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

Baseline Characteristics

Nebulized milrinone (n = 16)

IV milrinone (n = 16) 

Age, years

Male

BMI, kg/m²

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, %

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

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

Intravenous adrenaline post-CPB

Malignant arrhythmia

Vasopressors use > 24 hours Death

Death

Extubation, hour after ICU admission

ICU stay, d

Hospital stay, d

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. 

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

Outcome Measures

Baseline Characteristics

Jet (n= 6)

Mesh (n= 6)

Age, years

Female

Weight, kg

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

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.

Cardiovascular Effects of Prolonged Milrinone Inhalation in Patients with Pulmonary Hypertension Undergoing Mitral Valve Replacement

Design

Randomized, double-blinded, controlled trial

N= 40

Objective

To investigate the cardiovascular effects of prolonged inhalation of nebulized milrinone on patients with pulmonary hypertension undergoing mitral valve replacement

Study Groups

Milrinone (n= 20)

Placebo (n= 20)

Inclusion Criteria

Aged 17-45 years with an ejection fraction (EF) >40%, mean pulmonary artery pressure (mPAP) >25 mmHg and undergoing mitral valve replacement (MVR) with and indication of isolated mitral stenosis or isolated mitral regurgitation (or combined indication) 

Exclusion Criteria

Severe renal or hepatic disease, coagulopathy, and thromboembolic disease treated with anticoagulants

Methods

Patients were randomized to recieve inhaled milrinone or matching control. A loading dose of milrinone 50 μg/kg followed by a continuous maintenance dose of 0.5 mcg/kg/min (diluted to 5 mL in 0.9% normal saline) was administered and the other receiving an equivalent volume of 0.9% normal saline as a control. Milrinone nebulization was initiated prior to cardiopulmonary bypass (CPB) and continued for 2 hours after tracheal extubation. Outcomes were measure at various intervals: T0 – after induction of anesthesia and before sternotomy; T1-20 min after cessation of CPB; T2-1 h after cessation of CPB; T3-3 h after cessation of CPB; T4-1 h after tracheal extubation; and T5-1 h after discontinuation of milrinone. 

Duration

Not discussed

Outcome Measures

The primary outcome: mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure, pulmonary vascular resistance (PVR), and cardiac index (CI)

Secondary outcomes: duration of cardiopulmonary bypass (CPB) and timing of tracheal extubation

Baseline Characteristics

Milrinone (n= 20)

Placebo (n= 20)

Age, years

Female

Weight, kg

Type of surgery

Isolated mitral stenosis

Isolated mitral regurgitation

Combined mitral stenosis and regurgitation

50%

35%

15%

60%

25%

15% 

Results

Endpoint

Milrinone (n= 20)

Placebo (n= 20)

p-Value

Duration of cross-clamp, min

Duration of cardiopulmonary bypass (CPB), min*

Tracheal extubation time, min*

Total adrenaline, mg

*Statistically significant (p< 0.05)

No statistically signifi cant differences were noted between the two groups with respect to heart rate, mABP, central venous pressure, and systemic vascular resistance. The milrinone group experienced a statistically significant reduction in mPAP at T2 , T3 , and T4 readings, pulmonary capillary wedge pressure at T3 reading, and PVR at T2 , T3 , and T4 readings; milrinone group showed a statistically significant increase in CI at T3 and T4 readings.

Adverse Events

Study Author Conclusions

Prolonged inhalation of nebulized milrinone proved to be feasible in patients with pulmonary hypertension (PAH) undergoing mitral valve replacement. It decreased PVR and mPAP while increasing CI. This helped shorter CPB duration and earlier tracheal extubation.

InpharmD Researcher Critique

Limitations include small patient population, lack of safety outcomes, and short duration of follow-up in the study.

