Heart Vessels DOI 10.1007/s00380-014-0564-x
ORIGINAL ARTICLE
Myocardial protection of early extracorporeal membrane oxygenation (ECMO) support for acute myocardial infarction with cardiogenic shock in pigs Gang-jie Zhu • Li-na Sun • Xing-hai Li • Ning-fu Wang Hong-hai Wu • Chen-xing Yuan • Qiao-qiao Li • Peng Xu • Ya-qi Ren • Bao-gen Mao
•
Received: 3 December 2013 / Accepted: 1 August 2014 Ó Springer Japan 2014
Abstract The aim of this study was to explore myocardial protection of early extracorporeal membrane oxygenation (ECMO) support for acute myocardial infarction with cardiogenic shock in pigs. 24 male pigs (34.6 ± 1.3 kg) were randomly divided into three groups—control group, drug therapy group, and ECMO group. Myocardial infarction model was created in drug therapy group and ECMO group by ligating coronary artery. When cardiogenic shock occurred, drugs were given in drug therapy group and ECMO began to work in ECMO group. The pigs were killed 24 h after cardiogenic shock. Compared with in drug therapy group, left ventricular end-diastolic pressure in ECMO group decreased significantly 6 h after ligation (P \ 0.05). At the end of the experiments, LV - dp/ dt among three groups was significantly different, drug therapy group \ ECMO group \ control group. There was no difference in LV ? dp/dt between drug therapy group and ECMO group. Compared with drug group, myocardial infarct size of ECMO group did not reduce significantly, but myocardial enzyme and troponin-I decreased significantly. Compared with drug therapy, ECMO improves left ventricular diastolic function, and may improve systolic function. ECMO cannot reduce myocardial infarct size
G. Zhu L. Sun N. Wang (&) P. Xu Y. Ren Department of Cardiovasology, Affiliated Hangzhou Hospital of Nanjing Medical University, No.261, Huansha Road, 310006 Hangzhou City, China e-mail: [email protected] X. Li B. Mao Department of Cardiac Surgery, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou City, China H. Wu C. Yuan Q. Li Zhejiang University, Hangzhou City, China
without revascularization, but may have positive effects on ischemic areas by avoiding further injuring. Keywords Myocardial protection Extracorporeal membrane oxygenation (ECMO) Acute myocardial infarction Cardiogenic shock Pigs
Introduction Venoarterial extracorporeal membrane oxygenation (VAECMO) based approach is used for urgent hemodynamic stabilization in patients with cardiopulmonary failure, such as profound cardiogenic shock, cardiac arrest, etc. [1, 2]. This approach, also referred to as extracorporeal cardiopulmonary resuscitation (E-CPR), allows perfusion of vital organs during profound cardiogenic shock and provides a time span for myocardial recovery. Medicine supportive treatment and revascularization are very important for patients with cardiogenic shock after myocardial infarction. But when hemodynamics is still unstable with sufficient drugs, extracorporeal circulatory support is always necessary [3], which can decrease cardiac loading and myocardial oxygen consumption, and thus shorten recovery of stunned myocardium [4]. VA-ECMO is an optimal choice of extracorporeal circulatory support. It can improve systolic blood pressure (SBP), diastolic blood pressure (DBP) and tissue perfusion, meanwhile reduce cardiac preload [3– 5]. However, at present, there has been little research, especially in large animal, on myocardial protection of ECMO for acute myocardial infarction with cardiogenic shock (AMI-CS). The experiment established an AMI-CS model in pigs, and explored myocardial protection of early VA-ECMO support for AMI-CS in pigs.
123
Heart Vessels
Materials and methods This study was approved by IRB of Affiliated Hangzhou Hospital of Nanjing Medical University and performed at the Animal Laboratory, Department of Pharmacy, Zhejiang University in Hangzhou in accordance with the NIH Animal Care and Use Committee guidelines. Materials 24 Guangxi Bama male minipigs, 4–5 months old, weighing 34.6 ± 1.3 kg, were obtained from the animal experimental center of Zhejiang University. The pigs were randomly divided into three groups—Group C (shamoperation control group), Group T1 (drug therapy group), and Group T2 (ECMO group). And 22 pigs finished the experimental protocol. In the study, we used an animal ventilator (ALC-V10, Aoerkete, Shanghai, China, parameters setting: oxygen concentration 50 %, tidal volume 220 ± 20 ml, rate 20 ± 5 per min), blood gas analyzer (GEM3000, instrumentation laboratory company, USA), ECMO (including an Centrifugal Pump: Medtronic 550,Medtronic Inc, USA, and pediatric cannula: Medtronic silicone, Medtronic Inc, USA).
