|Year : 2015 | Volume
| Issue : 4 | Page : 474-478
Cardiovascular effects of prolonged milrinone inhalation in patients with pulmonary hypertension undergoing mitral valve replacement
Sherif S Sultan MD , Khaled M.A. Abdelsalam
Department of Anesthesia and Intensive Care, Faculty of Medicine, Ain Shams University, Cairo, Egypt
|Date of Submission||06-Jun-2014|
|Date of Acceptance||31-Aug-2014|
|Date of Web Publication||29-Dec-2015|
Sherif S Sultan
24 Muhammad Al-Maqreef St, Nasr City, Cairo 11762
Source of Support: None, Conflict of Interest: None
Inhaled milrinone has short-acting selective pulmonary vasodilator effect.
The aim of the study was to investigate the cardiovascular effects of prolonged inhalation of nebulized milrinone on patients with pulmonary hypertension undergoing mitral valve replacement.
Settings and design
This is a controlled, randomized, double-blinded study.
Patients and methods
Forty patients were divided into two groups: the milrinone group and the control group. The milrinone group received milrinone nebulization before cardiopulmonary bypass (CPB) as the loading dose at 50 mg/kg, followed by a maintenance dose of 0.5 mg/kg/min, which was continued for 2 h after tracheal extubation. The control group received an equivalent volume of 0.9% sodium chloride. The measured and calculated variables included heart rate, mean arterial blood pressure, central venous pressure, mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure, cardiac index (CI), pulmonary vascular resistance (PVR), and systemic vascular resistance. The time points of measurements and calculations were as follows: at T 0 - after anesthesia induction and before sternotomy; at T 1 - 20 min after CPB cessation; at T 2 - 1 h after CPB cessation; at T 3 - 3 h after CPB cessation; at T 4 - 1 h after tracheal extubation; and at T 5 - 1 h after milrinone discontinuation. The duration of CPB and time of tracheal extubation were recorded.
The milrinone group showed significant reduction in mPAP (T 2 to T 4 readings), pulmonary capillary wedge pressure (T 3 reading), and PVR (T 2 to T 4 readings), increase in CI (T 3 and T 4 readings), and shorter CPB duration and tracheal extubation time.
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.
Keywords: inhaled milrinone; mitral valve replacement; pulmonary hypertension
|How to cite this article:|
Sultan SS, Abdelsalam KM. Cardiovascular effects of prolonged milrinone inhalation in patients with pulmonary hypertension undergoing mitral valve replacement. Ain-Shams J Anaesthesiol 2015;8:474-8
|How to cite this URL:|
Sultan SS, Abdelsalam KM. Cardiovascular effects of prolonged milrinone inhalation in patients with pulmonary hypertension undergoing mitral valve replacement. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2018 Apr 22];8:474-8. Available from: http://www.asja.eg.net/text.asp?2015/8/4/474/172666
| Introduction|| |
Pulmonary hypertension (PH) is a major determinant of outcome after cardiac surgery  . In patients with PH undergoing mitral valve replacement (MVR), many factors may affect the pulmonary arterial pressure (PAP). Before cardiopulmonary bypass (CPB), hypoxia, hypercarbia, or positive pressure ventilation may increase PAP  . Inflammatory process secondary to CPB  or blood transfusion  is known to markedly affect PAP. Protamine administration may cause PH in different ways  . Postoperatively, factors such as hypoxia, hypercarbia, positive pressure ventilation, pulmonary embolism, patient-prosthesis mismatch  , or left ventricular dysfunction  may increase PAP. PH may proceed to right ventricular failure  , delay weaning from CPB, or even delay weaning from mechanical ventilation  . Therefore, a selective pulmonary vasodilator may be needed for a prolonged period to face possible factors that might affect PAP throughout the long perioperative period.
Inhaled milrinone proved to be a successful selective pulmonary vasodilator. It induces a dose - response decrease in PAP and pulmonary vascular resistance (PVR). No systemic hypotension was observed during its use  . However, the hemodynamic effects of inhaled milrinone persists only for 20 min after cessation of its inhalation  . Just as PAP may need to be controlled for a prolonged period, this short duration of inhaled milrinone may need to be prolonged as well. In cardiac surgery, inhaled milrinone was used as a bolus dose before  or after , CPB. Wang et al.  used it as maintenance dose for 4 h postoperatively and before tracheal extubation.
