Inhaled pulmonary vasodilators in pulmonary hypertension: Perioperative use and clinical considerations

Abstract

Pulmonary hypertension (PH) is a hemodynamic and pathophysiologic condition associated with increased perioperative morbidity and mortality, particularly in patients undergoing cardiac or high-risk non-cardiac surgery. Inhaled pulmonary vasodilators (iPVs) offer a targeted strategy to reduce pulmonary vascular resistance (PVR) and improve right ventricular (RV) function while minimizing systemic hypotension. Traditional vasodilators such as nitroglycerin and sodium nitroprusside lack pulmonary specificity and can exacerbate systemic hypotension. Inhaled agents including nitric oxide (NO), epoprostenol (iEPO), iloprost, milrinone (iMIL) and levosimendan provide selective pulmonary vasodilation with more favorable hemodynamic profiles. This narrative review summarizes current evidence and clinical considerations for the use of iPVs in the perioperative management of PH and discusses pharmacokinetics, delivery mechanisms, adverse effects, and logistical considerations for these agents. New emerging PH therapies are included based on early clinical trial data as they have the potential to impact perioperative care in the future.

Overall, iPVs represent a valuable tool in the perioperative care of patients with PH. Continued research is needed to refine clinical protocols, evaluate emerging agents, and establish outcome-based evidence for their routine use.

Introduction

Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure (mPAP) > 20 mmHg at rest as measured by right heart catheterization.¹ It is estimated that PH affects approximately 1% of the general population; however, its prevalence can be significantly higher in certain subgroups.² The most common causes of PH are left-heart disease and chronic obstructive pulmonary disease. Although echocardiography may suggest PH, right heart catheterization remains the diagnostic gold standard and is required for hemodynamic classification, which includes the following four groups; pre-capillary PH, isolated post-capillary PH, combined pre- and post-capillary PH (CpcPH), and exercise PH.1, 3

The 7th World Symposium on Pulmonary Hypertension (WSPH) in 2024 maintained previous PH clinical classification into five different groups:1. Pulmonary Arterial Hypertension, 2. PH associated with left heart disease, 3. PH associated with lung disease/hypoxia, 4. PH associated with pulmonary arterial obstructions, and 5. PH of unclear or multifactorial mechanisms.¹

This narrative review outlines perioperative pathophysiology and risk of adult patients with PH, followed by a comparative discussion of established inhaled pulmonary vasodilators (iPV), practical perioperative considerations, and future directions. Relevant literature was identified through review of PubMed and major cardiothoracic, anesthesiology, pulmonary, and critical care journals, emphasizing cardiac surgery, high-risk non-cardiac surgery, transplantation, and ICU populations. Evidence from randomized controlled trials, observational studies, and high-quality reviews was prioritized. Given the heterogeneity of patient populations, study designs, and endpoints, formal systematic review or meta-analysis was not performed.

Preoperative pathophysiology and risk in pulmonary hypertension

In 2022, a task force from the International Society for Heart & Lung Transplantation published a perioperative management of patients with PH and right heart failure consensus statement. In 2023, the American Heart Association published a scientific statement on the evaluation and management of PH in noncardiac surgery. Both statements advocate for a process that includes the classification of PH to define the etiology, preoperative risk assessment, PH optimization prior to surgery, intraoperative management to avoid right ventricular (RV) dysfunction, and postoperative management of PH.4, 5 A multidisciplinary discussion engaging anesthesiologists, surgeons, cardiologists, and pulmonary medicine specialists to review the risks and benefits of the procedure is necessary given that even low risk procedures in PH patients have an increased risk of major adverse cardiac events.⁶

As such, early detection of RV dysfunction in PH is crucial for risk stratification and management. Attempts should be made to optimize RV function and lower pulmonary vascular resistance (PVR) prior to the surgical procedure.⁴ Adjustments to diuretics and/or other PH evidence-based medicine may take several weeks to take effect, and surgery may need to be postponed. High-risk PH patients should be referred to a center that specializes in PH and ideally has access to resources including extracorporeal membrane oxygenation and iPVs. Additional consideration should be given to patients who present for preoperative assessment with signs and symptoms suggestive of PH (syncope, chest pain, exertional or resting dyspnea) that are not explained by any current diagnosis. These patients warrant a thorough PH evaluation prior to their surgical procedure.⁴