and connected to ECMO. Heparin (1 mg/kg, IV) was given before ECMO started. During ECMO support, activated clotting time (ACT) was monitored, and maintained between 180 and 220 s. Establishment of myocardial infarction model Incise tissues along with the median sternal line after regular sterilization. Open the sternum, incise and suspend the pericardium, expose the heart and left anterior descending coronary artery (LAD). Ultrasound flowmeter (T400, Transonic, USA) was placed after the first diagonal branch for monitoring the LAD flow rate. According to the LAD flow rate, ligate the LAD between the first diagonal branch and the second diagonal branch in Groups T1 and T2. Group C was threaded but was not ligated. Monitoring Puncture the ascending aorta, catheterize a cannula into the left ventricle by a guiding wire, connect the cannula to a pressure switch, and monitor the left ventricular pressure continually. Experimental protocol
Anesthesia After 24 h fasting, anesthesia was induced by azaperone (2 mg/kg IM), ketamine (15–20 mg/kg, intraperitoneal injection), and atropine (0.02 mg/kg, IM). Anesthesia was continued with initial propofol (2 mg/kg IV). Continuous IV infusion of propofol (8–10 mg/kg/h) was used to maintain anesthesia, the depth of which was regularly assessed by photoreaction and corneal reflex. Preoperative preparation The pigs were intubated (7F) by tracheostomy under anesthesia, and the tube was connected to the animal ventilator. Left femoral vein was intubated for liquid infusion and blood samples. Left femoral artery was intubated for monitoring peripheral arterial blood pressure by a pressure switch. Besides, electrocardiogram monitoring was performed. Establishment and management of ECMO ECMO and its cannula were pre-filled with Polygeline Injection and Sodium Lactate Ringer’s Injection (300 ml, respectively, and heparin: 1 mg/100 ml). Incise the skin along with the right groin after sterilization, and dissect the femoral artery and vein. Afterwards, the femoral artery and vein were catheterized with 12F and 14F ECMO cannulas
123
Large doses of dopamine (5–10 lg/kg min), and norepinephrine (0.1–0.2 lg/kg min) began to be used in Group T1 and ECMO began to work in Group T2 when cardiogenic shock occurred (systolic blood pressure \90 mmHg). The pigs were killed 24 h after cardiogenic shock. Measurement of myocardial infarction area (MIA) Infuse 2 % Evans Blue by the aorta before killing the pig to distinguish between ischemic area and non-ischemic area. And then, kill the pig, cut-off large vessels, atria and right ventricle. Place the heart in a -20° C refrigerator for 30 min. After that, cut the left ventricle into 2 mm thick slices, and incubate the slices in triphenyl tetrazolium chloride phosphate buffer solution (TTC-PBS) for 30 min at 37° C. The brick red area was myocardium of infarction and off-white area was myocardium of non-infarction. Collect images of slices by an image acquisition system, and measure MIA by Image Pro Plus. MIA = total area of myocardial infarction of left ventricular tissues slices/total area of left ventricular tissues slices 9 100 %. Data collection and statistics analysis We collected physical data, including LVEDP, LV dp/dt and peripheral arterial pressure, and hematology data,
Heart Vessels Table 1 Peripheral systolic blood pressure Group
Before ligation
4h
8h
12 h
16 h
20 h
24 h 103 ± 5.0
C, N = 7
129 ± 8.5
121 ± 7.1
117 ± 6.9
118 ± 7.1
112 ± 7.1
115 ± 5.4
T1, N = 7
127 ± 9.7
96 ± 5.4
97 ± 4.7
91 ± 7.3
94 ± 4.1
95 ± 6.2
95 ± 6.0
T2, N = 8
130 ± 8.5
99 ± 7.5
96 ± 6.1
99 ± 7.0
96 ± 5.2
96 ± 6.0
98 ± 6.1
Values are presented as mean ± standard deviation
including blood gas analysis and myocardial enzyme (collected from the coronary sinus). The data collection time points include: before ligation, and every 2 h after ligation. All the statistical analyses were performed by SPSS 17.0. ANOVA and q test was performed for different analyses of each group. P values \0.05 were considered statistically significant.
Myocardial infarction area and myocardial enzyme, troponin I In our study, we adapted the area method to calculate the infarction size. As shown in Table 3, there was no difference between Groups T1 and T2 (P = 0.377). However, the
Results Peripheral blood pressure We controlled peripheral systolic blood pressure of about 100 mmHg in Groups T1 and T2, by adjusting drugs and the flow of ECMO (Table 1). Left ventricular end-diastolic pressure (LVEDP) At baseline, there was no difference among three groups regrading LVEDP, which increased after ligation in Groups T1 and T2. The difference began to be significant 6 h after ligation in Groups T1 and T2, and became more significant over time (Fig. 1). The biggest difference of LVEDP between Groups T2 and C appeared 10 h after ligation (P \ 0.001). In the following time, the difference reduced gradually, even reversed at last. But the reversed difference was not significant (P = 0.102).
Fig. 1 Left ventricular end-diastolic pressure
LV dp=dt As shown in Fig. 2 and Table 2, LV ? dp/dt increased briefly after intravenous injection of dopamine and norepinephrine in Group T1, and then decreased gradually. But this change did not occur in LV - dp/dt (Fig. 3 and Table 2). In Group T2, there was no rise in LV ± dp/ dt after starting ECMO, but the rate of decline was slowly down obviously. At the end of the experiments, there was significant difference in LV - dp/dt among three groups (Group C \ Group T1 \ Group T2); compared with in Groups T1 and T2, LV ? dp/dt in Group C was different significantly, but there was no difference between Groups T1 and T2. In addition, the impaired LV - dp/dt was sightly earlier than the impaired LV ? dp/dt.