This study aimed to investigate patients with PH undergoing MVR for cardiovascular effects of prolonged inhalation of nebulized milrinone starting before CPB and continuing for 2 h after tracheal extubation. Duration of CPB, time needed for tracheal extubation, and amounts of vasoactive drugs used were reported.
| Patients and methods|| |
This controlled, randomized, double-blinded study was performed after obtaining approval from the Research Ethics Committee. Written informed consent was taken from 40 patients scheduled for MVR. The primary indication for surgery was isolated mitral stenosis or isolated mitral regurgitation, or their combination. The patients included in the study were aged 17-45 years and all of them had ejection fraction over 40% and mean pulmonary artery pressure (mPAP) greater than 25 mmHg. Patients with emergency or re-do surgeries were excluded. Exclusion criteria also included severe renal or hepatic disease, coagulopathy, and thromboembolic disease treated with anticoagulants.
On arrival at the operating room patients were attached to an ECG, pulse oximeter, and noninvasive blood pressure monitor; thereafter, a radial artery catheter was inserted under a local anesthetic. Induction of anesthesia included intravenous fentanyl (3-5 mg/kg) and propofol (1-2 mg/kg). Cisatracurium at 0.15 mg/kg was used to facilitate endotracheal intubation, followed by incremental doses to maintain muscle relaxation afterward. Anesthesia was maintained with sevoflurane (0.4-2%) and incremental doses of fentanyl. Propofol infusion 1% (8-12 ml/h) was used during CPB. Ventilation was adjusted to establish an end-tidal CO 2 of 32-36 mmHg. CPB was established for all patients and the core temperature was actively cooled to 32-34°C during CPB. All patients were monitored with ECG, pulse oximetry, a radial artery catheter, capnography, and a pulmonary artery catheter (Model 131H-7F; Edwards Laboratory, Santa Ana, California, USA). The measured hemodynamic variables included heart rate, mean arterial blood pressure (mABP), central venous pressure, mPAP, pulmonary capillary wedge pressure, and cardiac output (Datex-Ohmeda Inc., MA, USA). Cardiac output was measured with the thermodilution method at the end of expiration using 10 ml of iced dextrose 5%. The mean of three measures was taken for a single reading. The calculated hemodynamic variables included cardiac index (CI), PVR, and systemic vascular resistance. Calculations were performed using standard formulas  .
On completion of the procedure and starting of spontaneous heart beats, pharmacologic support was started. It consisted of adrenaline infusion at a rate of 0.05-0.2 mg/kg/min and nitroglycerin infusion at a rate of 0.5-5 mg/kg/min. Norepinephrine and dobutamine were also available. The choice and rate of vasoactive drugs were adjusted according to patient needs by the anesthetist intraoperatively and by the intensivist postoperatively.
Patients were randomly divided into two groups: the milrinone group and the control group. The milrinone group received inhaled milrinone and the control group received inhalation of an equivalent volume of 0.9% sodium chloride instead. Milrinone (Primacor; Sanofi-aventis, Auckland, New Zealand) was prepared and administered as a loading dose (50 mg/kg diluted to 5 ml in 0.9% sodium chloride) followed by a maintenance dose (0.5 mg/kg/min, that is, 30 mg/kg in each 8 ml), which continued until 2 h after weaning from mechanical ventilation. Randomization was performed by the hospital pharmacy through a computer-generated sequence contained in sealed, opaque envelopes. Thereafter, two prefilled syringes (one 5-ml syringe for the loading dose and one 60-ml syringe for the maintenance dose) containing either milrinone according to the patient's body weight or saline were sent to the operating room. The anesthesiologist, the intensivist, and the nurse collecting data were not informed about the nature of the nebulized drug.