Patients with PH are vulnerable to multiple perioperative physiologic insults including decreased mean arterial pressure, increased pulmonary artery pressure, direct myocardial depression, and vasodilation. This creates a milieu which can cause myocardial strain, and ischemia and culminate in worsening RV failure. Further, some surgical techniques can cause strain on the cardiopulmonary system and should be considered preoperatively. Abdominal and thoracic laparoscopic and robotic techniques require adequate insufflation with carbon dioxide (CO₂) to optimize surgical visualization and tissue manipulation. Abdominal insufflation comes with known physiologic changes that affect hemodynamics including decreased venous return, hypotension, decreased vital capacity, increased peak airway pressures, decreased ventilation with resultant ventilation-perfusion mismatch. The permeability of CO₂ into the tissue causes hypercarbia, increased risk of acidosis, increased PVR, and decreased systemic vascular tone.⁷

PH crisis is a feared complication in the perioperative period. It is characterized by acute RV failure, systemic hypotension, myocardial ischemia, and a spiral of events leading to cardiovascular collapse. Treatment is aimed at reducing PVR using iPVs, augmenting RV contractility with inotropes, decongesting with diuretics, and maintaining coronary perfusion pressure using vasopressors.⁵

History of inhaled pulmonary vasodilators

Pulmonary vasodilators are the primary pharmacologic treatment for acute perioperative PH.⁸ Intravenous (IV) vasodilators such as nitroglycerin and sodium nitroprusside, or IV phosphodiesterase-3-inhibitors were historically used to manage perioperative PH and RV failure. These agents lack specificity for pulmonary circulation, resulting in systemic hypotension as a notable side effect.⁹ Hypotension-mediated reductions in coronary perfusion further exacerbate the cycle of myocardial ischemia and RV failure. These limitations prompted interest in selective pulmonary vasodilators.¹⁰

John Vane and colleagues were the first to study prostacyclin analogs in the 1970s. The discovery of their vasodilatory, anti-thrombotic, and anti-proliferative effects won the Nobel Prize in 1982.¹¹ The Food and Drug Administration (FDA) approved epoprostenol as the first prostacyclin for PH treatment in 1995.¹²

In 1987, nitric oxide’s ability to relax vascular smooth muscle was discovered.¹³ Inhaled nitric oxide (NO) was subsequently approved by the FDA in 1999 for the treatment of neonates with hypoxic respiratory failure and persistent pulmonary hypertension. While NO is frequently used in the adult population, its use in adults remains off label in the United States.¹⁴ In 2010, Price and colleagues described that iPVs improve RV function following cardiac surgery and have a superior safety profile compared to intravenous vasodilators.¹⁵ Selective iPVs have since become the standard of care to treat perioperative PH and RV dysfunction in cardiac surgery.¹⁰

Table 1.