Fig. 2 LV ? dp/dt
123
difference of creatine kinase MB (CKMB) and troponin I (TNI) between Groups T1 and T2 was significant (Table 3). \0.01
315.5 ± 19.5
615.3 ± 14.4
172.8 ± 18.0
LV2
Heart Vessels
0.019 0.104 P* values
152.6 ± 15.9
319.8 ± 34.4
347.2 ± 30.6
441.1 ± 24.8
T1
T2
621.2 ± 23.1 972.8 ± 40.8 C
LV
LV
2
Group
0.271 P* values
Values are presented as mean ± standard deviation. LV1 and LV2 are LV ? dp/dt and LV - dp/dt, respectively * P values = P values (T1,T2)
\0.01 0.062 0.083
\0.01
277.0 ± 22.8
124.8 ± 10.7 265.4 ± 23.3
406.1 ± 18.6
136.3 ± 8.7 285.1 ± 18.7
299.3 ± 15.8
603.9 ± 18.6 978.0 ± 32.7
LV
1 1
437.6.4 ± 22.5
LV
953.0 ± 25.7
LV1
24 h 20 h 16 h
0.021 0.124
1030.9 ± 83.3
0.801
406.3 ± 19.6 509.9 ± 22.5
627.6 ± 34.3
T2
672.5 ± 41.1
675.5 ± 14.0
1009.8 ± 41.7 647.3 ± 41.5
667.5 ± 31.8
1023 ± 49.8
989.9 ± 69.8
C
T1
LV LV LV LV
288.1 ± 25.8
2
0.167
464.0 ± 18.9
975.7 ± 32.0
565.9 ± 48.5
LV
1
8h
2 1
4h
2 1
0h Group
Table 2 Changes of LV ± dp/dt
123
627.0 ± 13.6
LV2
0.470 0.014
472.6 ± 28.6 357.1 ± 19.7
460.4 ± 36.0
978.2 ± 30.6 622.5 ± 25.8
208.9 ± 23.1
LV1 LV
2
12 h
Discussion For the treatment of acute myocardial infarction with cardiogenic shock, it is primarily aimed at recovering and maintaining the perfusion pressure of vital organs, saving ischemic myocardium and restricting infarction scope [6]. ECMO can reach the goal of maintaining blood pressure and perfusion pressure by improving systolic pressure, diastolic pressure, mean arterial pressure and coronary flow [1, 2, 4]. In addition, ECMO unloads preload to reduce cardiac work, which can promote the functional recovery of stunned myocardium and improve cardiac systolic and diastolic function [4, 7]. However, there are few studies to confirm the improvement of cardiac systolic function or diastolic function, or both. ECMO unloads cardiac preload effectively, and maintains perfusion of vital organs. Meanwhile, ECMO increases cardiac afterload in some degree because of elevation of blood pressure, which has adverse impact on myocardial cell recovery. Therefore, peripheral systolic blood pressure of pigs in our experiments was controlled at a level of 100 mmHg so that cardiac afterload would not excessively increase on the premise of sufficient perfusion. In the study, we adopted LV ± dp/dt to evaluate cardiac systolic and diastolic function and LVDEP to reflect cardiac preload and part of systolic and diastolic function in pigs. From our experiments, we observed LVEP in Group T2 reduced more significantly than which in Group T1, and with the prolonging of time, this trend was more obvious. Meanwhile, the difference of LVDEP between Groups T2 and C reduced gradually over time. Interestingly, the difference was reversed at last, which might be attributed to effective unloading of cardiac preload. But whether this reversion could take a positive effect (such as rate of weaning, survival, etc.) on long-term results, it still needs more work. As shown in Table 2 and Fig. 2, the changes of LV ? dp/dt were not consistent with the changes of LV dp/dt. This difference suggested that recovery of cardiac diastolic function was better (or earlier) than recovery of systolic function. We supposed it might be related to the fact that ECMO increased cardiac afterload. Despite we had made a balance between maintaining perfusion pressure and reducing cardiac afterload, the difference occurred. Therefore, there is a reason to suspect that the difference among three would be more significant, and profoundly effected survival time and rate, if obvious time was prolonged. In Group T1, pressor agents and cardiac stimulants could increase LV dp/dt and peripheral arterial
Heart Vessels Table 3 Myocardial infarction area and myocardial enzyme, TNI from three groups Group C Infarction area CKMB1 TNI1 2
CKMB TNI2
–
Group T1
Group T2
P values (T1,T2)
42.2 ± 5.9
39.4 ± 5.0
0.337
51.3 ± 11.8
148.2 ± 17.9
114.8 ± 14.2
0.001
0.118 ± 0.106
30.6 ± 5.9
21.0 ± 2.0
0.012
62.5 ± 9.9
192.6 ± 22.4
157.7 ± 20.6
0.008
0.137 ± 0.190
45.2 ± 8.1
36.5 ± 6.6
0.040
Values are presented as mean ± standard deviation CKMB1, TNI1 were collected 12 h after ligation. CKMB2, TNI2 were collected 24 h after ligation The blood samples were collected from the coronary sinus
pressure rapidly in early stage of myocardial infarction. However, this cardiac and circulatory support was temporary. With the prolonging of time, LV dp/dt declined gradually. In addition, pressor agents and cardiac stimulants had adverse effect on perfusion of vital organs because of vasoconstrictive action. At present, few researches, especially large animal experiments, involve effects of ECMO on myocardial infarction. Some clinical researches indicated that ECMO could improve survival rate on patients with cardiogenic shock after acute myocardial infarction (no matter whether did percutaneous coronary intervention during that period), and early use benefited more [8, 9]. In our study, we found that ECMO did not reduce the myocardial infarction area, as compared with conventional drugs. But we noticed that the degree of myocardial enzyme and TNI elevation in Group T2 was lower than that in Group T1, and the difference was significant. Therefore, we supposed that ECMO might have positive effects on ischemic areas, such as increasing perfusion of coronary arteries, decreasing myocardial oxygen consumption, etc. Intra-aortic balloon pump was a class I recommendation for acute myocardial infarction with cardiogenic shock several years ago [10, 11]. However, the results of the Intra-aortic Balloon Pump in Cardiogenic Shock II (IABPSHOCK II) trial [12] recently reported that in patients with acute myocardial infarction and hemodynamic compromise who underwent revascularization, the routine use of an intra-aortic balloon pump (IABP), as compared with standard therapy, does not improve survival. Although many studies found that IABP can decrease cardiac afterload, and increase coronary flow by increasing diastolic pressure of aortic root [13–15], the long-term benefits of IABP are still controversial. The reasons may be relative to the fact that IABP cannot improve cardiac preload and output [14], and so many facts can affect outcomes, such as hemoglobin decline [16], pulse pressure [17], etc. ECMO has impressive effects on unloading cardiac preload and maintaining perfusion pressure, but has an adverse impact on cardiac afterload. Hence, ECMO combined with IABP has a good
Fig. 3 LV - dp/dt
prospect, but lacks random controlled trials and metaanalysis at present.
Study limitations ECMO has been implanted prior to induction of myocardial infarction, which is not the ‘‘real’’ clinical scenario model. However, urgent ECMO implantation during cardiogenic shock is a complex invasive procedure that would probably interfere with the primary aim of this study.
