Can you give milrinone via nebulization for pulmonary hypertension?

Can you give milrinone via nebulization for pulmonary hypertension?

Comment by InpharmD Researcher

Limited evidence evaluating the use of nebulized milrinone for pulmonary hypertension suggests that it may successfully facilitate weaning from cardiopulmonary bypass and is generally well-tolerated in high-risk cardiac surgery patients. However, findings supporting its use in this context are derived from small preliminary trials, necessitating further investigation. Additionally, there is a lack of robust data outside of the perioperative cardiac surgery setting, making the broader theraputic potential of nebulized milrinone for pulmonary hypertension unclear.

Background

A 2023 systematic review and meta-analysis of three randomized controlled trials involving 273 adult patients evaluated the effects of inhaled milrinone on pulmonary hypertension and systemic pressures. The analysis focused on mean pulmonary arterial pressure (PAP) and mean arterial pressure (MAP) as indicators of pulmonary and systemic hemodynamics, respectively. Inhaled milrinone was administered via nebulizer in the setting of cardiac surgery to explore its potential for intraoperative reduction of pulmonary pressures while avoiding the systemic hypotension commonly associated with its intravenous form. The findings demonstrated a statistically nonsignificant reduction in mean PAP, with a mean difference of -0.51 mmHg (95% confidence interval [CI] -3.02 to 2.00), accompanied by moderate heterogeneity (I² = 53%). Similarly, MAP showed a non-significant increase, with a mean difference of 1.6 mmHg (95% CI -0.96 to 4.15) and no observed heterogeneity (I² = 0%). These results suggest that while inhaled milrinone may exert localized effects on the pulmonary vasculature, its short half-life limits sustained improvements in pulmonary pressures. The authors note that future investigations should prioritize larger-scale studies conducted outside the perioperative cardiac surgery context to better assess the therapeutic potential of inhaled milrinone for pulmonary hypertension. [1], [2], [3], [4]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Can you give milrinone via nebulization for pulmonary hypertension?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