The inhaled agent was administered with jet nebulizers that are attached to the inspiratory limb of the ventilator circuit 10-15 cm from the endotracheal tube (or face mask used after tracheal extubation). The loading dose was administered by means of the jet nebulizer (Salter Labs, Arvin, California, USA) over 10 min using a bypass flow of 8 l/m. The maintenance dose was administered by the jet nebulizer (MiniHeart; Westmed Inc., Tucson, Arizona, USA) using a bypass flow of 2 l/m. The nebulizer was constantly replenished with the study drug solution, which was delivered through a syringe pump set at 8 ml/h. The FiO 2 of the nebulizer driving gas was the same as that being delivered by the mechanical ventilator.
The criteria to start weaning from CPB included hemodynamic stability (heart rate>60/min and mABP >65 mmHg), hemostatic stability (no major surgical bleeding), and core temperature greater than 36°C  . The duration of CPB was recorded. Criteria for tracheal extubation were full consciousness, hemodynamic stability, core temperature greater than 36.4°C, and chest drainage less than 50 ml/h , .
The time points of measurements and calculations were as follows: T 0 - after induction of anesthesia and before sternotomy; T 1 - 20 min after cessation of CPB; T 2 - 1 h after cessation of CPB; T 3 - 3 h after cessation of CPB; T 4 - 1 h after tracheal extubation; and T 5 - 1 h after discontinuation of milrinone. The study drug was terminated 2 h after tracheal extubation. Time of tracheal extubation (time between cessation of CPB and tracheal extubation) was recorded. Total amounts of vasoactive drugs were recorded.
As per Wang et al.  , mPAP was estimated to decrease about 8 mmHg under the effect of inhaled milrinone. The SD used in the study population of Wang and colleagues was 8.9. Therefore, 17 patients per group would be sufficient to give 80% power at a 5% significance level. We enrolled 20 patients in each group.
Data were presented as mean ± SD except for sex and type of surgery, for which number of patients was used. The unpaired Student t-test was used for comparison between the two groups at each time point of measurement and calculations for all variables except sex and type of surgery, for which the chi-square test was used. Statistical analysis was carried out using SPSS statistical package (version 15; SPSS Inc., Chicago, Illinois, USA), for Windows. A value of P less than 0.05 was considered statistically significant.
| Results|| |
No significant changes were noted between groups with respect to patient demographics and types of surgery [Table 1]. [Table 2] shows the values of the hemodynamic variables in the two groups. No statistically significant differences were noted between the two groups with respect to heart rate, mABP, central venous pressure, and systemic vascular resistance. The milrinone group showed a statistically significant reduction in mPAP (T 2 , T 3 , and T 4 readings), pulmonary capillary wedge pressure (T 3 reading), and PVR (T 2 , T 3 , and T 4 readings). The milrinone group showed a statistically significant increase in CI (T 3 and T 4 readings). No changes were noted between the two groups in T 5 readings for any of the hemodynamic variables. [Table 3] shows a significantly shorter duration of CPB and earlier tracheal extubation in the milrinone group. It also shows that significantly bigger amounts of nitroglycerine and dobutamine were used in the control group.
| Discussion|| |
PH is one of the important factors that predict outcome after cardiac surgery. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) estimates that operative mortality for adult patients undergoing open heart surgery increases two-fold because of PH  . Different therapeutic modalities were used for the treatment of PH. Intravenous vasodilators have the disadvantages of inducing systemic hypotension and may affect right ventricular coronary perfusion  . Inhaled therapy has the advantage of delivering high concentration of vasodilator drugs selectively to the pulmonary circulation. Inhaled nitric oxide was proven to be efficacious in treating PH  . However, it is not available in all hospitals where cardiac surgery is performed. Alternatively, selective pulmonary vasodilatation could be achieved through nebulization of systemic vasodilators directly to the pulmonary circulation. Drugs used in this situation include nitroprusside  , nitroglycerin  , prostacyclin  , and milrinone  . Inhalation of nitroglycerin for long periods carries the risk of methemoglobinemia  . Prostacyclin has the disadvantages of high cost and rebound PH after cessation of its inhalation  .
Inhaled milrinone was proven to be effective in decreasing PAP after cardiac surgery  . The effect of inhaled milrinone is short acting and ceased after about 20 min in the study by Haraldsson et al.  and by 30min in the study by Sablotzki et al.  . In the present study, the method described allows the administration of milrinone in a continuous nebulization for hours , . The loading dose used in the present study was chosen to be equal to the loading intravenous dose. The mean body weight in the present study was 64 and 62 kg in the two groups. This makes the loading dose a little above 3 mg, which is comparable to the dose in the study by Haraldsson et al.  and less than that in the study by Lamarche et al.  (up to 80 mg/kg).
