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CARDIOVASCULAR ANESTHESIA

The Additive Pulmonary Vasodilatory Effects of Inhaled Prostacyclin and Inhaled Milrinone in Postcardiac Surgical Patients with Pulmonary Hypertension

Department of Anesthesia and Intensive Care, Sahlgrenska University Hospital, Göteborg, Sweden

Address correspondence and reprint requests to Sven-Erik Ricksten, MD, PhD, Department of Anesthesia and Intensive Care, Sahlgrenska University Hospital, S-413 45 Göteborg, SWEDEN. Address e-mail to sven-erik.ricksten{at}aniv.gu.se

	Abstract

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Selective pulmonary vasodilation is an advantageous therapeutic strategy for cardiac surgical patients with increased pulmonary vascular resistance (PVR) and right ventricular failure. We hypothesized that milrinone, an adenosine-3',5'-cyclic monophosphate (cAMP)-selective phosphodiesterase enzyme (PDE) inhibitor may, when nebulized and inhaled, cause selective pulmonary vasodilation and potentiate the vasodilation by inhaled prostacyclin (iPGI₂). Consequently, we investigated the hemodynamic effects of inhaled milrinone or the combination iPGI₂ + inhaled milrinone in cardiac surgical patients with postoperative mean pulmonary arterial pressure (MPAP) >25 mm Hg and PVR >200 dynes · s^-1 · cm^-5. During mechanical ventilation and using a conventional nebulizing system, 9 patients inhaled incremental concentrations of milrinone (0.25, 0.5 and 1 mg/mL) in subsequent 10-min periods (Study Part 1). In the same manner, 11 patients received iPGI₂ (10 µg/mL) followed by the combination of iPGI₂ (10 µg/mL) and inhaled milrinone (1 mg/mL) (Study Part 2). Inhaled milrinone reduced PVR with a maximal effect (-20%, P < 0.001) at the largest concentration. As compared with iPGI₂ alone, iPGI₂ + inhaled milrinone caused a further and prolonged reduction of PVR (-8%, P < 0.05) and increased stroke volume (+5%, P < 0.05). Systemic vascular resistance or mean arterial pressure was not affected by inhalation of either drug(s). The authors conclude that inhalation of the cAMP-selective PDE-inhibitor milrinone selectively dilates the pulmonary vasculature without systemic effects in cardiac surgical patients with pulmonary hypertension. Furthermore, inhaled milrinone appears to potentiate and prolong the pulmonary selective vasodilatory effect of iPGI₂. Inhaled milrinone alone or combined with iPGI₂ may be an important therapeutic option in the treatment of patients with pulmonary hypertension and right ventricular failure.

IMPLICATIONS: Pulmonary hypertension may cause or aggravate right heart failure. IV vasodilators reduce systemic blood pressure and might thereby further impair coronary perfusion and right heart performance. In the present study of cardiac surgical patients with pulmonary hypertension, selective pulmonary vasodilation without systemic effects was induced by nebulized, inhaled vasodilators.

	Introduction

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Pulmonary hypertension and increased pulmonary vascular resistance (PVR) after cardiac surgery and orthotopic heart transplantation may cause right ventricular (RV) failure and increase perioperative morbidity and mortality (1). Traditional therapeutic strategy has consisted of IV vasodilators such as nitrates or prostaglandins but lack of selectivity for the pulmonary vasculature, and hence associated systemic hypotension with increasing dosage, is the limiting factor (2,3).

Nitric oxide (NO) and prostacyclin (PGI₂) are endothelium-derived potent modulators of vascular tone. NO and PGI₂ augment intracellular levels of cyclic nucleotides, cyclic guanosine monophosphate (cGMP), and cyclic adenosine monophosphate (cAMP) respectively, thus initiating a cascade of events resulting in vasodilation (4,5). Administering drugs by inhalation seems advantageous because large concentrations can be selectively presented to the pulmonary circulation. Consequently, the use of inhaled NO (iNO) for pulmonary vasodilation in the cardiac surgical setting has expanded but because of potential toxicity, iNO requires specialized delivery systems and monitoring (3,6,7). In contrast, PGI₂ exerts no toxic effects, and several investigators have reported pulmonary selective vasodilation by inhaled PGI₂ (iPGI₂) in patients with pulmonary hypertension of various etiologies (5,8–10).