Conclusion Compared with drug therapy, early ECMO improves left ventricular diastolic function, and may improve systolic function. ECMO cannot reduce myocardial infarct size without revascularization, but may have positive effects on ischemic areas by avoiding further injuring.
123
Heart Vessels Conflict of interest This study was conducted independently; no company or institution supported it financially. 11.
References 1. Chung ES, Lim C, Lee HY, Choi JH, Lee JS, Park KH (2011) Results of extracorporeal membrane oxygenation (ECMO) support before coronary reperfusion in cardiogenic shock with acute myocardial infarction. Korean J Thorac Cardiovasc Surg 44(4):273–278 2. Mols G, Loop T, Geiger K, Farthmann E, Benzing A (2000) Extracorporeal membrane oxygenation: a ten-year experience. Am J Surg 180(2):144–154 3. Sua´rez de Lezo J, Pan M, Medina A, Pavlovic D, Romero M, Segura J, Ruiz M, Ojeda S, Mun˜oz J, Rodriguez M (2002) Percutaneous cardiopulmonary support in critical patients needing coronary interventions with stents. Catheter Cardiovasc Interv 57:467–475 4. Marasco SF, Lukas G, McDonald M, McMillan J, Ihle B (2008) Review of ECMO (extra corporeal membrane oxygenation) support in critically ill adult patients. Heart Lung Circ 17(4):S41– S47 5. Bakhtiary F, Keller H, Dogan S, Dzemali O, Oezaslan F, Meininger D, Ackermann H, Zwissler B, Kleine P, Moritz A (2008) Venoarterial extracorporeal membrane oxygenation for treatment of cardiogenic shock: clinical experiences in 45 adult patients. J Thorac Cardiovasc Surg 135:382–388 6. Roders KG (1995) Cardiovascular shock. Emer Med Clin North Am 13(4):793–809 7. Subramaniam K, Boisen M, Shah PR, Ramesh V, Pete A (2012) Mechanical circulatory support for cardiogenic shock. Best Pract Res Clin Anaesthesiol 26(2):131–146 8. Kim H, Lim SH, Hong J, Hong YS, Lee CJ, Jung JH, Yu S (2012) Efficacy of veno-arterial extracorporeal membrane oxygenation in acute myocardial infarction with cardiogenic shock. Resuscitation 83(8):971–975 9. Chung SY, Sheu JJ, Lin YJ, Sun CK, Chang LT, Chen YL, Tsai TH, Chen CJ, Yang CH, Hang CL, Leu S, Wu CJ, Lee FY, Yip HK (2012) Outcome of patients with profound cardiogenic shock after cardiopulmonary resuscitation and prompt extracorporeal membrane oxygenation support: a single-center observational study. Circ J 76(6):1385–1392 10. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ, Ornato JP, Pearle DL, Sloan MA, Smith SC Jr (2004) American College of Cardiology, American Heart Association ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1999
123
12.
13.
14.
15.
16.
17.
guidelines for the management of patients with acute myocardial Infarction). Circulation 110(9):e82–292 Rosengren A, Steg PG, Tubaro M, Verheugt F, Weidinger F, Weis M, Task Force per il Trattamento dell’Infarto Miocardico Acuto con, Sopraslivellamento del Tratto ST della Societa` Europea di Cardiologia, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Silber S, Aguirre FV, Al-Attar N, Alegria E, Andreotti F, Benzer W, Breithardt O, Danchin N, Di Mario C, Dudek D, Gulba D, Halvorsen S, Kaufmann P, Kornowski R, Lip GY, Rutten F, Societa´ Europea di Cardiologia (2008) Management of acute myocardial infarction in patients presenting with persistent ST segment elevation. Eur Heart J 29:2909–2945 Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, Richardt G, Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I, Hambrecht R, Fuhrmann J, Bo¨hm M, Ebelt H, Schneider S, Schuler G, Werdan K (2012) IABP-SHOCK II Trial Investigators intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 367(1):1287–1296 Scheidt S, Wilner G, Mueller H, Summers D, Lesch M, Wolff G, Krakauer J, Rubenfire M, Fleming P, Noon G, Oldham N, Killip T, Kantrowitz A (1973) Intra-aortic balloon counterpulsation in cardiogenic shock: report of a cooperative clinical trial. N Engl J Med 288:979–984 Prondzinsky R, Unverzagt S, Russ M, Lemm H, Swyter M, Wegener N, Buerke U, Raaz U, Ebelt H, Schlitt A, Heinroth K, Haerting J, Werdan K, Buerke M (2012) Hemodynamic effects of intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP shock trial. Shock 37:378–384 Bia D, Cabrera-Fischer EI, Zo´calo Y, Armentano RL (2012) Intra-aortic balloon pumping reduces the increased arterial load caused by acute cardiac depression, modifying central and peripheral load determinants in a time- and flow-related way. Heart Vessels 27(5):517–527 Mare´chaux S, Barrailler S, Pinc¸on C, Decourcelle V, Guidez T, Braun S, Bouabdallaoui N, Bauchart JJ, Auffray JL, Juthier F, Banfi C, Susen S, Jude B, Asseman P, Van Belle E, Ennezat PV (2012) Prognostic value of hemoglobin decline over the GRACE score in patients hospitalized for an acute coronary syndrome. Heart Vessels 27(2):119–127 Shiraishi J, Kohno Y, Sawada T, Hashimoto S, Ito D, Kimura M, Matsui A, Yokoi H, Arihara M, Irie H, Hyogo M, Shima T, Nakamura T, Matoba S, Yamada H, Matsumuro A, Shirayama T, Kitamura M, Furukawa K, Matsubara H (2013) Prognostic impact of pulse pressure at admission on in-hospital outcome after primary percutaneous coronary intervention for acute myocardial infarction. Heart Vessels 28(4):434–441