Summary of key studies of iPVs

Study	Design	Population	Interventions	Primary Outcome	Key Findings
Bhorade et al., 199916	Prospective interventional cohort	Acute right heart syndrome	NO 10 ppm titrated to 80 ppm (n=26)	Response defined as >20% increase in CO and/or decrease in PVR	14 patients responded to NO Responders had significant improvements in CO, SV, and PVR Mean dose for response was 35 ppm
Ardehali et al., 200117	Prospective case series with historical control cohort	Heart transplant recipients with MPAP >25 mmHg	NO 20 ppm (n= 16)	Differences in hemodynamic parameters	Significant reduction in RAP, PVR, RV SWI at 6 h with NO
Gerlach et al., 200318	Randomized, single-arm	ARDS	NO 10 ppm (n=20)	Change in oxygenation	Significant reduction in PaO2/FiO2 with NO in day 0. Not sustained in days 1–5 Reduction in ECMO cannulation (1/20 v 6/20 p=0.045) Sensitization to NO occurred within 96 h
Fernandes et al., 201119	Randomized, controlled	Mitral stenosis with SPAP >60 mmHg undergoing valve surgery	NO 10 ppm (n=14)	Difference in change in CI and PVR in 48 h	Significant difference in improvement in CI with NO (p<0.0001) Significant difference in reduction in PVR with NO (p=0.005)
Solina et al., 200120	Randomized, controlled	Adult cardiac surgery patients with PVR >125 dynes/sec/cm5	NO 10 ppm (n=11), NO 20 ppm (n=12), NO 30 ppm (n=12), NO 40 ppm (n=12)	Change in PVR	No significant difference in PVR reduction among NO groups HR and CI significantly higher post-CPB in control (milrinone) group
Khan et al., 200921	Randomized, cross-over	Heart and lung transplant with MPAP >25 mmHg or CVP >12 mmHg with CI <2.2 L/min/m2	NO 20 ppm (n=14)	Change in hemodynamics	Significant reduction in PAP, CVP and increase in CI in both groups No significant difference between groups
McGinn et al., 201522	Retrospective, observational, historical-control cohort	Cardiac surgery with MPAP ≥30 mmHg	NO 40 ppm (n=49)	Reduction of MPAP to <30 mmHg	No difference in MPAP, ICU or hospital LOS, duration of mechanical ventilation between NO and iEPO groups; Cost savings with iEPO
Ghadimi et al., 202323	Randomized, double-blind	Heart transplant and LVAD recipients	NO 20 ppm (n=116)	Composite rate of RVF	No difference in RVF rate, MV, ICU or hospital LOS No significant difference in hemodynamics between NO and iEPO groups
Meyer et al., 202624	Retrospective, cross-over	Cardiac surgery	NO 20 ppm transitioned to inhaled epoprostenol 50 mcg/kg/min (n=77)	Change in hemodynamics	No difference in MAP, MPAP, SPAP, CVP, and CO before and after transition Significant reductton in mixed venous and peripheral oxygenation after transition
Yurtseven et al., 200325	Prospective, single-arm	Mitral valve replacement surgery with PH	Nebulized NTG 2.5 mcg/kg/min (n=20)	Change in hemodynamics	Significant reduction in MPAP, PVR, intrapulmonary shunt fraction. No change in SVR, MAP, HR, CI
Mandal et al., 201026	Case control	Valve replacement surgery	Inhaled NTG 2.5 mcg/kg/min +/- dobutamine 10 mcg/kg/min (n=40)	Change in hemodynamics	Inhaled NTG reduced MPAP, PVR, PVR/SVR ratio without changing arterial pressure, SVR, or SvO2 IV NTG reduced both pulmonary and systemic parameters
Yurtseven et al., 200627	Randomized, controlled	Mitral valve surgery with MPAP >25 mmHg	Inhaled NTG 20 mcg/kg (n=50)	Change in MPAP and PVR	MPAP and PVR improved in both groups MPAP and PVR were significantly lower with iloprost
Hache et al., 200328	Randomized, double-blind	Cardiac surgery with SPAP >30 mmHg or MPAP >25 mmHg	Inhaled epoprostenol 60 mcg (n=10)	Change in hemodynamics	Significant reduction in SPAP and RV stroke work with epoprostenol versus placebo SPAP returned to baseline after 25 min No significant changes in MPAP and arterial pressures
De Wet et al., 200429	Prospective, single-arm	Cardiac surgery with MPAP ≥30 mmHg or SPAP ≥40 mmHg, CVP ≥16 mmHg and CI <2.2 L/min/m2, or PaO2/FiO2 <150 mmHg	Inhaled epoprostenol 160 mcg/h weaned to 20 mcg/h (n=126)	Change in hemodynamics	Significant reduction in MPAP No change in MAP and PaO2/FiO2 Significant reduction in PVR in PH cohort