Comparison of Nebulized Versus Intravenous Milrinone on Reducing Pulmonary Arterial Pressure in Patients with Pulmonary Hypertension Candidate for Open-cardiac Surgery: A Double-Blind Randomized Clinical Trial
Design	Double-blind, randomized trial N= 32
Objective	To compare the effects of nebulized versus intravenous (IV) administration of milrinone on reducing pulmonary arterial pressure in patients with pulmonary hypertension who are candidates for open-cardiac surgery
Study Groups	Nebulized milrinone (n = 16) IV milrinone (n = 16)
Inclusion Criteria	Patients who underwent open-heart surgery during study period, 20-70 years, on-pump cardiac surgery, mean pulmonary artery pressure (MPAP) > 40 mmHg measured preoperative by right-sided catheterization or echocardiography
Exclusion Criteria	Refusal to participate, Redo surgery, emergency surgery, chronic obstructive pulmonary disease, hepatic or renal dysfunction, and hemoptysis
Methods	Patients were randomized 1:1 to receive nebulized milrinone or intravenous milrinone. After cardiac defect repair and aortic cross-clamping, one group received nebulized milrinone (50-80 mcg/kg) by a jet nebulizer, and the other group received IV milrinone (50 mcg/kg bolus, then 0.5 mcg/kg/min infusion) before cardiopulmonary bypass weaning. Dobutamine (5-10 mcg/kg/min) was administered based on patient response, with epinephrine (0.05-0.1 mcg/kg/min) added if measured blood pressure remained below 50 mmHg. Following surgery, patients were transferred to the cardiovascular intensive care unit (ICU) and extubated upon meeting weaning criteria based on mechanical ventilation predictors.
Duration	January 2021 to January 2022
Outcome Measures	Hemodynamic variables and safety
Baseline Characteristics		Nebulized milrinone (n = 16)	IV milrinone (n = 16)
	Age, years	46 ± 4	48 ± 4
	Male	37%	62%
	BMI, kg/m²	25 ± 3	25 ± 2
	NYHA class 1 2 3 4	0 75% 25% 0	0 75% 25% 0
	Type of surgery Isolated valve Multiple valve CABG with valve surgery Other	25% 12.5% 37.5% 25%	37.5% 25% 12.5% 25%
	Comorbidities Hypertension Diabetes mellitus COPD Coronary artery disease Hyperlipidemia Hypothyroidism No comorbidities	25% 37.5% 12.5% 12.5% 37.5% 25% 62.5%	37.5% 37.5% 25% 12.5% 62.5% 12.5% 37.5%
	Left ventricular ejection fraction, %	45 (40 - 50)	49 (45 - 50)
	Duration of surgery, min CPB Aorta clamping	104 ± 33 80 ± 34	163 ± 38 123 ± 31
	MPAP before surgery, mmHg	43.38 ± 6.32	53.25 ± 10.50	0.09
	Abbreviations: BMI, body mass index; MPAP, mean pulmonary artery pressure; NYHA, New York Heart Association; CABG, coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; CPB, cardiopulmonary bypass
Results	Endpoint	Nebulized milrinone (n = 16)	IV milrinone (n = 16)	p-value
	Difficult separation from CPB	2 (12.5%)	12 (75%)	--
	Intravenous adrenaline post-CPB	4 (25%)	16 (100%)	--
	Malignant arrhythmia	2 (12.5%)	0	--
	Vasopressors use > 24 hours Death	0	6 (37%)	--
	Death	0	0	--
	Extubation, hour after ICU admission	11 ± 5	48 ± 25	0.001
	ICU stay, d	3 ± 1	8 ± 5	0.009
	Hospital stay, d	8 ± 1	12 ± 2	0.026
	Abbreviations: CPB, cardiopulmonary bypass; ICU, intensive care unit.
	For central venous pressure, stroke volume, and cardiac index, no significant changes were observed over time in either group (p>0.05). Significant changes were seen over time in the nebulized and IV groups for heart rate (p<0.0001 vs. p= 0.02), mPAP (p= 0.001 vs. p<0.0001), MAP/mPAP (p= 0.0032 vs. p<0.0008), and pulmonary vascular resistance (p<0.0001 in both groups). Changes were noted in patients receiving nebulized milrinone for cardiac output (p = 0.01), systemic vascular resistance (p = 0.005), systolic blood pressure (p= 0.04), diastolic blood pressure (p= 0.04), and MAP (p= 0.01).
Adverse Events	See Result
Study Author Conclusions	Nebulized milrinone administration before weaning off cardiopulmonary bypass (CPB) can be accelerated and facilitate weaning off CPB. Moreover, despite maintaining MAP, nebulized milrinone significantly reduces mPAP. According to the results of this study, nebulized milrinone is recommended in patients undergoing cardiac surgery with pulmonary hypertension.
InpharmD Researcher Critique	The study's limitations include its single-center design, small sample size, and challenges with long-term follow-up. A larger, multi-center study with extended follow-up would provide more reliable results.

References:
[1] Jorairahmadi S, Javaherforooshzadeh F, Babazadeh M, Gholizadeh B, Bakhtiari N. Comparison of Nebulized Versus Intravenous Milrinone on Reducing Pulmonary Arterial Pressure in Patients with Pulmonary Hypertension Candidate for Open-cardiac Surgery: A Double-Blind Randomized Clinical Trial. Anesth Pain Med. 2022;12(3):e122994. Published 2022 Jul 21. doi:10.5812/aapm-122994