ORIGINAL ARTICLE
Myocardial protection of early extracorporeal membrane oxygenation (ECMO) support for acute myocardial infarction with cardiogenic shock in pigs Gang-jie Zhu • Li-na Sun • Xing-hai Li • Ning-fu Wang Hong-hai Wu • Chen-xing Yuan • Qiao-qiao Li • Peng Xu • Ya-qi Ren • Bao-gen Mao
•
Received: 3 December 2013 / Accepted: 1 August 2014 Ó Springer Japan 2014
Abstract The aim of this study was to explore myocardial protection of early extracorporeal membrane oxygenation (ECMO) support for acute myocardial infarction with cardiogenic shock in pigs. 24 male pigs (34.6 ± 1.3 kg) were randomly divided into three groups—control group, drug therapy group, and ECMO group. Myocardial infarction model was created in drug therapy group and ECMO group by ligating coronary artery. When cardiogenic shock occurred, drugs were given in drug therapy group and ECMO began to work in ECMO group. The pigs were killed 24 h after cardiogenic shock. Compared with in drug therapy group, left ventricular end-diastolic pressure in ECMO group decreased significantly 6 h after ligation (P \ 0.05). At the end of the experiments, LV - dp/ dt among three groups was significantly different, drug therapy group \ ECMO group \ control group. There was no difference in LV ? dp/dt between drug therapy group and ECMO group. Compared with drug group, myocardial infarct size of ECMO group did not reduce significantly, but myocardial enzyme and troponin-I decreased significantly. Compared with drug therapy, ECMO improves left ventricular diastolic function, and may improve systolic function. ECMO cannot reduce myocardial infarct size
G. Zhu L. Sun N. Wang (&) P. Xu Y. Ren Department of Cardiovasology, Affiliated Hangzhou Hospital of Nanjing Medical University, No.261, Huansha Road, 310006 Hangzhou City, China e-mail: [email protected] X. Li B. Mao Department of Cardiac Surgery, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou City, China H. Wu C. Yuan Q. Li Zhejiang University, Hangzhou City, China
without revascularization, but may have positive effects on ischemic areas by avoiding further injuring. Keywords Myocardial protection Extracorporeal membrane oxygenation (ECMO) Acute myocardial infarction Cardiogenic shock Pigs
Introduction Venoarterial extracorporeal membrane oxygenation (VAECMO) based approach is used for urgent hemodynamic stabilization in patients with cardiopulmonary failure, such as profound cardiogenic shock, cardiac arrest, etc. [1, 2]. This approach, also referred to as extracorporeal cardiopulmonary resuscitation (E-CPR), allows perfusion of vital organs during profound cardiogenic shock and provides a time span for myocardial recovery. Medicine supportive treatment and revascularization are very important for patients with cardiogenic shock after myocardial infarction. But when hemodynamics is still unstable with sufficient drugs, extracorporeal circulatory support is always necessary [3], which can decrease cardiac loading and myocardial oxygen consumption, and thus shorten recovery of stunned myocardium [4]. VA-ECMO is an optimal choice of extracorporeal circulatory support. It can improve systolic blood pressure (SBP), diastolic blood pressure (DBP) and tissue perfusion, meanwhile reduce cardiac preload [3– 5]. However, at present, there has been little research, especially in large animal, on myocardial protection of ECMO for acute myocardial infarction with cardiogenic shock (AMI-CS). The experiment established an AMI-CS model in pigs, and explored myocardial protection of early VA-ECMO support for AMI-CS in pigs.
123
Heart Vessels
Materials and methods This study was approved by IRB of Affiliated Hangzhou Hospital of Nanjing Medical University and performed at the Animal Laboratory, Department of Pharmacy, Zhejiang University in Hangzhou in accordance with the NIH Animal Care and Use Committee guidelines. Materials 24 Guangxi Bama male minipigs, 4–5 months old, weighing 34.6 ± 1.3 kg, were obtained from the animal experimental center of Zhejiang University. The pigs were randomly divided into three groups—Group C (shamoperation control group), Group T1 (drug therapy group), and Group T2 (ECMO group). And 22 pigs finished the experimental protocol. In the study, we used an animal ventilator (ALC-V10, Aoerkete, Shanghai, China, parameters setting: oxygen concentration 50 %, tidal volume 220 ± 20 ml, rate 20 ± 5 per min), blood gas analyzer (GEM3000, instrumentation laboratory company, USA), ECMO (including an Centrifugal Pump: Medtronic 550,Medtronic Inc, USA, and pediatric cannula: Medtronic silicone, Medtronic Inc, USA).