Laflamme et al., 201530	Prospective, single-arm	Cardiac surgery with SPAP >30 mmHg or MPAP >25 mmHg	Inhaled epoprostenol 60 mcg and inhaled milrinone 5 mcg (n=41)	Change in hemodynamics	Significant reduction in CVP and MPAP with therapy Significant increase in HR, CI, MAP/MPAP with therapy
Elmi-Sarabi et al., 202331	Retrospective, cohort	Cardiac surgery with PH, RV dysfunction, or portal hypertension	Inhaled epoprostenol 60–70 mcg and inhaled milrinone 4–5 mg for 15 min (n=128)	Response to therapy based on change in MAP and MPAP	77.3% responders with ≥20% increase in MAP/MPAP ratio from baseline Responders more likely to have PH with higher MPAP and SPAP
Hu et al., 202032	Retrospective, cohort	Cardiac surgery under CPB	Milrinone 4 mg mixed with iloprost 20 mcg and delivered via nebulizer over 20 min at two timepoints (n=48)	Incidence of vasopressor used in OR or ICU; hemodynamic profile, cost	Use of any IV inotrope was lower in iPV cohort; lower ICU hours LOS in iPV cohort; no significant cost difference
Winterhalter et al., 200833	Randomized, controlled	Cardiac surgery with MPAP >25 mmHg	Iloprost 20 mcg over 4–6 min (n=23)	Change in hemodynamics	Significant reduction in MPAP and PVR after 30 min with both therapies Significant increase in CO at 30 min with both therapies Significantly greater change with iloprost versus NO
Denault et al., 201634	Randomized, double-blind, placebo-controlled	Cardiac surgery with MPAP >30 mmHg or SPAP >40 mmHg	Inhaled milrinone 5 mg (n=55)	Separation from CPB	No differences in separation from CPB difficulty Significant increase in CO and SV with inhaled milrinone
Cox et al., 202435	Prospective, single-arm, Phase 1 clinical trial	Stage D HFrEF	Nebulized milrinone 60 mcg TID (n=10)	Adverse events and pharmacokinetic profiles	Nebulized milrinone achieved goal serum concentrations without adverse events Significant increase in CI and pulmonary artery saturation
Nguyen et al., 202036	Randomized, controlled	Cardiac surgery	Nebulized milrinone via jet (n=6)	Change in hemodynamics	Significant reduction in MPAP and increase in MAP/MPAP with mesh delivery
Wang et al., 200937	Randomized, controlled	Mitral valve surgery with MPAP >25 mmHg	Inhaled milrinone 6 mg/h for 4 h	Change in hemodynamics	No difference in change in MPAP and PVR Significant reduction in MAP and SVR with IV
Kim et al., 201438	Randomized, double-blind, controlled	Mitral valve surgery with RVSP >50 mmHg	Inhaled milrinone 55 mcg/kg for 10 min (n=10)	Change in hemodynamics	Significant reduction in MPAP and PVR after milrinone Higher percent change in PVR and PVR/SVR ratio with inhaled Significant reduction in SVR with IV
Patel et al., 202139	Prospective, interventional	Mitral valve surgery with RVSP >50 mmHg	Inhaled milrinone 5 mg nebulized at two time points with total dose 120–180 mcg/kg (n=50)	Changes in hemodynamics	Significant reduction in PAP, CVP, PCWP; no systemic hypotension in iMIL group Significant increase in CI and decrease in PVR and MAP; in IV milrinone group
Jorairahmadi et al., 202240	Randomized, controlled, double-blind	Cardiac surgery	Nebulized milrinone 50–80 mcg/kg (n=16)	Change in hemodynamics	Significant increase in MAP and MAP/MPAP in nebulized versus IV Significant decrease in time to extubation, ICU LOS, hospital LOS in nebulized versus IV
Hegazy et al., 201041	Randomized, comparator	Cardiac surgery with SPAP >30 mmHg or MPAP >25 mmHg	Inhaled milrinone 50–80 mcg/kg for 5 min (n=46)	Change in hemodynamics	No significant difference in MAP, MPAP, SVR, or PVR
Theodoraki et al., 201742	Retrospective, cohort, comparator	Cardiac surgery with SPAP >55 mmHg or MPAP >25 mmHg	Inhaled milrinone 50 mcg/kg for 15 min (n=18)	Change in hemodynamics	Significant reduction in PVR and MPAP/MAP ratio Iloprost has prolonged effect compared to milrinone
Abdelbaser et al., 202143	Randomized, double-blind, controlled	Surgical pediatric CHD patients	Nebulized levosimendan 26 mcg/kg over 6 h every 6 h for 24 h (n=22)	Change in SPAP	No difference in SPAP Significantly higher HR and lower blood pressure with IV