Inhaled milrinone in cardiac surgical patients: a pilot randomized controlled trial of jet vs. mesh nebulization
Design	Pilot randomized controlled trial N= 12
Objective	To investigate inhaled milrinone dosing in vitro and early plasma concentrations in vivo after jet and mesh nebulization
Study Groups	Jet (n= 6) Mesh (n= 6)
Inclusion Criteria	Patients diagnosed with preoperative pulmonary hypertension (PH) and scheduled for elective cardiac surgery using cardiopulmonary bypass (CPB)
Exclusion Criteria	Patients with preoperative hemodynamic instability, defined as acute requirement for vasoactive or mechanical support prior to surgery
Methods	Patients were premedicated with lorazepam (1–2 mg orally) one hour before surgery, morphine (0.1 mg/kg intramuscularly) before entering the operating room, and midazolam (0.01–0.05 mg/kg intravenously [IV]) at the anesthesiologist’s discretion. Standard and advanced monitors, including a five-lead electrocardiogram, radial and femoral arterial catheters, a central venous pressure catheter, and a fast-response thermodilution pulmonary artery catheter, were placed prior to anesthesia induction. Anesthesia was induced with sufentanil (1 mcg/kg IV), midazolam (0.04 mg/kg), and pancuronium (0.1 mg/kg IV). Maintenance anesthesia included continuous infusions of sufentanil (1 mcg/kg/h) and midazolam (0.04 mg/kg/h). After induction of anesthesia and baseline transesophageal echocardiography examination, 5 mg (50-80 mcg/kg) of milrinone was administered by inhalation before initiation of CPB.
Duration	Between December 2006 and June 2007
Outcome Measures	Hemodynamic monitoring and plasma concentrations after the end of inhalation
Baseline Characteristics		Jet (n= 6)	Mesh (n= 6)
	Age, years	65 ± 9	74 ± 8
	Female	5 (83.3%)	2 (33.3%)
	Weight, kg	76 ± 20	73 ± 23
	Surgical procedure CABG Single valve Complex Other	1 (16.6%) 2 (33.3%) 2 (33.3%) 1 (16.6%)	0 (0%) (16.6%) 4 (66.6%) (16.6%)
	Abbreviations: CABG = coronary artery bypass grafting
Results	Endpoint	Jet (n= 6)*	Mesh (n= 6)	p-Value
	mAP, mmHg Baseline Post-inhalation	82.6 ± 10.2 77.6 ± 15.9	67.4 ± 5.3 65.0 ± 8.9	0.009 0.13
	mPAP, mmHg Baseline Post-inhalation	30.3 ± 11.5 25.8 ± 3.7	25.8 ± 3.7 19.3 ± 4.0	0.47 0.02
	mAP/mPAP, mmHg Baseline Post-inhalation	3.0 ± 1.0 3.1 ± 1.1	2.6 ± 0.5 3.5 ± 0.8	0.44 0.55
	Abbreviations: mAP = mean arterial pressure; mPAP = mean pulmonary artery pressure *n= 5 for post-inhalation values Milrinone plasma concentrations were 2–3 times higher with mesh nebulization compared to jet nebulization.
Adverse Events	N/A
Study Author Conclusions	In conclusion, adequate administration of inhaled drugs relies on careful evaluation of aerosol devices, delivery systems and dosing. Low plasma concentrations of milrinone are observed in cardiac surgical patients following both jet and mesh nebulization. However, mesh nebulization provides better efficiency in delivering aerosolized milrinone to mechanically ventilated patients, resulting in almost threefold increased inhaled dose and systemic exposure compared to conventional jet nebulization.
InpharmD Researcher Critique	The small sample size limits the study's generalizability, and while it provides preliminary insights into the concentration-effect relationship of inhaled milrinone, larger studies are needed to confirm its clinical applicability.

References:
[1] Nguyen AQ, Denault AY, Théoret Y, Perrault LP, Varin F. Inhaled milrinone in cardiac surgical patients: a pilot randomized controlled trial of jet vs. mesh nebulization. Sci Rep. 2020;10(1):2069. Published 2020 Feb 7. doi:10.1038/s41598-020-58902-x