and connected to ECMO. Heparin (1 mg/kg, IV) was given before ECMO started. During ECMO support, activated clotting time (ACT) was monitored, and maintained between 180 and 220 s. Establishment of myocardial infarction model Incise tissues along with the median sternal line after regular sterilization. Open the sternum, incise and suspend the pericardium, expose the heart and left anterior descending coronary artery (LAD). Ultrasound flowmeter (T400, Transonic, USA) was placed after the first diagonal branch for monitoring the LAD flow rate. According to the LAD flow rate, ligate the LAD between the first diagonal branch and the second diagonal branch in Groups T1 and T2. Group C was threaded but was not ligated. Monitoring Puncture the ascending aorta, catheterize a cannula into the left ventricle by a guiding wire, connect the cannula to a pressure switch, and monitor the left ventricular pressure continually. Experimental protocol
Anesthesia After 24 h fasting, anesthesia was induced by azaperone (2 mg/kg IM), ketamine (15–20 mg/kg, intraperitoneal injection), and atropine (0.02 mg/kg, IM). Anesthesia was continued with initial propofol (2 mg/kg IV). Continuous IV infusion of propofol (8–10 mg/kg/h) was used to maintain anesthesia, the depth of which was regularly assessed by photoreaction and corneal reflex. Preoperative preparation The pigs were intubated (7F) by tracheostomy under anesthesia, and the tube was connected to the animal ventilator. Left femoral vein was intubated for liquid infusion and blood samples. Left femoral artery was intubated for monitoring peripheral arterial blood pressure by a pressure switch. Besides, electrocardiogram monitoring was performed. Establishment and management of ECMO ECMO and its cannula were pre-filled with Polygeline Injection and Sodium Lactate Ringer’s Injection (300 ml, respectively, and heparin: 1 mg/100 ml). Incise the skin along with the right groin after sterilization, and dissect the femoral artery and vein. Afterwards, the femoral artery and vein were catheterized with 12F and 14F ECMO cannulas
123
Large doses of dopamine (5–10 lg/kg min), and norepinephrine (0.1–0.2 lg/kg min) began to be used in Group T1 and ECMO began to work in Group T2 when cardiogenic shock occurred (systolic blood pressure \90 mmHg). The pigs were killed 24 h after cardiogenic shock. Measurement of myocardial infarction area (MIA) Infuse 2 % Evans Blue by the aorta before killing the pig to distinguish between ischemic area and non-ischemic area. And then, kill the pig, cut-off large vessels, atria and right ventricle. Place the heart in a -20° C refrigerator for 30 min. After that, cut the left ventricle into 2 mm thick slices, and incubate the slices in triphenyl tetrazolium chloride phosphate buffer solution (TTC-PBS) for 30 min at 37° C. The brick red area was myocardium of infarction and off-white area was myocardium of non-infarction. Collect images of slices by an image acquisition system, and measure MIA by Image Pro Plus. MIA = total area of myocardial infarction of left ventricular tissues slices/total area of left ventricular tissues slices 9 100 %. Data collection and statistics analysis We collected physical data, including LVEDP, LV dp/dt and peripheral arterial pressure, and hematology data,
Heart Vessels Table 1 Peripheral systolic blood pressure Group
Before ligation
4h
8h
12 h
16 h
20 h
24 h 103 ± 5.0
C, N = 7
129 ± 8.5
121 ± 7.1
117 ± 6.9
118 ± 7.1
112 ± 7.1
115 ± 5.4
T1, N = 7
127 ± 9.7
96 ± 5.4
97 ± 4.7
91 ± 7.3
94 ± 4.1
95 ± 6.2
95 ± 6.0
T2, N = 8
130 ± 8.5
99 ± 7.5
96 ± 6.1
99 ± 7.0
96 ± 5.2
96 ± 6.0
98 ± 6.1
Values are presented as mean ± standard deviation
including blood gas analysis and myocardial enzyme (collected from the coronary sinus). The data collection time points include: before ligation, and every 2 h after ligation. All the statistical analyses were performed by SPSS 17.0. ANOVA and q test was performed for different analyses of each group. P values \0.05 were considered statistically significant.
Myocardial infarction area and myocardial enzyme, troponin I In our study, we adapted the area method to calculate the infarction size. As shown in Table 3, there was no difference between Groups T1 and T2 (P = 0.377). However, the
Results Peripheral blood pressure We controlled peripheral systolic blood pressure of about 100 mmHg in Groups T1 and T2, by adjusting drugs and the flow of ECMO (Table 1). Left ventricular end-diastolic pressure (LVEDP) At baseline, there was no difference among three groups regrading LVEDP, which increased after ligation in Groups T1 and T2. The difference began to be significant 6 h after ligation in Groups T1 and T2, and became more significant over time (Fig. 1). The biggest difference of LVEDP between Groups T2 and C appeared 10 h after ligation (P \ 0.001). In the following time, the difference reduced gradually, even reversed at last. But the reversed difference was not significant (P = 0.102).
Fig. 1 Left ventricular end-diastolic pressure
LV dp=dt As shown in Fig. 2 and Table 2, LV ? dp/dt increased briefly after intravenous injection of dopamine and norepinephrine in Group T1, and then decreased gradually. But this change did not occur in LV - dp/dt (Fig. 3 and Table 2). In Group T2, there was no rise in LV ± dp/ dt after starting ECMO, but the rate of decline was slowly down obviously. At the end of the experiments, there was significant difference in LV - dp/dt among three groups (Group C \ Group T1 \ Group T2); compared with in Groups T1 and T2, LV ? dp/dt in Group C was different significantly, but there was no difference between Groups T1 and T2. In addition, the impaired LV - dp/dt was sightly earlier than the impaired LV ? dp/dt.
