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Journal of Applied Sciences Research, 6(1): 38-44, 2010 © 2010, INSInet Publication Comparison of Hemodynamic Effects of Inhaled Milrinone and Inhaled Prostacyclin after Adult Cardiac Surgery 1 Nasr Hegazy, MD; 2 Abdelsalam Elhenawy, MD. 1 2 Assistant professor of Anesthesia,Ain Shams University,Egypt Assistant professor of Cardiothoracic surgery, Al Azhar University,Egypt Abstract: Several preoperative conditions increase the risk of developing perioperative pulmonary hypertension in cardiac surgery. The use of inhaled milrinone has recently been described to induce a dose-dependent selective pulmonary vasodilatation in cardiac surgical patients with pulmonary hypertension. Also, aerosolized form of PGI 2 causes a selective dilatation of the pulmonary vessels without systemic hypotension encountered with the intravenous administration. The aim of the present study was to compare the effects of inhaled milrinone and aerosolized prostacyclin on pulmonary and systemic hemodynamic responses in cardiac surgery patients with pulmonary hypertension. 95 patients with pulmonary hypertension electively scheduled for cardiac operations required cardiopulmonary bypass were enrolled in this prospective, randomized non-blind study. The patients were randomly allocated to one of 2 groups, GroupI: Received inhaled milrinone which was administered through endotracheal tube by inhalation preceding the initiation of CPB.5milligrams (1mg/ml) was administered, resulting in a dose ranging from 50-80 ug/kg, over 5 minutes. Group II: Received Epoprostenol which was given through the endotracheal tube by inhalation, preceding the CPB, as Epoprostenol salt dissolved in a sterile glycine buffer, for a concentration of 15 ug/ml.Each patient received 5 ml of solution containing PGI 2. Hemodynamic parameters were measured after induction of anaesthesia (T1) ,15 minutes after nebulization of the study drug(T2) , 15 (T3) and 30 minutes(T4) after weaning from CPB and on arrival to ICU(T5).The hemodynamic variables were: heart rate(HR),mean arterial pressure(MAP), mean pulmonary artery pressure (MPAP),cardiac index(CI),systemic vascular resistance (SVR)and pulmonary vascular resistance (PVR).There were no differences in M AP, M PAP, SVR or PVR among the two groups at any data point. Also, there were no significant differences among the two groups for CI or right ventricular ejection fraction (RVEF) .Patients in prostacyclin group had longer intubation time, ICU LOS, hospital LOS than that in milrinone group.However,none of these differences reach statistical significance. W e concluded that inhaled milrinone is as effective as inhaled prostacyclin in reducing the pulmonary artery pressure and pulmonary vascular resistance without systemic hemodynamic side effects. Key words: Milrinone,prostacyclin,pulmonary hypertension,cardiopulmonary bypass,cardiac surgery dysfunction after CPB carries a poor prognosis with a perioperative mortality ranging from 44% to 86% [7]. The pulmonary vascular endothelium has an important role in regulating the vascular tone by releasing several vasorelaxing and vasoconstrictor substances [5,8]. Several pharmacologic agents have been used to limit the increase in pulmonary vascular resistance after cardiac surgery including nitroglycerin [9,10] milrinone [6,11] prostacyclin (PGI 2) [12,13] and nitric oxide [1,10,14]. In fact, it is a relatively common practice to employ inodilators empirically during separation from CPB in patients with a history of valve disease complicated by pulmonary hypertension with or without right ventricular systolic dysfunction. However ,intravenous administration of many of these agents is INTRODUCTION Pulmonary hypertension is a frequent and morbid condition at the time of cardiac surgery. Several preoperative conditions increase the risk of developing perioperative pulmonary hypertension, including preexisting pulmonary hypertension, mitral stenosis or regurgitation and left ventricular dysfunction [1,2]. During cardiac surgery, pulmonary hypertension and its deleterious effects on the right side of the heart may be aggravated by the release of vasoactive substances d u r in g c a r d io p u lm o n ary b y p a s s ( C P B ) [ 3-5] a nd unfavourable changes in loading conditions which sometimes are imposed on left ventricle as a consequence of valve replacement[6]. Right ventricular Corresponding Author: Nasr Hegazy, Anaesthesia Dept., Faculty of Medicine, Ain Shams University, Egypt. E-mail: [email protected] 38 J. Appl. Sci. Res., 6(1): 38-44, 2010 limited by systemic hypotension because of nonselective vasodilatation [15]. Inhaled vasodilators may circumvent potentially systemic side effects because large concentrations can be selectively presented to pulmonary