega4,Reference Zimmerman and Sable6} In these environments, milrinone is frequently adopted based on biologic plausibility, extrapolation from global practice norms, and the absence of alternative pulmonary vasodilators such as inhaled nitric oxide. Recent analyses have associated milrinone use with increased fluid requirements, higher catecholamine exposure, and a lack of clear mortality benefit in broader paediatric cardiac surgery populations. ^{Reference Burkhardt, Hummel, Rücker and Stiller27,Reference Saengsin, Sperotto and Lu28} While hypotension is a well-recognised adverse effect, data on arrhythmogenicity are inconsistent and appear context-dependent. ^{Reference Smith, Owen, Borgman, Fish and Kannankeril26–Reference Saengsin, Sperotto and Lu28,Reference Karamlou, Silber and Lao54} This debate underscores that milrinone’s effects, both beneficial and adverse, are likely mediated by underlying physiology.

Summary of the evidence landscape

In summary, the evidence supporting milrinone in late tetralogy of Fallot repair is indirect and derived from physiologically distinct populations (Figure 2). While its pharmacologic profile is mechanistically attractive, high-quality, lesion-specific data are absent. This evidence gap is most acutely felt in clinical environments where the burden of late repair is high, and therapeutic decisions must balance physiologic rationale against uncertain comparative effectiveness.

Figure 2.

The milrinone evidence landscape in repaired tetralogy of Fallot (TOF): existing data and critical gaps. The schematic illustrates a hierarchy of evidence supporting the use of milrinone after congenital heart surgery. The broad upper tier represents robust data from landmark randomised controlled trials (e.g., PRIMACORP) conducted in heterogeneous paediatric cardiac surgery populations, predominantly infants. The intermediate tier reflects limited observational data from CHD cohorts that include some TOF patients, often across mixed age groups. The narrow lower tier highlights the critical evidence gap: the absence of dedicated, high-quality studies focusing specifically on older, cyanotic children undergoing late TOF repair—particularly in low- and middle-income country (LMIC) settings, where delayed presentation is common and post-operative physiology differs fundamentally from early-repair cohorts. This gap underscores the need for future pragmatic, lesion-specific research to define optimal therapeutic use. RCT = randomised controlled trial.