Fig. 2 LV ? dp/dt
123
difference of creatine kinase MB (CKMB) and troponin I (TNI) between Groups T1 and T2 was significant (Table 3). \0.01
315.5 ± 19.5
615.3 ± 14.4
172.8 ± 18.0
LV2
Heart Vessels
0.019 0.104 P* values
152.6 ± 15.9
319.8 ± 34.4
347.2 ± 30.6
441.1 ± 24.8
T1
T2
621.2 ± 23.1 972.8 ± 40.8 C
LV
LV
2
Group
0.271 P* values
Values are presented as mean ± standard deviation. LV1 and LV2 are LV ? dp/dt and LV - dp/dt, respectively * P values = P values (T1,T2)
\0.01 0.062 0.083
\0.01
277.0 ± 22.8
124.8 ± 10.7 265.4 ± 23.3
406.1 ± 18.6
136.3 ± 8.7 285.1 ± 18.7
299.3 ± 15.8
603.9 ± 18.6 978.0 ± 32.7
LV
1 1
437.6.4 ± 22.5
LV
953.0 ± 25.7
LV1
24 h 20 h 16 h
0.021 0.124
1030.9 ± 83.3
0.801
406.3 ± 19.6 509.9 ± 22.5
627.6 ± 34.3
T2
672.5 ± 41.1
675.5 ± 14.0
1009.8 ± 41.7 647.3 ± 41.5
667.5 ± 31.8
1023 ± 49.8
989.9 ± 69.8
C
T1
LV LV LV LV
288.1 ± 25.8
2
0.167
464.0 ± 18.9
975.7 ± 32.0
565.9 ± 48.5
LV
1
8h
2 1
4h
2 1
0h Group
Table 2 Changes of LV ± dp/dt
123
627.0 ± 13.6
LV2
0.470 0.014
472.6 ± 28.6 357.1 ± 19.7
460.4 ± 36.0
978.2 ± 30.6 622.5 ± 25.8
208.9 ± 23.1
LV1 LV
2
12 h
Discussion For the treatment of acute myocardial infarction with cardiogenic shock, it is primarily aimed at recovering and maintaining the perfusion pressure of vital organs, saving ischemic myocardium and restricting infarction scope [6]. ECMO can reach the goal of maintaining blood pressure and perfusion pressure by improving systolic pressure, diastolic pressure, mean arterial pressure and coronary flow [1, 2, 4]. In addition, ECMO unloads preload to reduce cardiac work, which can promote the functional recovery of stunned myocardium and improve cardiac systolic and diastolic function [4, 7]. However, there are few studies to confirm the improvement of cardiac systolic function or diastolic function, or both. ECMO unloads cardiac preload effectively, and maintains perfusion of vital organs. Meanwhile, ECMO increases cardiac afterload in some degree because of elevation of blood pressure, which has adverse impact on myocardial cell recovery. Therefore, peripheral systolic blood pressure of pigs in our experiments was controlled at a level of 100 mmHg so that cardiac afterload would not excessively increase on the premise of sufficient perfusion. In the study, we adopted LV ± dp/dt to evaluate cardiac systolic and diastolic function and LVDEP to reflect cardiac preload and part of systolic and diastolic function in pigs. From our experiments, we observed LVEP in Group T2 reduced more significantly than which in Group T1, and with the prolonging of time, this trend was more obvious. Meanwhile, the difference of LVDEP between Groups T2 and C reduced gradually over time. Interestingly, the difference was reversed at last, which might be attributed to effective unloading of cardiac preload. But whether this reversion could take a positive effect (such as rate of weaning, survival, etc.) on long-term results, it still needs more work. As shown in Table 2 and Fig. 2, the changes of LV ? dp/dt were not consistent with the changes of LV dp/dt. This difference suggested that recovery of cardiac diastolic function was better (or earlier) than recovery of systolic function. We supposed it might be related to the fact that ECMO increased cardiac afterload. Despite we had made a balance between maintaining perfusion pressure and reducing cardiac afterload, the difference occurred. Therefore, there is a reason to suspect that the difference among three would be more significant, and profoundly effected survival time and rate, if obvious time was prolonged. In Group T1, pressor agents and cardiac stimulants could increase LV dp/dt and peripheral arterial
Heart Vessels Table 3 Myocardial infarction area and myocardial enzyme, TNI from three groups Group C Infarction area CKMB1 TNI1 2
CKMB TNI2
–
Group T1
Group T2
P values (T1,T2)
42.2 ± 5.9
39.4 ± 5.0
0.337
51.3 ± 11.8
148.2 ± 17.9
114.8 ± 14.2
0.001
0.118 ± 0.106
30.6 ± 5.9
21.0 ± 2.0
0.012
62.5 ± 9.9
192.6 ± 22.4
157.7 ± 20.6
0.008
0.137 ± 0.190
45.2 ± 8.1
36.5 ± 6.6
0.040
Values are presented as mean ± standard deviation CKMB1, TNI1 were collected 12 h after ligation. CKMB2, TNI2 were collected 24 h after ligation The blood samples were collected from the coronary sinus
pressure rapidly in early stage of myocardial infarction. However, this cardiac and circulatory support was temporary. With the prolonging of time, LV dp/dt declined gradually. In addition, pressor agents and cardiac stimulants had adverse effect on perfusion of vital organs because of vasoconstrictive action. At present, few researches, especially large animal experiments, involve effects of ECMO on myocardial infarction. Some clinical researches indicated that ECMO could improve survival rate on patients with cardiogenic shock after acute myocardial infarction (no matter whether did percutaneous coronary intervention during that period), and early use benefited more [8, 9]. In our study, we found that ECMO did not reduce the myocardial infarction area, as compared with conventional drugs. But we noticed that the degree of myocardial enzyme and TNI elevation in Group T2 was lower than that in Group T1, and the difference was significant. Therefore, we supposed that ECMO might have positive effects on ischemic areas, such as increasing perfusion of coronary arteries, decreasing myocardial oxygen consumption, etc. Intra-aortic balloon pump was a class I recommendation for acute myocardial infarction with cardiogenic shock several years ago [10, 11]. However, the results of the Intra-aortic Balloon Pump in Cardiogenic Shock II (IABPSHOCK II) trial [12] recently reported that in patients with acute myocardial infarction and hemodynamic compromise who underwent revascularization, the routine use of an intra-aortic balloon pump (IABP), as compared with standard therapy, does not improve survival. Although many studies found that IABP can decrease cardiac afterload, and increase coronary flow by increasing diastolic pressure of aortic root [13–15], the long-term benefits of IABP are still controversial. The reasons may be relative to the fact that IABP cannot improve cardiac preload and output [14], and so many facts can affect outcomes, such as hemoglobin decline [16], pulse pressure [17], etc. ECMO has impressive effects on unloading cardiac preload and maintaining perfusion pressure, but has an adverse impact on cardiac afterload. Hence, ECMO combined with IABP has a good
Fig. 3 LV - dp/dt
prospect, but lacks random controlled trials and metaanalysis at present.
Study limitations ECMO has been implanted prior to induction of myocardial infarction, which is not the ‘‘real’’ clinical scenario model. However, urgent ECMO implantation during cardiogenic shock is a complex invasive procedure that would probably interfere with the primary aim of this study.