The inodilator milrinone is a nonglycosidic, nonsympathomimetic drug that increases myocardial and vascular smooth muscle cAMP concentrations by inhibiting phosphodiesterase fraction III (PDE III) enzymes, thus modulating intracellular calcium levels with resultant increased myocardial contractility and systemic vasodilation (11). These properties of PDE III inhibitors offer an important therapeutic option for patients with ventricular dysfunction undergoing cardiac surgery (12). Because vasodilation is induced by a different mechanism, as compared with PGI₂, milrinone may, when inhaled, offer potential additive and pulmonary selective vasorelaxant effects to iPGI₂. Therefore, we investigated the effects of incremental concentrations of inhaled aerosolized milrinone on pulmonary hemodynamics (Study Part 1) and the potential additive and prolonged pulmonary vasodilatory effects of inhaled milrinone when combined with iPGI₂ (Study Part 2) in patients with pulmonary hypertension after cardiac surgery or heart transplantation.

	Methods

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The study was performed at Sahlgrenska University Hospital, Göteborg, Sweden and approved by the Human Ethics Committee of the Medical Faculty, University of Göteborg and The Swedish Medical Products Agency, Uppsala, Sweden.

Patients
Patients undergoing coronary artery bypass grafting and/or valvular heart surgery presenting with RV systolic pressure >60 mm Hg, as assessed by preoperative transthoracic echocardiography, as well as heart transplant candidates with a preoperative PVR >200 dynes · s^-1 · cm^-5 were enrolled in the study from the 1^st of February 1997 to the 31^st of January 1998. During this time period, 64 patients undergoing coronary artery bypass grafting and/or valvular heart surgery and 16 heart transplant recipients were enrolled after informed consent. Twenty of these patients fulfilled the following inclusion criteria: postoperative PVR >200 dynes · s^-1 · cm^-5 and postoperative mean pulmonary arterial pressure (MPAP) >25 mm Hg both obtained twice within a 30 min period. Nine patients in Study Part 1 (Table 1) and 11 in Study Part 2 (Table 2) were included. Two patients had undergone orthotopic heart transplantation because of ischemic or dilated cardiomyopathy, and 18 patients had undergone coronary artery bypass grafting and/or valvular surgery (Tables 1 and 2). The study was performed in the immediate postoperative period in the cardiothoracic intensive care unit. The patients were treated by the attending anesthesiologist and were mechanically ventilated (Servo ventilator 900/900c; Siemens Elema, Solna, Sweden) to normocapnia (4.5–5 kPa) and sedated with propofol or the combination of ketamine and midazolam. Fifteen patients received pharmacological inotropic support and three patients were in addition treated with intraaortic balloon counterpulsation.

Delivery of Milrinone and Prostacyclin
The drugs were administered with jet nebulizers (Micro Mist Nebulizer model 1880; Hudson RCI, Temecula, CA) attached to the inspiratory limb of the ventilator circuit, just before the Y-piece, approximately 15 cm proximal to the endotracheal tube. The mean mass diameter of particles delivered by this nebulizer from aqueous solution is 2.1 µm at a rate of 0.25–0.3 mL/min. Nebulizing was synchronized to the inspiratory phase with a timing device (Servo Nebulizer 945; Siemens Elema). Humidification of the ventilatory circuit was stopped before and during the period of inhalation. When PGI₂ was administered with milrinone, each drug was nebulized separately in one of two identical and serially attached nebulizing systems, both systems triggered in the inspiratory phase. Accessory inspiratory gas flow from the nebulizer(s) was compensated for by adjustment of minute ventilation settings on the ventilator, keeping minute ventilation constant during the experimental procedure. Inspiratory oxygen fraction (FIO₂) was kept constant throughout the experimental procedure. If MAP decreased below 60 mm Hg, inhalation of drug(s) was stopped and the patient excluded from the study.