circulation [16]. Milrinone is a nonglycosidic, nonsympathomimetic, phosphodiesterase III inhibitor that increases intracellular levels of cyclic adenosine monophosphate (cAMP), induces positive cardiac inotropy and systemic vasorelaxation. Doolan et al., [17], in a placebocontrolled study, demonstrated the benefit of intravenous milrinone in facilitating weaning of high risk patients with pulmonary artery mean pressures>20 mmHg from CPB .W hen administered intravenously, milrinone decreases systemic vascular resistance ,causing hypotension [18]. The use of inhaled milrinone has recently been described by Haraldson and colleagues [19] to induce a dose-dependent selective pulmonary vasodilatation in cardiac surgical patients with pulmonary hypertension. Prostacyclin (PGI 2) is an endogenous prostaglandin derived from arachidonic acid metabolism through cyclooxygenase pathway in the vascular endothelium. The physiological effects are the vascular dilatation, inhibition of endothelin secretion, inhibition of platelet aggregation and inhibition of leukocyte adhesion to the endothelium [20]. Due to these systemic side effects, researchers have favoured the bronchial tree as a route of administration, because the aerosolized form of PGI 2 causes a selective dilatation of the pulmonary vessels without systemic hypotension encountered with the intravenous administration [21]. Fattouch and colleagues [22] have shown similar effectiveness for iNO and inhaled prostacyclin for treatment of pulmonary hypertension after mitral valve replacement in a randomized, double-blinded clinical trial. It is stabilized as pharmaceutical preparation by freeze drying and can be reconstituted for use in man in an alkaline glycine buffer [23]. The aim of the present study was to compare the relative effects of inhaled milrinone and aerosolized prostacyclin on pulmonary and systemic hemodynamic responses in cardiac surgery patients with pulmonary hypertension. >30mmHg or mean pulmonary artery pressure >25 mmHg [24] as estimated preoperatively by Doppler echocardiography [25]. Exclusion criteria included emergency surgery, pregnancy, history of recurrent ventricular arrhythmia, left ventricular ejection fraction < 30%, obstructive cardiomyopathy, bleeding diatheses, bronchial asthma or had biochemical evidence of hepatic disease or renal impairment defined as a serum creatinine >2.0 mg/dl. Patients who were preoperatively dependent on inotropes, vasopressors, or vasodilators were excluded from the study. Anesthetic M anagement: All patients received premedication with sublingual lorazepam 2mg ,1-2 hours before surgery.Anesthetic technique was standardized to include fentanyl 10-20ug/kg, midazolam 0.1mg/kg, pancuronium 0.15 to 0.20mg/kg, and isoflurane 0.5% to 1.5% .All patients received tranexamic acid 50 mg/kg intravenously after induction of anesthesia. Each patient was monitored with intraarterial catheter for continuous blood pressure monitoring. A right ventricular ejection fraction(RVEF)cap ab le pulm onary a rte ry c a the ter(Sw an-G anz thermodilution Ejection Fraction/volumetric catheter, Baxter International, Santa Ana,CA)coupled to a RVEF/thermodilution cardiac output computer (RVEF1,Baxter International) was used. It provided continuous pulmonary artery pressure and central venous pressure monitoring, intermittent pulmonary capillary wedge pressure monitoring, thermodilution cardiac output determination, and RVEF determinations. Urinary catheter for monitoring urine output and serial blood gas analysis up to the discretion of attending anaesthesiologist. After surgery, patients were transferred to the intensive care unit for postoperative ventilation .Sedation was achieved with propofol infusion 0.5 to 4 mg/kg / hour and morphine boluses. Patients were extubated according to the standard criteria. Operative Technique and M anagement of CPB:” After median sternotomy, Heparin was given to maintain activated clotting time >400 seconds. M anagement of CPB included systemic temperature drift to 33 oc to 34 oc(nasopharyngeal), alpha-stat pH management, mean perfusion pressure between 60 and 80 mmHg, pump flow rates of 2.0 to 2.4 L/min per square meter, and hematocrit >20%. A single aortic cross clamp technique was used in all patients. Myocardial protection was achieved with intermittent antegrade and occasionally retrograde cold blood cardioplegia. Before separation from CPB, patients were rewarmed to 36 oc - 37 oc.During rewarming, the maximum inflow temperature was limited to 37 oc. M ATERIALS AND M ETHODS After approval by research and ethics committee and obtaining informed consent, 95 patients with pulmonary hypertension electively scheduled for cardiac operations required cardiopulmonary bypass were enrolled in this prospective, randomized non-blind study. Patients