The maintenance dose described in the present study was chosen so as not to exceed the total allowed intravenous dose. It is considered safe for two reasons. First, if milrinone is expected to have effects behind the pulmonary circulation, the complications will manifest as systemic effects of milrinone in the form of systemic vasodilatation, hypotension, and tachycardia. These systemic effects are usual when milrinone is utilized after CPB as an inodilator and easy to counteract in cases of cardiac anesthesia if these effects are not needed. Second, no systemic effects were encountered during conduction of the study and the vasopressors used in the milrinone group were comparable to those in the control group. If we consider that only 10% of a nebulized agent can reach the alveoli  , the possibility that all of the administered dose of milrinone might reach the circulation and induce systemic effects is a remote possibility. The dose of inhaled agents may be 5-10 times that of the intravenous dose. Prostacycline's plateau intravenous dose is 7.2 ± 3.4 ng/kg/min  , whereas the inhalation dose is around 50 ng/kg/min  .
Single-dose inhaled milrinone induces significant reduction in mPAP and PVR index, with no affection of mABP or systemic vascular resistance , . These effects are considered dose-dependent and short acting  . No differences were noted when milrinone was inhaled before CPB versus after CPB in terms of CPB duration and tracheal extubation time  . However, in the present study we compared these effects with control and the results showed significant reduction in CPB duration and tracheal extubation time. In the present study we tried to prolong the effects of inhaled milrinone by extending the inhalation time, which allowed prolonged reduction in mPAP. These effects are beneficial in cases of cardiac surgery because, if right ventricular dysfunction developed after CPB, mortality would be very high (44%)  .
PH per se does not predispose the patient to prolonged postoperative ventilation after open heart surgery  . However, valve surgery is an important factor that constitutes a high risk for prolonged postoperative ventilation  . Maintaining low PVR may be desired to augment cardiac output, allowing weaning from mechanical ventilation. Schulze-Neick et al.  proved a direct correlation between high PVR and prolonged ventilation after cardiac surgery involving CPB.
The amounts of nitroglycerine and dobutamine used in the study were significantly lower in the milrinone group compared with the control group. This may be explained by the need to control the existing PH that may be exaggerated after CPB through the use of systemic drugs in the control group. The possibility that this lower use of nitroglycerine and dobutamine in the milrinone group is due to the systemic effects of milrinone is unlikely because hypotension was not recorded and the amounts of vasopressors used in the milrinone group were comparable to the control group.
| Conclusion|| |
Prolonged inhalation of nebulized milrinone proved to be feasible for patients with PH undergoing MVR. It decreased PVR and PAP while increasing the CI. This helped shorter CPB duration and earlier tracheal extubation. No systemic effects of milrinone were noted throughout the study. Future studies are encouraged to understand the pharmacokinetics of continuous inhalation of nebulized milrinone and the optimum dose to be utilized.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
| References|| |
Denault AY, Lamarche Y, Couture P, Haddad F, Lambert J, Tardif JC, Perrault LP. Inhaled milrinone: a new alternative in cardiac surgery? Semin Cardiothorac Vasc Anesth 2006; 10: 346-360.
Fischer LG, Van Aken H, Bürkle H. Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists. Anesth Analg 2003; 96:1603-1616.
Lesage AM, Tsuchioka H, Young WG Jr, Sealy WC. Pathogenesis of pulmonary damage during extracorporeal perfusion. Arch Surg 1966; 93:1002-1008.
Kaul TK, Fields BL. Postoperative acute refractory right ventricular failure: incidence, pathogenesis, management and prognosis. Cardiovasc Surg 2000;8:1-9.
Viaro F, Dalio MB, Evora PR. Catastrophic cardiovascular adverse reactions to protamine are nitric oxide/cyclic guanosine monophosphate dependent and endothelium mediated: should methylene blue be the treatment of choice? Chest 2002; 122:1061-1066.