Protocol
Dose-Response Study of Inhaled Milrinone (Study Part 1).
Characteristics of included patients (n = 9) are given in Table 1. After control measurements and blood sampling for oxygenation variables, stepwise increased concentrations of milrinone (Corotrop^®; Sanofi Winthrop, Paris, France) were administered by inhalation for three subsequent 10-min periods, each followed by hemodynamic measurements and blood sampling. Twenty minutes after termination of milrinone inhalation, postdrug measurements were performed.

Three concentrations of milrinone were used in this study. Other than the original preparation manufactured for IV administration, 1 mg/mL (dissolved in dextrose, pH 3.2–4), 2 concentrations of milrinone were prepared by dilution with 0.9% sodium chloride to 0.25 mg/mL and 0.5 mg/mL respectively.

Inhalation of Prostacyclin and Prostacyclin + Milrinone (Study Part 2).
Characteristics of included patients (n = 11) are given in Table 2. After control measurements and blood sampling for oxygenation variables, prostacyclin (PGI₂; epoprostenol; Flolan^®; Glaxo Wellcome Laboratories, Beckenham, Kent, UK) was administered by inhalation for a 10-min period at a concentration of 10 µg/mL. PGI₂ was prepared immediately before use in a glycine buffer (0.188% glycine, 0.147% sodium chloride, pH 10.5). After hemodynamic measurements and blood sampling with continued administration of iPGI₂, another nebulizing system, identical to the system already in use, was attached serially to the nebulizing system for PGI₂-delivery. Milrinone, in a concentration of 1 mg/mL, was then administered concomitantly with iPGI₂ for a 10-min period. After hemodynamic measurements and blood sampling, inhalation of both drugs was terminated and postdrug measurements were obtained after 20 min.

During the experimental procedure of both Study Part 1 and Study Part 2, the infusion rates of concomitant inotropic drugs and sedatives were not changed and the patients did not receive additional fluid administration.

Data Analysis
The results in both studies were analyzed with a one-way analysis of variance (ANOVA) for repeated measurements and to determine the differential effects of the three concentrations of inhaled milrinone and the different effects of iPGI₂ versus iPGI₂+inhaled milrinone and pre- to postdrug control values, ANOVA was followed by planned single degree of freedom contrast analyses with correction for multiple comparisons as described by Keppel (13). A P value < 0.05 was considered to indicate statistical significance. Data are presented as mean ± SEM.

	Results

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Hemodynamic Effects of Inhaled Milrinone (Study Part 1)
Mean values for systemic and pulmonary hemodynamics during inhalation of milrinone are presented in Table 3. The relative changes in PVR and SVR are shown in Figure 1.

View larger version (21K): [in this window] [in a new window]   Figure 1. Percentage changes in pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) during inhalation of incremental concentrations of milrinone (mil) (0.25; 0.5 and 1.0 mg/mL) and 20 min postinhalation (A) and during inhalation of prostacyclin (PGI2)(10 µg/mL) and PGI2 (10 µg/mL) + milrinone (mil)(1.0 mg/mL) and 20 min postinhalation (B). * P < 0.05 control versus inhaled milrinone 0.25; 0.5 and 1.0 mg/mL and 20 min postinhalation or inhaled PGI2 (10 µg/mL), PGI2 (10 µg/mL) + mil (1.0 mg/mL), and 20 min postinhalation. *** P < 0.001 control versus inhaled milrinone 0.25, 0.5, and 1.0 mg/mL and 20 min postinhalation or inhaled PGI2 (10 µg/mL), PGI2 (10 µg/mL) + mil (1.0 mg/mL) and 20 min postinhalation. P < 0.05 inhaled PGI2 (10 µg/mL) vs PGI2 (10 µg/mL) + mil (1.0 mg/mL).

Hemodynamic Effects of Inhaled Prostacyclin and Inhaled Prostacyclin + Inhaled Milrinone (Study Part 2)
Mean values for systemic and pulmonary hemodynamics during inhalation of PGI₂ and PGI₂ + milrinone are presented in Table 4. Relative changes in PVR and SVR are presented in Figure 1.