were considered to have pulmonary hypertension if systolic pulmonary artery pressure was 39 J. Appl. Sci. Res., 6(1): 38-44, 2010 After separation from CPB, heparin was neutralized with protamine sulphate. The study 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 Y-piece, approximately 15 cm proximal to the endotracheal tube. The mean mass diameter of the particles delivered by this nebulizer from aqueous solution is 2.1um at a rate of 0.25-0.3 ml/min.Nebulization was synchronized to the inspiratory phase with a timing device (Servo Nebulizer 945; Seimens Elema). Humidification of ventilatory circuit was stopped before and during the period of inhalation. Accessory inspiratory gas flow from the nebulizer was compensated for by adjustment of minute ventilation settings on the ventilator, keeping minute ventilation constant. Inspiratory oxygen fraction (FiO 2) was kept constant throughout the procedure. If MAP decreased below 60 mmHg, inhalation of the study drug was stopped and the patient excluded from the study. pulmonary artery diastolic pressure > 15 mmHg, the use of inotropic support for at least 1 hour, intra-aortic balloon pump or CPB reinitiating. Statistical A nalysis: Statistical analyses were performed using SAS version 9.1 (SAS institute, Cary, NC). Categorical variables were summarized as frequencies and percentages; continuous variables as means with standard deviation. A logarithmic transformation was used when a continuous variable was not normally distributed. For continuous variables, comparison of groups was performed using parametric (student’s t test) or non parametric (W ilcoxon) test depending on the distribution. For categorical variables, comparison of groups was performed using Pearson Chi-square test. To test variation between groups and over time, repeated measures with ANOVA with group, time and group x time were performed. A p value of less than 0.05 was considered to indicate statistical significance. RESULTS AND DISCUSSION The patients were randomly allocated to one of 2 groups: A total of 95 patients were enrolled in the study.2 patients were not randomized as they failed to meet the inclusion criteria of pulmonary hypertension on arrival to the operating room. Another patient was withdrawn from the study after randomization, before completion of their study period because of failure of hemodynamic monitoring caused by early dysfunction of the pulmonary artery catheter. Twenty seven patients had CABG, 51 had valve procedures and 14 had combined valvular and CABG.As shown in Table 1, patients were randomized to receive milrinone or prostacyclin were well matched. Specifically, there were no significant difference between the two groups regarding age, gender, weight, height, associated comorbidities and preoperative medications. Also, the two study groups were statistically comparable as regard the type of surgery, CPB time, cross clamp time (table 2) or baseline hemodynamic parameters (table 3). After administration of the study drug (milrinone or prostacyclin), there was no statistically significant difference in MAP, M PAP, SVR or PVR among the two groups at any data point. Also, there was no statistically significant difference among the two study groups for CI or RVEF at any time. At all data points after initiation of the study regimen, the milrinone group tended to have a higher heart rate, although did not reach statistical significance (Table 3). As shown in table (4), 12 patients in milrinone group and 15 patients in prostacyclin group had a difficulty in weaning from CPB as defined in patients Group I: Received inhaled milrinone (Primacor, Sanofi-Synthelabo Canada Inc., M arkham, ON, Canada) which was administered through endotracheal tube by inhalation preceding the initiation of CPB.5milligrams (1mg/ml) was administered, resulting in a dose ranging from 50-80 ug/kg, over 5 minutes. Group II: Received Epoprostenol (Folan, Glaxo W ellcome Inc, Mississauga, ON, Canada) which was given through the endotracheal tube by inhalation, preceding the CPB, as Epoprostenol salt dissolved in a sterile glycine buffer, for a concentration of 15 ug/ml. Each patient received 5 ml of solution containing PGI 2. M easurements: Hemodynamic parameters were measured after induction of anesthesia(T1), 15 minutes after nebulization of the study drug(T2), 15 (T3) and 30 minutes(T4) after weaning from CPB and on arrival to ICU(T5).The hemodynamic variables were: heart rate(HR),mean arterial pressure(MAP), mean pulmonary artery pressure (MPAP),cardiac index(CI),systemic vascular resistance (SVR) right ventricular ejection fraction and pulmonary vascular resistance (PVR). Also, we monitored the vasopressor need in the 1 st 24 hours postoperatively, postoperative intubation time, ICU length of stay(ICU LOS) and