NO nitric oxide; N/A not applicable; CO cardiac output; PVR pulmonary vascular resistance; SV stroke volume; HR heart rate; CI cardiac index; CPB cardiopulmonary bypass; RAP right atrial pressure; RV SWI right ventricular stroke work index; PAO2 arterial oxygen partial pressure; FiO2 fractional inspired oxygen; MPAP mean pulmonary arterial pressure; ARDS acute respiratory distress syndrome; ECMO extracorporeal membrane oxygenation; SPAP systolic pulmonary artery pressure; CVP central venous pressure; MAP mean arterial pressure; PH pulmonary hypertension; ICU intensive care unit; LOS length of stay; SVR systemic vascular resistance; SvO2 mixed venous oxygen saturation; NTG nitroglycerin; 6MWT 6 min walk test; PCWP pulmonary capillary wedge pressure; HFrEF heart failure with reduced ejection fraction; IV intravenous; CHD congenital heart disease; RVF right ventricular failure.

Table 2.

Summary of drug, pharmacokinetics, adverse effects, and delivery considerations for established iPVs

Drug	Dose and Pharmacokinetics	Adverse Effects and Toxicities	Considerations	Alternate Routes
Nitric Oxide Donors
Nitric Oxide	1–80 ppm continuously 10–20 s onset 30 s half-life	Methemoglobinemia, NO2 exposure	Expensive and cumbersome delivery system; risk of rebound PH with abrupt discontinuation	Bubble oxygenator via CPB circuit44
Nitroglycerin	2.5–5 mcg/kg/min over 10–30 min 3–5 min onset 1–4 min half-life	Headache	Not studied for prolonged durations; tachyphylaxis concern	IV PR SL TD TL
Prostacyclins
Epoprostenol	10–50 ng/kg/min continuously 30–60 s onset 1–2 min half-life	Cough, flushing, headache, jaw pain, nausea	Available as glycine-mannitol or more stable arginine-sucrose buffered solution; dosing based on ideal body weight; rebound pH with abrupt withdrawal	IV
Treprostinil	18–54 mcg QID (solution) 16–64 mcg QID (dry powder) 5–30 min time to peak 3–4 h half-life	Cough, flushing, headache, nausea, syncope, throat irritation	Proprietary delivery system	IV PO SQ
Iloprost	2.5–5 mcg 6–9 times/day (ambulatory); 5–25 mcg over 10–15 min (vasodilatory testing) 5-minute time to peak 7–8 min half-life	Cough, flushing, headache, hypotension, nausea, syncope, trismus	Proprietary delivery system for ambulatory use; not studied for prolonged durations in inpatients; extended half-life of pulmonary effects ∼21–25 min	IV
Inodilators
Milrinone	Variable dosing reported: 60 mg/4 mL via nebulization 3 times daily for 48 h; 5 mg (50–80 µg·kg−1) in 5 mL diluent; 4–5 mg milrinone with iEPO; 10 min time to peak 30 min duration of action Pharmacokinetics vary based on delivery mechanism	Cough, headache, shortness of breath, throat irritations, wheezing	No concern for arrhythmias with nebulization; administered via jet nebulizer attached to the inspiratory limb of the ventilator	IV
Levosimendan	36mcg/kg for 6 h Unknown pharmacokinetics of inhaled drug	Dizziness, headache, nausea	Does not increase myocardial oxygen consumption	IV

IV intravenous; PR per rectum; SL sublingual; TD transdermal; TL translingual; PO by mouth; SQ subcutaneous; QID four times daily.

Inhaled vasodilator overview

Inhaled nitric oxide donors

Nitric oxide

NO is an endogenously synthesized gas that activates soluble guanylate cyclase to increase cyclic guanosine monophosphate (cGMP) levels, resulting in vascular smooth muscle relaxation. Additionally, NO exhibits antiplatelet, anti-inflammatory, and pro-angiogenic activity.⁴⁵ The dose of NO in studies ranges from 1 to 80 ppm, although data suggest hemodynamic and clinical response plateau at 20 ppm.9, 18, 20 Due to its short half-life, NO exerts minimal systemic effects and thus does not result in hypotension. NO is effective at reducing PVR to reduce RV afterload and improve RV function with minimal clinical toxicities.⁴⁶

Nitroglycerin

Nitroglycerin is metabolized to nitric oxide within smooth muscle cells, acting in the same pathway as exogenous NO to vasodilate. During administration, inhaled nitroglycerin decreases PVR and mPAP without affecting other hemodynamic parameters.9, 26 The improvement in hemodynamic effects persists for less than 1 h from therapy cessation. Thus, inhaled nitroglycerin must be administered continuously or with high frequency to be effective for a prolonged duration. Due to concerns about tachyphylaxis, it is not commonly used for prolonged periods.⁹

Prostacyclins

Inhaled prostacyclin therapy

Prostacyclin is an endogenous prostaglandin produced by arachidonic acid in the vascular endothelium that increases cyclic adenosine monophosphate (cAMP) levels. The downstream effect of this cell signaling is vasodilation, as well as platelet aggregation inhibition. As a class of medications, prostacyclins most commonly cause hypotension, flushing, jaw pain, headache, nausea, and diarrhea. However, when aerosolized, prostacyclins provide selective therapy to the pulmonary vascular beds, thereby reducing associated systemic adverse effects and preventing pulmonary shunting.⁴⁷

Epoprostenol

Traditionally used as an IV vasodilator, epoprostenol is synthetic prostacyclin that can be administered as a solution for inhalation via a syringe nebulization system. Epoprostenol is available in two different buffered solutions, glycine with mannitol (GM) and arginine with sucrose (AS). Epoprostenol GM is pH-sensitive and thermo-sensitive, limiting stability to 8 h at room temperature. Alternatively, epoprostenol AS is both pH- and thermo-stable, and thus can be reconstituted with sterile water, and syringes are stable for up to 48 h at room temperature.⁴⁸ Epoprostenol must be administered continuously to maintain therapeutic doses.⁴⁶ Clinical outcomes data for iEPO have shown decreased PVR and mPAP. Like NO, iEPO therapy carries the risk of hemodynamic deterioration upon withdrawal of medication.⁴⁷