Effects of Inhaled PGI₂ (10 µg/mL) + Inhaled Milrinone (1 mg/mL) on Central Hemodynamics.
Inhaled PGI₂+ milrinone decreased PVR by an additional 8% as when compared with iPGI₂ alone (P < 0.05). Furthermore, inhaled PGI₂+milrinone increased SV by another 5% compared with iPGI₂ alone (P < 0.05). Inhaled PGI₂+milrinone did not further change MPAP, PAOP, PVR/SVR-ratio, TPG, PAO₂, SvO₂ or O₂ extraction as when compared with iPGI₂ alone. The post-drug control values of MPAP, PVR, TPG, O₂ extraction or SvO₂ did not return to predrug control values. In contrast, there were no significant differences between the postdrug control values of PAOP, CO, SV, PVR/SVR-ratio, or PaO₂ compared with predrug values. None of the patients experienced reduction in MAP <60 mm Hg during the experimental procedure.

	Discussion

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In the present study, we noted that inhaled milrinone induced dose-dependent selective pulmonary vasodilation. In the first part of the study, a decrease in PVR by inhaled milrinone was found with a maximal effect (-20%) at the largest administered concentration (1 mg/mL) without associated systemic effects. This is the first report on inhaled milrinone as a therapeutic modality in patients with pulmonary hypertension.

In the second part of the study, aerosolized milrinone was administered with concomitant inhalation of PGI₂ to test the hypothesis that inhaled milrinone may potentiate the pulmonary vasodilatory effects of iPGI₂. The combination of iPGI₂ and milrinone resulted in a further significant decrease in PVR by approximately 8% and increased SV as compared with iPGI₂ alone. The mechanisms behind this additive pulmonary vasodilatory effect have not been addressed in the present study. However, because PGI₂-induced receptor activation of vascular smooth muscle stimulates adenylate cyclase enzyme with a resultant increase in cellular cAMP levels, the further increase in cellular cAMP resulting from PDE inhibition by milrinone is likely to cause an additional vasodilatory response.

One could argue that the almost 30% decrease in PVR seen in the present study, when iPGI₂ and inhaled milrinone were combined, could be achieved by IV infusion of either PGI₂ or milrinone alone. However, consistent with the effects of potent IV vasodilators on patients with pulmonary hypertension and RV failure, PDE inhibitors may induce systemic hypotension with consequent deterioration of RV coronary perfusion and performance. Furthermore, ventilation-perfusion mismatch of the lung may, at least temporarily, decrease PaO₂ (2,14).

The clinical importance of the 20%–30% PVR reduction and moderate effects on MPAP seen in this study can be questioned. However, the expected improvement in CO during inhalation of a vasodilator is dependent on baseline PVR and RV performance. The higher the PVR and the more pronounced the RV failure, the more CO will increase when inhaling NO (3) or PGI₂ (9). As our study was not designed to evaluate the effects of inhaled milrinone or inhaled milrinone plus iPGI₂ on patients with evident RV failure and high postoperative PVR, the former condition was not an inclusion criterion. However, baseline PVR and CVP were higher and SV lower in the second study group (Table 4) as compared with the first study group (Table 3), suggesting that RV performance was more depressed in the second study group. This could in turn explain the increase in SV during combined inhalation with milrinone and PGI₂, which was not seen with inhaled milrinone alone. Both iNO and iPGI₂ improve RV performance in patients with pulmonary hypertension accompanied by RV failure after cardiac surgery or heart transplantation (3,9). However, the potential clinical importance of milrinone inhaled as a sole drug or combined with other vasodilators, in terms of improved RV performance, should be investigated in future studies.

To further address the issue of the observed increase in SV when the combination of aerosolized milrinone and iPGI₂ was administered, one could argue that this indicates a direct positive inotropic action by milrinone resulting from significant "spill-over" into the systemic circulation. However, no accompanied increase in HR was evident and SV remained unchanged when milrinone was inhaled as a sole drug. Also, in both parts of the study, MAP, SVR, and Qs/Qt remained unchanged by either intervention. Furthermore, the reduced PVR/SVR ratio, as an index of pulmonary selectivity, suggests selective pulmonary vasodilation. In other words, no systemic effects were evident.