Magne J, Mathieu P, Dumesnil JG, Tanné D, Dagenais F, Doyle D, Pibarot P. Impact of prosthesis-patient mismatch on survival after mitral valve replacement. Circulation 2007; 115:1417-1425.
Bakhtiary F, Schiemann M, Dzemali O, Dogan S, Schächinger V, Ackermann H, et al.
Impact of patient-prosthesis mismatch and aortic valve design on coronary flow reserve after aortic valve replacement. J Am Coll Cardiol 2007; 49:790-796.
Haraldsson s A, Kieler-Jensen N, Ricksten SE. The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension. Anesth Analg 2001; 93:1439-1445.
Schulze-Neick I, Li J, Penny DJ, Redington AN. Pulmonary vascular resistance after cardiopulmonary bypass in infants: effect on postoperative recovery. J Thorac Cardiovasc Surg 2001; 121:1033-1039.
Sablotzki A, Starzmann W, Scheubel R, Grond S, Czeslick EG. Selective pulmonary vasodilation with inhaled aerosolized milrinone in heart transplant candidates. Can J Anaesth 2005; 52:1076-1082.
Lamarche Y, Perrault LP, Maltais S, Tétreault K, Lambert J, Denault AY. Preliminary experience with inhaled milrinone in cardiac surgery. Eur J Cardiothorac Surg 2007; 31:1081-1087.
Wang H, Gong M, Zhou B, Dai A. Comparison of inhaled and intravenous milrinone in patients with pulmonary hypertension undergoing mitral valve surgery. Adv Ther 2009; 26:462-468.
Melo J, Peters JI. Low systemic vascular resistance: differential diagnosis and outcome. Crit Care 1999; 3:71-77.
Licker M, Diaper J, Cartier V, Ellenberger C, Cikirikcioglu M, Kalangos A, et al.
Clinical review: management of weaning from cardiopulmonary bypass after cardiac surgery. Ann Card Anaesth 2012; 15:206-223.
Knapik P, Ciesla D, Borowik D, Czempik P, Knapik T. Prolonged ventilation post cardiac surgery - tips and pitfalls of the prediction game. J Cardiothorac Surg 2011; 6:158.
Siddiqui MM, Paras I, Jalal A. Risk factors of prolonged mechanical ventilation following open heart surgery: what has changed over the last decade? Cardiovasc Diagn Ther 2012; 2:192-199.
Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999; 16:9-13.
Brilli RJ, Krafte-Jacobs B, Smith DJ, Passerini D, Moore L, Ballard ET. Aerosolization of novel nitric oxide donors selectively reduce pulmonary hypertension. Crit Care Med 1998; 26:1390-1396.
Palhares DB, Figueiredo CS, Moura AJ. Endotracheal inhalatory sodium nitroprusside in severely hypoxic newborns. J Perinat Med 1998; 26:219-224.
Yurtseven N, Karaca P, Kaplan, M Ozkul V, Tuygun AK, Aksoy T, et al.
Effect of nitroglycerin inhalation on patients with pulmonary hypertension undergoing mitral valve replacement surgery. Anesthesiology 2003; 99:855-858.
Van Heerden PV, Barden A, Michalopoulos N, Bulsara MK, Roberts BL. Dose-response to inhaled aerosolized prostacyclin for hypoxemia due to ARDS. Chest 2000; 117:819-827.
Lowson SM. Inhaled alternatives to nitric oxide. Anesthesiology 2002; 96:1504-1513.
Thomas SH, O'Doherty MJ, Fidler HM, Page CJ, Treacher DF, Nunan TO. Pulmonary deposition of a nebulised aerosol during mechanical ventilation. Thorax 1993; 48: 154-159.
Opitz CF, Wensel R, Bettmann M, Schaffarczyk R, Linscheid M, Hetzer R, Ewert R. Assessment of the vasodilator response in primary pulmonary hypertension. Comparing prostacyclin and iloprost administered by either infusion or inhalation. Eur Heart J 2003; 24:356-365.
Dávila-Román VG, Waggoner AD, Hopkins WE, Barzilai B. Right ventricular dysfunction in low output syndrome after cardiac operations: assessment by transesophageal echocardiography. Ann Thorac Surg 1995; 60:1081-1086.
[Table 1], [Table 2], [Table 3]