Treprostinil

Treprostinil, a prostacyclin analog, is available as both a nebulization solution and a dry powder inhaler, both of which require proprietary inhalation devices. Compared to epoprostenol, treprostinil is more stable at room temperature and has a longer half-life.⁴⁹ In addition to common side effects of prostacyclins, inhaled treprostinil has a higher incidence of cough, wheezing, throat irritation, and syncope compared to placebo,⁴⁷ although cough and headache may be attenuated with long-term use.⁵⁰ Due to its specific mechanism of delivery, inhaled treprostinil use is reserved for the ambulatory setting⁴⁷ and may not have a place in the perioperative theater.

Iloprost

Iloprost is primarily used as an inhalation solution. Clinically, inhaled iloprost decreases PVR and mPAP while increasing CO without impacting systemic vascular resistance.47, 51 Compared to NO when used in PH patients following cardiac surgery, iloprost administration resulted in more significant reductions in PVR and mPAP and greater increase in CO.³³

Inodilators

Milrinone

Milrinone, a phosphodiesterase-3 inhibitor, enhances cAMP, leading to pulmonary vasodilation and improved right ventricular function.⁸ A comparison of inhaled (nebulized) milrirone (iMIL) versus intravenous milrinone in a trial of patients with PH undergoing open-cardiac surgery revealed favorable hemodynamics (higher mean arterial pressure [MAP], lower mPAP, and higher MAP/mPAP ratio) and less use of vasopressor in the inhalation group.⁴⁰ iMIL is a selective pulmonary vasodilator associated with decreases in inflammatory cytokines and pulmonary hypertension biomarkers (mPAP, PVR index, and PCWP) while maintaining mean systemic blood pressure, and improving CO and indices of RV function. Delivery is described as either tracheal bolus, jet nebulization, or mess net nebulization, with the latter technique associated with higher plasma concentrations.⁸

Levosimendan

Levosimendan, a calcium channel sensitizer, can be administered by inhalation technique. In a randomized, controlled trial of 50 pediatric patients with PH undergoing cardiopulmonary bypass surgery, four nebulized doses of 36 mcg/kg over 6 h were found noninferior to intravenous administration with favorable heart rate and blood pressure response and decreased need for vasoactive blood pressure support.⁴³ Of note, the increased cardiac contractility caused by the binding of calcium to troponin C is balanced by vascular smooth muscle relaxation from potassium-ATP channel activation, thus providing improved CO without increasing myocardial oxygen demands. The inhalation preparation has the added benefit of systemic vascular resistance and MAP maintenance.⁵²

Combined therapy

Utilizing a combination of iPVs acting on distinct signaling pathways may produce synergistic pulmonary vasodilation without systemic effects.⁵³ Previous systematic reviews of iPVs in cardiac surgery have demonstrated benefits of decreased length of ICU stay, mechanical ventilation and hospital mortality, however the use of combined inhaled therapies were excluded.54, 55

At the time of this writing, a recent scoping review revealed that the combination iPV therapy reported in the literature includes NO or iMIL combined with prostacyclin analogues. Of 23 studies reviewed by Soto, et al.,18 reported a positive hemodynamic effect; decreased pulmonary pressure and improved right ventricular function. Additionally, decreases in intraoperative and postoperative inotropic and/or vasopressor agents were observed.⁵⁶ Dual administration of NO and iEPO have shown improved hemodynamics and right ventricular function without clear improvements in ICU length of stay or mortality. NO and iloprost have been used in combination during LVAD implantation with a reduction in the need for RVAD placement.¹² Of note, a recent retrospective cohort review of 128 patients with PH or RV dysfunction undergoing on-pump cardiopulmonary bypass (CPB) surgery reported 77% of the patients had a favorable hemodynamic response (% change MAP/MPAP ratio ≥20%) to combined iMIL and iEPO administered pre-CPB. Patients with PH were more likely to be responders with the highest probability noted in the moderate to severe PH group. Using the European system for cardiac operative risk evaluation (EuroSCORE II), a validated predictive mortality risk model for cardiac surgery patients, the authors found that a EuroSCORE II > 6.5% was a predictor of non-response in this study.³¹