Twenty minutes after termination of inhalation of milrinone as a sole drug, all patient’s values returned to baseline in all measured variables. This is consistent with what has been shown in a similar group of patients 20 minutes after discontinuation of iPGI₂ (9). In contrast, when inhaled milrinone was combined with iPGI₂, there were still significant decreases in MPAP, PVR, TPG, and systemic O₂ extraction, as well as an increase in SvO₂, compared with predrug control values 20 minutes after termination of inhalation. One could argue that this represented a time-dependent drift in baseline during the procedure. However, all other variables resumed baseline values and the individual values of MPAP, PVR, TPG, and O₂ extraction all increased toward baseline after discontinuation of iPGI₂+milrinone. Possibly, the combination of the two inhaled drugs may prolong the duration of pulmonary vasodilation as compared with the effect duration of each drug when inhaled alone. Such an enhanced and prolonged hemodynamic action of iPGI₂ has been reported in an animal model of induced pulmonary hypertension where concomitant IV infusion of PDE inhibitors was administered (15). Similar effects have also been shown experimentally with the combination of two inhaled drugs with different vasodilator action. In an animal study with induced pulmonary hypertension by Ichinose et al. (16), inhalation of the cGMP-selective PDE-inhibitor zaprinast selectively dilated pulmonary vessels and potentiated and prolonged the pulmonary vasorelaxant effects of iNO.

The exact dose of either milrinone or PGI₂ reaching the alveolar space cannot be determined because of losses in the nebulizer chamber, ventilator- and endotracheal tubing. Furthermore, alveolar deposition of aerosols during mechanical ventilation has been estimated to be <10% (17). These uncertainties regarding dosing are a concern. Therefore a dose-response procedure as performed in the present and in a previous study by our group (9) is a familiar and safe procedure in well-monitored cardiac surgical patients. We have thus shown that the optimal concentration of iPGI₂ is 10 µg/mL, which is the dose causing a maximal decrease in PVR with no effects on SVR (9). We have also shown that 10 µg/mL of iPGI₂ is equipotent to iNO (40 ppm) in pretransplant candidates with high PVR (18). The optimal dose of inhaled milrinone is still elusive because the largest commercially available concentration (1 mg/mL) was used in the present study.

So far, the most ideal selective pulmonary vasodilator identified clinically seems to be iNO (4,6,7) and, with comparable efficacy, iPGI₂ (8,10,18). iNO has the disadvantage of considerable potential toxicity, which requires specialized delivery systems (7). Furthermore, there are reports indicating an inhibition of platelet aggregation by iNO, which must be considered, especially in cardiac surgical patients already suffering from hemostatic perturbation (19). Inhaled PGI₂ has a number of salutary effects, not only on pulmonary hemodynamics in patients with pulmonary hypertension (8,9,20), but also on splanchnic perfusion and oxygenation in patients with septic shock (21). Side effects such as pulmonary toxicity and platelet dysfunction by iPGI₂ are matters of concern. However, during prolonged (eight-hour) PGI₂ inhalation in an animal setting, no effects on platelet aggregation or signs of acute pulmonary toxicity were demonstrated (22). In a recent study of postcardiac surgical patients, we have demonstrated in vitro platelet antiaggregatory effects of a six-hour inhalation of PGI₂ without any in vivo signs of platelet dysfunction (23). Further investigation is also needed to assess the potential antiaggregatory effects of inhaled milrinone on platelets though IV milrinone in postcardiac surgical patients did not impair platelet aggregation significantly (24). Finally, studies are needed to address the potential pulmonary toxicity of inhaled milrinone or its preservative (dextrose) for long-term use.

In summary, in this study of a limited number of patients with increased PVR after cardiac surgery, inhaled aerosolized milrinone induced selective pulmonary vasodilation and appeared to have an additive pulmonary vasodilatory effect to iPGI₂, notably without systemic effects. Inhaled milrinone alone or in combination with iPGI₂ may present a therapeutic option for marginal patients with pulmonary hypertension and severe RV failure after cardiac surgery or heart transplantation.

	Acknowledgments

 
Supported, in part, by the Swedish Medical Research Council (No. 8682), The Medical Faculty of Göteborg (LUA), Göteborg Medical Association, Sahlgrenska University Hospital Foundations and Scandinavian Heart Center Foundations.

	Footnotes

 
Presented in part at an annual meeting of The European Association of Cardiothoracic Anaesthesiologists (EACTA) 1998, June 17th-20th, Bergen, Norway.

	References

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