Inhaled Milrinone via HFNC as a Postextubation Cardiopulmonary Elixir: Case Series and Review of Literature

Background

Pulmonary hypertension (PH) due to congenital heart disease (CHD) manifests either secondary to pulmonary vasculature remodeling consequent to increased pulmonary blood flow or postcapillary elevation of pulmonary venous pressure in left-sided obstructive lesions. Ventricular septal defect (VSD) is the most common underlying CHD (42%) predisposing to PH with risks of PH persisting even after surgical management of the defect.¹ Notably so, PH after surgically repaired CHD is associated with worse outcomes compared with other etiologies of PH.²

Moreover, the present day perioperative cardiac surgical challenges have only been intensified considering increasing number of patients presenting for surgical intervention post-coronavirus disease 2019 (COVID-19) infection because of its long-term ill effects and multiorgan involvement. In this context, COVID-19 infection may exacerbate and escalate PH secondary to CHD.³

Perioperative PH can peculiarly lead to a protracted intensive care unit (ICU) stay with enhanced morbidity and mortality owing to its perilous cardiopulmonary effects.² Therefore, the current strategies to treat PH focus on pharmacological agents that may unload right ventricle while maintaining systemic pressures as well as applying cardiopulmonary protective ventilatory approach.⁴

In this background, we report a series of six pediatric PH predisposed cardiac surgical cohort who were administered inhaled milrinone (iMil), a pulmonary vasodilator via high-frequency nasal cannula (HFNC) postextubation, with an aim to avert residual PH-associated cardiopulmonary repercussion, thereby expediting ICU recovery and discharge. Furthermore, the article reviews role of iMil, HFNC, and combination thereof in alleviating deleterious cardiopulmonary interactions in PH.

Case Series

Discussion

PH is a progressive disorder adversely affecting both cardiac and pulmonary systems, toiling weaning both from CPB as well as ventilator. Consequent to pulmonary vascular remodeling, proliferation, and occlusion, transpiring into right heart and eventual left heart dysfunction culminating into low cardiac output syndrome. It may persist postoperatively even after successful CHD repair.², ⁵, ⁶ Pulmonary vasculature remodeling along with enhanced pulmonary vasoreactivity, and endothelial injury due to CPB are likely contributors to persistent PH postoperatively.⁵ In addition, rebound PH due to negative feedback inhibition by iNO may also activate endogenous vasoconstrictors resulting in brief vasoconstriction. This may prolong mechanical ventilation, lengthen ICU stay, and enhance morbidity and mortality. In this background, typical therapy to treat PH should address the hemodynamic and ventilatory effects of the precarious cardiopulmonary liaison, with the aim to ensure smooth weaning from ventilator and eventual recovery. With this aim, we administered milrinone (a pulmonary vasodilator and inotrope that inhibits enzyme phosphodiesterase-3) via HFNC (continuously delivers continuous positive airway pressure [CPAP] with humidified oxygen at high flow rates), in the aforementioned cases immediately postextubation as to mitigate deleterious effects of residual PH as well as addressing the problem of rebound PH following iNO discontinuation.

With respect to aforesaid, Maggiore et al and Hernández et al in their respective studies highlight the role of preemptive postextubation high-flow oxygen therapy via HFNC in favorably modulating the postoperative oxygenation status and minimizing the reintubation rate, when compared with conventional oxygenation therapy.⁷, ⁸ HFNC by the virtue of providing heated and humidified gas at flow commensurate to peak flow rate generated by the patient reduces the work of breathing and fatigue, creates an oxygen reservoir in the upper airways thereby improving oxygenation and avoiding accumulation of carbon dioxide, preventing inspissation of secretions. It also splints open the airway and prevents collapse during exhalation as well thereby preventing atelectasis and acting like CPAP support. Apart from above physiological advantages, there is an increased comfort and compliance to the machine as compared with other noninvasive modes of oxygenation, and early introduction of oral feeds and medications.⁹

Of relevance to PH predisposed cohort, HFNC by avoiding positive pressure ventilation not only avoids pulmonary vessel compression but also circumvents hypoxic pulmonary vasoconstriction that decrescents right ventricular (RV) preload as well.¹⁰ Even from a strict cardiac perioperative perspective, Kumar et al very recently proposed role of HFNC in postoperative acyanotic CHD patients, where the authors reported improvement in postextubation partial pressure of oxygen/fraction of inspired oxygen concentration (PaO₂/FiO₂).¹¹ While our patients were postoperative adult CHD patient akin to the Kumar et al study,¹¹ the additional attributes such as a previous history of COVID-19 infection, collapsed lung lobe, intraoperative PH crisis, and recent tapering of iNO, implied an accentuated risk in our setting.³