iPVs should be used with caution in patients with PH due to left heart or pulmonary venous occlusive disease. The iPV-induced reduction in PVR yields passive transmission of elevated left-sided filling pressures backward into the pulmonary circulation, thereby causing pulmonary edema. The improved RV CO can lead to left ventricular volume overload and potentially worse left ventricular function.4, 10 Alternatively, Elmi-Sarabi et al. (2023) suggest that the positive inotropic effects of iMIL in combination with another iPV may mitigate the deleterious effects of isolated NO or iEPO in that patient population.³¹ In addition to a preferred hemodynamic profile, benefits of combined iPVs in cardiac surgery may include decreased IV inotrope use and decreased ICU LOS,³² though more studies are needed.

Practical considerations in the perioperative setting

Outpatient treatment of PH can include a variety of pharmacological interventions. In the perioperative period, there may be limited access to continue the outpatient regimen depending on NPO status and enteral access during the case. iPVs have the advantage of being deliverable in the perioperative period with no enteral access. Practical considerations of iPV can include mode of delivery, cost, availability, side effect profile, and weaning strategy.

Mode of delivery

Mode of delivery is a consideration in the perioperative period. Given that different iPVs have differing delivery devices, care must be taken to ensure the drug is administered to the patient without interruption. Typically, NO is delivered as a compressed mixture with nitrogen gas via the inhalational route which requires a special delivery system for continuous administration. Particular care should be taken during patient transportation that the delivery device is functioning and not under or over delivering the iPV being prescribed.

Inhaled prostacyclins may be administered using a syringe pump connected to a nebulizer spliced into the inspiratory limb of the breathing circuit. They can be connected to an anesthesia machine or an ICU ventilator. Potential disadvantages include difficulty with continuous drug nebulization during transport, inadvertent delivery of medication bolus from accidental tipping of the nebulizer, requirement of high-flow oxygen for jet nebulizers, risk of ventilator valve immobilization if glycine is used as buffering agent, difficulty measuring drug loss between the nebulizer and alveoli, and possible incompatibility of nebulization with volatile anesthetics and CO₂ gas analyzers.9, 10

Cost

Different iPVs have different cost profiles associated with their clinical use. Rao et al. (2018) discussed the cost profiles of various iPV and condensed the information to the cost per hour for a 70 kg patient. Their work described NO is the most expensive iPV at $220 per hour of use which does not vary based on the dosing of up to 80 ppm. iEPO’s cost per hour varies between the two formulations with Flolan costing between $2.01 and $10.05 based on the dose and Veletri costing between $1.30 and $6.52. Cost is dependent on numerous factors and must be considered at the institutional level in most cases. In a 2023 study of advanced heart failure patients undergoing major cardiac surgery, iEPO appeared to be as efficacious as NO in managing acute RV failure and had the benefit of significant cost saving.²³ Likewise, Austin et al. (2022) demonstrated significant cost savings by initiating an iEPO-favoring iPV protocol in their single-center quaternary hospital study.⁵⁷

Availability

Given the niche market for many of these agents, not all iPVs will be available at every hospital for perioperative care. Therefore, clinicians should be familiar with which iPVs, if any, are available for use. Additionally, given that different countries have different governing boards for the approval of new medications, some medications may be available for clinical use in some countries but not in others.

Side-effect profile

The side effect profile should be considered when choosing a perioperative iPV. NO is generally favorable, but the most common toxic byproducts are methemoglobin and nitrogen dioxide (NO₂). Toxicity is dose-related and rarely occurs in therapeutic dose ranges. Methemoglobin levels should be monitored regularly, and the iNO dose should be decreased, or an alternative iPV selected if levels exceed 7%. NO₂ accumulation may cause bronchospasm and pulmonary edema. Maintenance of ventilator flow rates higher than the patient’s minute ventilation and continuous in-line monitoring reduces the risk of NO₂ toxicity. NO should be administered using the lowest possible FiO₂ because hyperoxia promotes further NO release with its proinflammatory and toxic side effects.9, 12, 58 Inhaled prostacyclin analogs have an overall low risk of toxicity. While they have a theoretical risk of antiplatelet effects, they have been used clinically without an increased risk of bleeding.9, 10

Weaning strategy

The plan for weaning iPVs perioperatively should be based on the degree of preoperative PH, timeframe for restarting the home medication regimen, and clinical status of the patient. iPVs may be weaned in the operating room at the end of the case or may require continuation in the post-operative period to the ICU for slower weaning. NO must be weaned incrementally because of its very short half-life. Abrupt discontinuation can result in severe rebound PH and RV dysfunction.9, 12, 58 While there are several studies on weaning protocols for iPVs in the neonatal ICU population, there is a lack of excellent evidence on the best weaning strategies for iPVs in the adult population. Many hospitals have their own institutional protocols where iPVs are weaning according to mPAP, CVP, or additional hemodynamic data. An additional practical concern is how to deliver the iPV once the patient has met extubation criteria. This may be achieved by delivering the iPV through a high flow nasal cannula or noninvasive positive pressure ventilation system.