hospital length of stay (Hospital LOS). Difficult separation from CPB was defined as systolic blood pressure <80 mmHg, 40 J. Appl. Sci. Res., 6(1): 38-44, 2010 and methods. Also, 7 patients in milrinone group and 5 patients in prostacyclin group needed vasopressor infusion in ICU for >24 hours postoperatively. Also, the noreadrenaline dose needed in milrinone group was higher than that in prostacyclin group. On the other hand, patients in prostacyclin group had longer intubation time, ICU LOS, hospital LOS than that in milrinone group. However, none of these differences shown in Table 4 reached a statistical significance i.e. p$ 0.05. Discussion: Although cardiac index is thought to be a good hemodynamic surrogate endpoint in cardiac surgery, most of large scale studies have confirmed that pulmonary arterial pressure represents the most predictive hemodynamic variable in regard to postoperative outcome [26-28]. The present study sought to determine the differential effect that two recent therapies for pulmonary hypertension in cardiac surgery, inhaled milrinone and inhaled prostacyclin, have on hemodynamic parameters. Table 1: Demographic and preoperative data of the study population Milrinone Group (n=46) Prostacyclin Group ( n=46) P value Demographic Data: Age (years) 63 ±11 59 ±13 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Male/Female(No,) 32/14 30/16 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Weight (Kg) 78 ±10 72 ±17 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Height(cm) 164 ± 10 162 ± 19 >0.05 Preoperative Comorbidities: Hypertension 15 13 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Diabetes Mellitus 9 12 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Peripheral vascular disease 7 8 >0.05 Preoperative Medications: ACE Inhibitors 8 8 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Beta Blockers 11 13 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Diuretics 6 5 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Angiotensin receptor blocker 2 1 >0.05 ËData are presented as mean ±SD or number ËP value #0.05 =statistically significant ËACE=angiotensin converting enzyme Table 2: Operative characteristics Milrinone (n=46) Prostacyclin (n=46) P value CABG n (%) 13(27) 14(30) >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------MVR n (%) 15(32) 15(32) >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------MV Repair n (%) 6(12) 7(15) >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------AVR n (%) 5(9) 4(8) >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Complex procedure n (%) 8(17) 6((13) >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------CPB time (min+SD) 156.7 ±93 127.9 ±53 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Cross clamp time (min+SD) 99 ±67 77.8 ±31.7 >0.05 ËData are presented as mean ± SD, or number (n) and percentage Ë P value #0.05 =Statistical significance ËCABG= coronary artery bypass graft; MVR= mitral valve replacement; MV repair =mitral valve repair; AVR=aortic valve replacement; CPB=cardiopulmonary bypass; complex procedure= CABG + valvular surgery 41 J. Appl. Sci. Res., 6(1): 38-44, 2010 Table 3: Hemodynamic Data T1 T2 T3 T4 T5 HR(bpm) 80±23 87±17 103±14 105±17 103±17* -------------------------------------------------------------------------------------------------------------------------------------------------------MAP(mmHg) 89±15 79±12 75±11 78±10 80±10 -------------------------------------------------------------------------------------------------------------------------------------------------------MPAP(mmHg) 43±13 35±8 26±7* 28±7* 26±6* -------------------------------------------------------------------------------------------------------------------------------------------------------CI (L/min/m2 ) 2.2±0.8 2.2±0.7 2.8±0.6* 2.7±0.7* 2.8±0.8* -------------------------------------------------------------------------------------------------------------------------------------------------------SVR(dyne.sec.cm-5 ) 2014±679 1838±1217 1537±646 1537±633 1504±690 -------------------------------------------------------------------------------------------------------------------------------------------------------PVR(dyne.sec.cm-5 ) 344±229 189±197 175±87* 158±69* 145±82* -------------------------------------------------------------------------------------------------------------------------------------------------------RVEF(%) 26±12 31±12 37±7* 35±10* 35±9* Prostacyclin Group HR(bpm) 75±18 83±19 92±9 99±21* 100±22* -------------------------------------------------------------------------------------------------------------------------------------------------------MAP(mmHg) 87±18 84±12 77±11 78±8 81±15 -------------------------------------------------------------------------------------------------------------------------------------------------------MPAP(mmHg) 