Conclusion Compared with drug therapy, early ECMO improves left ventricular diastolic function, and may improve systolic function. ECMO cannot reduce myocardial infarct size without revascularization, but may have positive effects on ischemic areas by avoiding further injuring.
123
Heart Vessels Conflict of interest This study was conducted independently; no company or institution supported it financially. 11.
References 1. Chung ES, Lim C, Lee HY, Choi JH, Lee JS, Park KH (2011) Results of extracorporeal membrane oxygenation (ECMO) support before coronary reperfusion in cardiogenic shock with acute myocardial infarction. Korean J Thorac Cardiovasc Surg 44(4):273–278 2. Mols G, Loop T, Geiger K, Farthmann E, Benzing A (2000) Extracorporeal membrane oxygenation: a ten-year experience. Am J Surg 180(2):144–154 3. Sua´rez de Lezo J, Pan M, Medina A, Pavlovic D, Romero M, Segura J, Ruiz M, Ojeda S, Mun˜oz J, Rodriguez M (2002) Percutaneous cardiopulmonary support in critical patients needing coronary interventions with stents. Catheter Cardiovasc Interv 57:467–475 4. Marasco SF, Lukas G, McDonald M, McMillan J, Ihle B (2008) Review of ECMO (extra corporeal membrane oxygenation) support in critically ill adult patients. Heart Lung Circ 17(4):S41– S47 5. Bakhtiary F, Keller H, Dogan S, Dzemali O, Oezaslan F, Meininger D, Ackermann H, Zwissler B, Kleine P, Moritz A (2008) Venoarterial extracorporeal membrane oxygenation for treatment of cardiogenic shock: clinical experiences in 45 adult patients. J Thorac Cardiovasc Surg 135:382–388 6. Roders KG (1995) Cardiovascular shock. Emer Med Clin North Am 13(4):793–809 7. Subramaniam K, Boisen M, Shah PR, Ramesh V, Pete A (2012) Mechanical circulatory support for cardiogenic shock. Best Pract Res Clin Anaesthesiol 26(2):131–146 8. Kim H, Lim SH, Hong J, Hong YS, Lee CJ, Jung JH, Yu S (2012) Efficacy of veno-arterial extracorporeal membrane oxygenation in acute myocardial infarction with cardiogenic shock. Resuscitation 83(8):971–975 9. Chung SY, Sheu JJ, Lin YJ, Sun CK, Chang LT, Chen YL, Tsai TH, Chen CJ, Yang CH, Hang CL, Leu S, Wu CJ, Lee FY, Yip HK (2012) Outcome of patients with profound cardiogenic shock after cardiopulmonary resuscitation and prompt extracorporeal membrane oxygenation support: a single-center observational study. Circ J 76(6):1385–1392 10. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, Mullany CJ, Ornato JP, Pearle DL, Sloan MA, Smith SC Jr (2004) American College of Cardiology, American Heart Association ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1999
123
12.
13.
14.
15.
16.
17.
guidelines for the management of patients with acute myocardial Infarction). Circulation 110(9):e82–292 Rosengren A, Steg PG, Tubaro M, Verheugt F, Weidinger F, Weis M, Task Force per il Trattamento dell’Infarto Miocardico Acuto con, Sopraslivellamento del Tratto ST della Societa` Europea di Cardiologia, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Silber S, Aguirre FV, Al-Attar N, Alegria E, Andreotti F, Benzer W, Breithardt O, Danchin N, Di Mario C, Dudek D, Gulba D, Halvorsen S, Kaufmann P, Kornowski R, Lip GY, Rutten F, Societa´ Europea di Cardiologia (2008) Management of acute myocardial infarction in patients presenting with persistent ST segment elevation. Eur Heart J 29:2909–2945 Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, Richardt G, Hennersdorf M, Empen K, Fuernau G, Desch S, Eitel I, Hambrecht R, Fuhrmann J, Bo¨hm M, Ebelt H, Schneider S, Schuler G, Werdan K (2012) IABP-SHOCK II Trial Investigators intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 367(1):1287–1296 Scheidt S, Wilner G, Mueller H, Summers D, Lesch M, Wolff G, Krakauer J, Rubenfire M, Fleming P, Noon G, Oldham N, Killip T, Kantrowitz A (1973) Intra-aortic balloon counterpulsation in cardiogenic shock: report of a cooperative clinical trial. N Engl J Med 288:979–984 Prondzinsky R, Unverzagt S, Russ M, Lemm H, Swyter M, Wegener N, Buerke U, Raaz U, Ebelt H, Schlitt A, Heinroth K, Haerting J, Werdan K, Buerke M (2012) Hemodynamic effects of intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP shock trial. Shock 37:378–384 Bia D, Cabrera-Fischer EI, Zo´calo Y, Armentano RL (2012) Intra-aortic balloon pumping reduces the increased arterial load caused by acute cardiac depression, modifying central and peripheral load determinants in a time- and flow-related way. Heart Vessels 27(5):517–527 Mare´chaux S, Barrailler S, Pinc¸on C, Decourcelle V, Guidez T, Braun S, Bouabdallaoui N, Bauchart JJ, Auffray JL, Juthier F, Banfi C, Susen S, Jude B, Asseman P, Van Belle E, Ennezat PV (2012) Prognostic value of hemoglobin decline over the GRACE score in patients hospitalized for an acute coronary syndrome. Heart Vessels 27(2):119–127 Shiraishi J, Kohno Y, Sawada T, Hashimoto S, Ito D, Kimura M, Matsui A, Yokoi H, Arihara M, Irie H, Hyogo M, Shima T, Nakamura T, Matoba S, Yamada H, Matsumuro A, Shirayama T, Kitamura M, Furukawa K, Matsubara H (2013) Prognostic impact of pulse pressure at admission on in-hospital outcome after primary percutaneous coronary intervention for acute myocardial infarction. Heart Vessels 28(4):434–441