Future directions

Inhaled seralutinib

Seralutinib is a novel inhaled platelet-derived growth factor receptor (PDGFR) inhibitor being investigated for its role in PH. Phase 2 clinical trial results suggest PVR reduction and improved RV function without significant systemic side effects. The efficacy and safety of inhaled seralutinib were evaluated in 80 PAH patients in the phase 2 TORREY study. The study demonstrated PVR reduction at 24 weeks (p=0.0310) with improvement in six-minute walk distance, NT-proBNP, and echocardiographic measures of cardiac structure and function with a favorable safety profile.⁵⁹ Additional investigations are required to confirm its long-term efficacy, safety, and applicability in the perioperative setting.

Vardenafil

Vardenafil, a phosphodiesterase-5 (PDE5) inhibitor, is commonly used for erectile dysfunction but has been studied as an inhaled agent (iVardenafil) for pulmonary hypertension.⁶⁰ Compared to oral PDE5 inhibitors like sildenafil, iVardenafil has a faster onset of action, lower systemic absorption, and potentially fewer systemic side effects, such as hypotension or headache. This targeted action reduces PVR, improves RV function, and enhances oxygenation. Phase 2b trials suggest that iVardenafil could be beneficial in managing PH, particularly in settings like cardiac surgery, where rapid and localized pulmonary vasodilation is desirable. However, further research is needed to establish its long-term efficacy, safety, and comparative benefits in PH management.

Inhaled MK-5475

MK-5475 (Merck Sharp & Dohme Corp., Kenilworth, NJ, United States) is a soluble guanylate cyclase (sGC) stimulator that acts similar to riociguat, a medication that has previously demonstrated efficacy in PAH management. In analogy with riociguat, MK-5475 directly stimulates sGC, independent of NO, and sensitizes sGC to endogenous NO by stabilizing their interaction, resulting in increased production of cGMP, relaxation of vascular smooth muscle cells, and, ultimately, vasodilation. Clinical trials have demonstrated the efficacy of riociguat in treating pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). In the PATENT-1 study, riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with PAH.⁶¹ Similarly, the CHEST-1 trial⁶² reported significant benefits in patients with inoperable or persistent CTEPH. Elevated cGMP levels promote relaxation of vascular smooth muscle cells, thereby inducing vasodilation.62, 63, 64

Early data suggest MK-5475’s potential for managing PH in cardiac surgery, though more research is needed. The multicenter Phase 2/3 INSIGNIA-PAH study (NCT04732221) evaluated the efficacy of MK-at three different doses (32,100, and 380 mg) versus placebo for a 12-week base period with a 24-month optional extension period. Initial results showed that inhaled MK-5475 at 100 mg and 380 mg significantly reduced PVR in participants with PAH but did not significantly change in 6-min walk distance. The treatment was tolerated at all tested doses.⁶⁵

Inhaled serotonin antagonists (e.g., terguride)

Serotonin contributes to pulmonary vasoconstriction in PH. It has been hypothesized that serotonin antagonists may offer an alternative mechanism for pulmonary vasodilation. The serotonin receptor 5-HT2A & 5-HT2B inhibitor, terguride, showed favorable effects in reducing pulmonary vasoconstriction and PA smooth muscle cell proliferation in a monocrotaline rat model of PAH.⁶⁶ However, in a phase 2a clinical trial, the drug showed no hemodynamic benefit in PAH patients, with high rates of severe adverse events and drug discontinuation, limiting its clinical potential.⁶¹

Conclusion

iPVs offer a targeted approach to reduce PVR while minimizing the risk of systemic hypotension and remain an essential tool to aid in the treatment of PH and PH crisis in the perioperative setting. While NO and inhaled prostacyclins have been the historic mainstays of iPVs, there are other agents available to consider including iMIL. Further well-designed clinical trials are needed to define optimal dosing strategies, clinically meaningful outcomes, and cost-effectiveness across perioperative settings.

Funding

This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.