39±9 34±9 27±7* 26±9* 27±7* -------------------------------------------------------------------------------------------------------------------------------------------------------CI(L/min/m2 ) 2.3±1.0 2.2±0.7 2.6±0.4 2.7±0.7* 2.6±0.8 -------------------------------------------------------------------------------------------------------------------------------------------------------SVR(dyne.sec.cm-5 ) 1987±592 1804±703 1680±303 1625±287 1589±447 -------------------------------------------------------------------------------------------------------------------------------------------------------PVR(dyne.sec.cm-5 ) 435±321 360±316 159±124* 147±94* 165±99* -------------------------------------------------------------------------------------------------------------------------------------------------------RVEF (%) 27±14 30±9 30±11 35±11* 36±10* ËData are presented as mean±SD Ë* = P value#0.05 =statistically significant compared to the baseline measurement ËT1=after induction of anesthesia; T2=15 minutes after nebulization of the study drug; T3=15minutes after weaning from CPB; T4=30 minutes after weaning from CPB; T5= on arrival to ICU.HR=heart rate; MAP=mean arterial pressure; MPAP= mean pulmonary artery pressure; CI= cardiac index; SVR=systemic vascular resistance; PVR= pulmonary vascular resistance; RVEF= right ventricular ejection fraction ;bpm=beat per minute. Milrinone Group Table4: Postoperative outcome: Milrinone Prostacyclin P value Difficult weaning from CPB (n) 12 15 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Vasopressors > 24hrs 7 5 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Noreadrenaline dose(Mcg/min)(mean+SD) 9.9±8.5 8.1±8.7 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Intubation time(h) (mean±SD) 38±66 48±78 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ICU LOS (days) (mean±SD) 5.6±5.8 5.3±7.5 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Hospital LOS(days) (mean±SD) 12.5±10.6 12.5±14.1 >0.05 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Mortality(n) 1 2 >0.05 ËData are presented as mean ±SD or number (n). ËP value#0.05 =statistically significant ËICU LOS= intensive care unit length of stay; Hospital LOS =hospital length of stay. During the study design, we chose the inhaled milrinone to be 1mg/ml as this dose was demonstrated by Haraldsson and his colleagues [19] to cause the maximum pulmonary vasodilatation without associated side effects. Also, the administration of the study drug in our study was before the cardiopulmonary bypass as it was found in a previous study that inhaled milrinone is more effective if administered before CPB than the post-CPB administration [24]. Both of study drugs induced a statistically significant decrease in PVR and MPAP without statistically significant decrease in MAP and SVR .This indicates that both of treatment strategies have a selective pulmonary vasodilator effect without “spillover” of the drug in the systemic circulation. There was no significant disparity in the cardiac indices of patients treated with inhaled milrinone versus inhaled prostacyclin. It might have been anticipated that 42 J. Appl. Sci. Res., 6(1): 38-44, 2010 the patients in the milrinone group would have a a statistically significant higher cardiac index and RVEF on the basis of milrinone being a positive inotrope. However, this can be explained on the basis of unloading the right ventricle by prostacyclin, similar to that produced by milrinone, allowed the right ventricle to work as effective as that in the milrinone group. The milrinone treated patients tended to have a higher heart rate when compared with prostacyclin group. However, this difference did not reach statistical significance. It is unclear if the lower MAP in the milrinone group induced a reflex tachycardia or the higher heart rate was a result of chronotropic effect of milrinone. Although patients treated with inhaled milrinone had a shorter intubation time, ICU LOS, hospital LOS, these differences were statistically insignificant. These findings of our study were comparable to that demonstrated in previous studies about milrinone [16,18,19,24,29] or prostacyclin [13,19,21,22] which studied therapeutic modalities of pulmonary hypertension in experimental animals and humans. 5. 6. 7. 8. 9. 10. Conclusion: CPB causes an increase in pulmonary vascular resistance, which may induce right ventricular dysfunction. This study comparing the effects of inhaled milrinone and inhaled prostacyclin on the pulmonary vasculature in cardiac surgery demonstrated that inhaled milrinone is as effective as inhaled prostacyclin in reducing the pulmonary artery pressure and pulmonary vascular resistance without systemic hemodynamic side effects. 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