Preliminary experience with inhaled milrinone in cardiac surgery

Design

Retrospective, observational cohort study

N= 73

Objective

To determine the impact and timing of administration of inhaled milrinone

Study Groups

BE (n= 30)

AF (n= 40)

Inclusion Criteria

Received inhaled milrinone

Exclusion Criteria

Include relevant exclusion criteria (not a comprehensive list).

Methods

Data were obtained of transesophageal echocardiograms of consecutive patients at a single institution meeting inclusion criteria. Patients received preoperative risk assessment via Parsonnet and American Society of Anesthesiologists (ASA) scoring systems and were monitored throughout and following procedures. Inhaled milronine (doses of 50-80 mcg/kg over 5 minutes) was administered via endotracheal tube prior to (BE) cardiopulmonary bypass (CPB), or after (AF) CPB discontinuation, based on surgical and anesthesiology team preference; outcomes were analyzed for these cohorts.

Duration

June 2002 to February 2005

Outcome Measures

Clinical outcomes

Baseline Characteristics

Study cohort (N= 73)

Age, years

Male

Procedures, n

CABG

Valve

Valvular and CABG

Other

17

25

15

16

Reoperative surgery

More diabetic patients were present in the pre-inhalation group (p= 0.048). Additionally, reinitiation of CPB occurred in 9 AF vs 1 BE patient (p= 0.023).

Results

Endpoint

Odds ratio

95% confidence interval

p-value

Analysis for mortality

Parsonnet score

CPB time, min

Cross clamp time, min

Very difficult weaning from CPB

Intubation time, h

Postoperative IABP*

1.065

1.016

1.017

11.7

1.007

17.7

1.016-1.116

1.005-1.028

1.003-1.031

2.6-52.99

1.002-1.01

3.7-84.5

0.009

0.006

0.02

0.002

0.005

0.003

Analysis for very difficult weaning from CPB

CPB time, min

Cross clamp time, min

Inhaled milrinone timing (BE)

1.02

1.013

0.2

1.007-1.03

1.0-1.03

0.05-0.8

0.002

0.04

0.02

Abbreviations: IABP= intra-aortic balloon pump

* Univariate and multivariate analyses produced the same odds ratios

Overall, 54 patients (74%) had difficult separation from CPB, 14 patients (19%) required an intra-aortic balloon pump, and 10 patients (14%) needed emergency reinitiation of CPB for hemodynamic instability.

Mean pulmonary artery pressure (mPAP) decreaed in BE vs AF (p= 0.009), though both groups saw a significant reduction in mean arterial pressure (MAP), increase in heart rate, and increase in cardiac index after CPB. Development of relative pulmonary hypertension, as observed by MAP/mPAP ratio, was observed more often in the AF group (p= 0.01).

BE group patients experienced increase in fractional area change (p= 0.002) vs no change in AF. Regional wall motion score index was similar between groups both pre- and post-CPB.

Adverse Events

Ten patients died in the perioperative period (13.7%); however, no detectable adverse events were associated with milrinone use.

Study Author Conclusions

The major findings of this study are: (1) in high-risk patients with similar preoperative and operative characteristics, administration of a single bolus of inhaled milrinone before initiation of CPB is associated with lower mPAP after CPB than post CPB administration; (2) maintains or improves LV systolic function; and (3) is associated with a lower rate of CPB reinitiation compared to those receiving inhaled milrinone after CPB.

InpharmD Researcher Critique

Limitations include the small sample size and potential selection bias, as timing of inhaled milrinone was not standardized. Surgical and anesthesiology team were also not blinded to timing of milrinone inhalation.

Nebulized milrinone use in a pulmonary hypertensive crisis

Design

Case presentation

A 42-year-old woman with World Health Organization functional class III idiopathic pulmonary arterial hypertension (PAH) presented with syncope and overt heart failure. She had started sildenafil 20 mg 3 times/day 1 month earlier, with plans to begin intravenous prostanoid therapy if no improvement was noted. Upon admission to the cardiac ICU, she was treated with dobutamine, high-dose diuretics, and continued sildenafil. By hospital day 2, minimal improvement was noted, so sildenafil was discontinued, and intravenous treprostinil 2 ng/kg/min was initiated. Three hours later, she developed progressive hypotension, requiring vasopressin 0.04 U/min and epinephrine, but blood pressure remained unresponsive. Over the next 9 hours, her mixed venous oxygen saturation (SvO2) declined from 65% to 44%.