With reference to the role of pulmonary vasodilators, the literature bespeaks the advantages of inhaled therapy over intravenous with the former being pulmonary selective, ameliorates RV function better, improves oxygenation, and reduces inflammation while avoiding associated systemic side effects.¹² Literature is accruing describing additional benefits of iMil therapy in PH like attenuating CPB-induced inflammation and facilitating weaning from CPB, and improving pulmonary endothelial function. Laflamme et al found a reduction in rate of difficult separation from CPB to 51% in group receiving combined inhaled prostaglandin and iMil as compared with 70% (p = 0.1638) in the inhaled group. There was also a reduction in postoperative vasoactive requirement both at 12 hours (35.9 vs. 73.7%, p < 0.01) and 24 hours (25.6 vs. 57.9%, p < 0.05) postoperatively.¹³ Similarly, Haraldsson et al in their study on patients with postoperative PH found a reduction in pulmonary vascular resistance (PVR) by 20% (p < 0.001) in patients administered iMil as compared with inhaled prostacyclin, while the former accentuated the effect of latter in reducing the PVR and increasing stroke volume.¹⁴ Singh et al in their series of 35 children with acyanotic CHD,¹⁵ Patel et al in their study on 100 patients with mitral valve stenosis,¹⁶ Nguyen et al in their series of patients,¹⁷ and Sablotzki et al in 18 consecutive male heart transplant patients¹⁸ have posited the safety and efficacy of iMil in the management of PH and subsequent RV dysfunction. Lamarche et al in their porcine model have further demonstrated a decrease in heart rate and hence myocardial oxygen demand when iMil was administered to study CPB effects on pulmonary endothelium.¹⁹

As mentioned, PH is a syndrome whose treatment involves not only optimizing ventilation and oxygenation but also demands decongesting right ventricle for achieving adequate left ventricular function. Propounding the advantages of combination therapy of pulmonary vasodilator and HFNC, Tominaga et al successfully employed the delivery of iNO via HFNC for postoperative management in patients undergoing Fontan procedure.²⁰ The authors propose, iNO via HFNC may be indicated in other conditions with postoperative PH predisposition, for example, tetralogy of Fallot with pulmonary stenosis with major aortopulmonary collaterals. Li et al administered epoprostenol through HFNC in 11 subjects with PH and/or RV dysfunction and found improved PaO₂/FiO₂ ratio (07.5 ± 26.3 to 125.5 ± 31.6, p = 0.026).²¹

Hence with the motive to address both cardiac as well as pulmonary components, we aerosolized milrinone at a rate of 0.1 μg/kg/min based on a previous study²² through HFNC (using vibrating mesh nebulizer, Aerogen Solo, Aerogen Ltd., Ireland, which is considered not to interfere with the airflow and pressures in the circuit as well as deliver very fine particles beyond larger airways),²³ where in heated-humidified oxygen at slight PEEP, improves alveolar recruitment, oxygenation status, and lung compliance and avoids reintubation (Fig. 1).²⁰

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Fig. 1

(A) Assembly for administering inhaled milrinone (iMil) via high-frequency nasal cannula (HFNC). (B) Aerosolization of milrinone solution. (C) Calculation of dosage and volume of milrinone solution administered.

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Second, liberation from positive-pressure ventilation has resultant circulatory benefits from a specific context of an elevated afterload-induced RV dysfunction, pertinent to a setting of PH.²⁰, ²⁴ Third, the positive cardiopulmonary liaison only strengthens in the backdrop of a selective inhalational delivery of vasodilator therapy, curtailing the systemic hypotensive effects of intravenous vasodilator (Fig. 2).²⁰

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Fig. 2

The complementary action of inhaled milrinone (iMil) via high-frequency nasal cannula (HFNC) in alleviating after effects of postoperative pulmonary hypertension.

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To the best of authors' knowledge, this article presents a unique research endeavor combining iMil and HFNC therapy harnessing the benefits of both the therapies in management of the PH syndrome and its aftereffects. The article reprises the continued oxygenation, reduced work of breathing, RV unloading, and a simultaneous improved left ventricular function leading to smooth weaning from ventilator and recovery, as a result of administration of aerosolized milrinone through HFNC, a combination complementing each other's mechanism of action to treat PH. The article also adequately reiterates that COVID-19 superadded infection in patients already predisposed or suffering from PH, notoriously perpetuates PH by worsening lung parenchymal inflammation and injury,²⁵, ²⁶ and PA obstruction, as evident by cases 3 and 4 who were acyanotic CHD post-COVD-19 infection status and exhibited turbulent CPB as well as ventilator weaning requiring meticulous pulmonary vasodilator therapy as well as ventilation-sedation strategy. Here in the role of iMil as well as HFNC has adequately been elucidated in curbing COVID-19 detrimental effects on oxygenation and RV function.²⁷ Lastly, transnasal aerosol delivery is particularly preferable for small children in view of comfort and better tolerance.²⁸

Conclusion

The projection of prophylactic iMil administration via HFNC in PH predisposed cohort, as to ensure smooth recovery postextubation, in the above case series is remarkable enough to motivate the fraternity to explore the promises of a combination therapy of iMil and HFNC, as a postextubation cardiopulmonary elixir in peculiarly predisposed perioperative settings, in future large-scale research endeavors.