Nebulized milrinone was introduced at a dose of 4 mg/hr for worsening hypoxemia and hemodynamic instability, initially administered via a face mask. After intubation, it was delivered through the ventilator circuit. The nebulizer, at 2 L/min and a drug concentration of 0.5 mg/mL, delivered 4 mg/hour of solution. SvO2 increased dramatically from 44% to 56% after the first dose. A drop in SvO2 to 14% occurred when the nebulizer was empty, but re-administration raised SvO2 to 54% within 10 minutes. After 3 days, the nebulized milrinone dose was reduced from 4 mg/hr to 1 mg/hr over 24 hours. It and nitric oxide were successfully tapered off, and after 6 weeks, the patient was discharged on sildenafil and treprostinil therapy. Eighteen months later, she continued to thrive, receiving sildenafil 20 mg TID and intravenous treprostinil 60 ng/kg/min without significant adverse effects.

Study Author Conclusions

Nebulized milrinone in addition to inhaled nitric oxide and low-dose intravenous treprostinil may have played a major role in the acute management of her PAH crisis. Further studies are needed to assess the role of nebulized milrinone in patients with PAH.

Inhaled milrinone for the management of severe pulmonary hypertension in non-cardiac surgery

Design

Case presentation

A 56-year-old man with bilateral carotid disease, extensive cardiac comorbidities, and a history of coronary artery disease, myocardial infarctions, congestive heart failure, mitral and tricuspid insufficiency, and peripheral vascular disease (left carotid occlusion) presented for a repeat left carotid subclavian bypass before a planned mitral valve replacement. His baseline function was New York Heart Association (NYHA) class IV, and he used nitroglycerin spray for severe angina. Transesophageal echocardiography showed severe mitral regurgitation and moderate tricuspid regurgitation, with a right ventricular systolic pressure estimated at 65-75 mmHg. His surgical history included a previous coronary artery bypass graft and a failed left carotid subclavian bypass one year earlier.

The initial pulmonary artery pressure was 88/62 mmHg, and the radial arterial pressure was 110/85 mmHg. An induction with fentanyl 300 mg, phenylephrine 100 mg, ketamine 70 mg, and rocuronium 100 mg resulted in a peak pulmonary artery pressure of 108/58 mmHg, with concurrent arterial pressures of 138/91 mmHg. General anesthesia was maintained with isoflurane (0.7 minimum alveolar concentration [MAC]) and a remifentanil infusion (0.02 to 0.1 mg/kg/min). Post-induction, pulmonary artery pressures stabilized at 90/45 mmHg, and systemic pressures were 115/75 mmHg.

After 30 minutes, milrinone 4 mg was delivered via an ultrasonic nebulizer over 30 minutes, reducing pulmonary artery pressures to 70/28 mmHg, with systolic pressures remaining below 80 mmHg for 30 minutes. A second 4 mg nebulized milrinone dose reduced pressures to 77/30 mmHg, maintaining this level for 45 minutes until the end of anesthesia. Two doses of hydromorphone were administered during the milrinone treatments. No further interventions were made to reduce pulmonary hypertension. Following surgery, the patient was successfully extubated in the operating room and transported awake and stable to the Post-Anesthesia Care Unit.

Study Author Conclusions

While inhaled nitric oxide and inhaled prostaglandins have been demonstrated to be efficacious for intraoperative management of pulmonary hypertension, inhaled milrinone may be a worthwhile consideration, especially in centers where the former two inhaled agents are unavailable.