© 1997 by European Society of Cardiology
Copyright © 1997, European Society of Cardiology
Targeting of dobutamine to ischemic myocardium without systemic effects by selective suction and pressure-regulated retroinfusion
Department of Internal Medicine I, Klinikum Großhadern, University of Munich, Marchioninistr. 15, 81377 Munich, Germany
* Corresponding author. Tel.: +49 (89) 70953092; fax: +49 (89) 70953064.
Received 14 November 1996; accepted 6 May 1997
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
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Objective: To study the effects of low-dose dobutamine and/or glyceryl trinitrate in addition to selective suction and pressure-regulated retroinfusion with arterial blood on regional myocardial function of the ischemic myocardium and systemic hemodynamics. Methods: Using a pig model of repeated brief (90 s) occlusions of the left anterior descending artery, selective suction and pressure-regulated retroinfusion was carried out either with arterial blood alone (SSRalone) or with arterial blood and simultaneous application of low-dose dobutamine (0.1 µg/kg/min) (SSRDOB), glyceryl trinitrate (0.03 mg/kg/min) (SSRNIT) or the combination of both drugs (SSRDOB+NIT). Regional myocardial function of the ischemic and non-ischemic myocardium was determined by sonomicrometry (segment shortening). Results: Segment shortening in the ischemic area after 90 s of ischemia was preserved at 57.5±9.2% with SSRalone but at 78.0±22.3% of baseline with SSRDOB (P<0.05). The addition of glyceryl trinitrate did not improve regional myocardial function further. No effects of locally applied dobutamine were observed with regard to non-ischemic myocardium or heart rate. Cardiac output and mean arterial blood pressures tended to be further stabilized with SSRDOB. Conclusions: Local application of low-dose dobutamine together with arterial blood by selective suction and pressure-regulated retroinfusion during brief myocardial ischemia resulted in improved regional myocardial function without undesired effects on non-ischemic myocardium or systemic hemodynamics.
KEYWORDS Retroinfusion; Myocardial ischemia; Dobutamine; Nitrates; Hibernation; Pig, anesthetized
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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In patients with coronary artery disease chronically ischemic myocardium may remain viable despite contractile dysfunction [1, 2]. The identification of such viable ischemic myocardium is of clinical importance, because it recovers contractile function following revascularization in contrast to irreversibly infarcted tissue [1, 3–5]. Different methods to detect viable myocardium exist including positron emission tomography (PET), thallium scintigraphy and dobutamine stress echocardiography [6, 7]. Nevertheless, the quantitative effect of revascularization on regional myocardial dysfunction often remains uncertain [3–5]. This is due in part to the systemic administration of dobutamine, which is non-selective and therefore stimulates the entire heart. The resulting tachycardia and left ventricular hyperkinesia with subsequent ‘tethering’ of the akinetic ischemic myocardium hampers echocardiographic assessment of the effects of dobutamine on the ischemic area [5, 8]. Moreover, the systemic effects of dobutamine may lead to additional stress on the challenged ischemic myocardium [9]. More selective administration of dobutamine into the ischemic area together with arterial blood by selective suction and pressure-regulated retroinfusion (SSR) [10]might permit a more precise echocardiographic assessment of the contractile reserve and might be better tolerated by the ischemic myocardium.
SSR is a cardioprotective catheter device which allows selective delivery of arterial blood to ischemic myocardium through the coronary veins. It has been shown to preserve regional myocardial function and global hemodynamics during acute coronary ischemia in experimental models [11, 12]and in clinical studies [13, 14].
Application of low-dose dobutamine together with arterial blood by means of SSR might allow detection of the contractile reserve of ischemic myocardium without the drawbacks of conventional intravenous dobutamine stress echocardiography outlined above: the effects of dobutamine should be limited to the ischemic myocardial area without causing systemic side-effects. This might permit enhanced, quantitative or semiquantitative echocardiographic assessment of the contractile reserve of the ischemic myocardium. Moreover, the simultaneous retrograde application of arterial blood together with low-dose dobutamine should avoid dobutamine induced ischemic effects.
The aim of the present study was to investigate whether the addition of low-dose dobutamine to SSR targets the drug selectively to ischemic myocardium in a pig model of brief acute regional myocardial ischemia. Glyceryl trinitrate was added to the retrogradely delivered arterial blood to investigate the potential benefit of local venous vasodilation on the efficacy of SSR. The local inotropic and/or vasodilator effects on the preservation of regional myocardial function during ischemia were analyzed with regard to pressure–flow relationships obtained during SSR.
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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The present study was carried out in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985) and was approved by the Bavarian Animal Care and Use Committee.
2.1 Experimental preparation
Ten German farm pigs (mean weight 28.5±4.6 kg) were sedated by i.m. injection of 500 mg ketamine (Parke-Davis, Freiburg, Germany), 0.35 mg/kg body weight midazolam (Hoffmann La Roche, Grenzach-Wyhlen, Switzerland) and 0.5 mg atropine (Braun, Melsungen, Germany). Following oral endotracheal intubation, anesthesia was maintained by 10 mg/h midazolam, 10 mg/h piritramide (Janssen, Neuss, Germany) and nitrous oxide. Mechanical ventilation was adjusted to keep arterial pO2 between 100 and 180 mmHg and expiratory CO2 at 4.5 vol%. The pig was fixed on a heating pad to maintain core temperature close to 37°C. Subcutaneous ECG electrodes were placed at all extremities. Placement of all catheters was carried out under fluoroscopy (Philips Diagnost-OP C9, Philips Medical Systems, Netherlands). A 6F microtip pressure transducer catheter (Altron, Switzerland) was placed into the left ventricle through an 8.5F catheter introducer sheath in the left carotid artery (Arrow, Reading, USA) to measure left ventricular pressure and its first derivative (dP/dt). Arterial blood pressure was measured through the same 8.5F catheter introducer sheath in the left carotid artery.
2.2 Selective suction and pressure-regulated retroinfusion of coronary veins (SSR)
The system for SSR has been described in detail previously [11, 12]. Briefly, it consists of a pumping unit for arterial blood withdrawn from an arterial sheath, a small extracorporeal circuit, a 4-lumen retroinfusion catheter and a suction device. For safety and efficacy reasons [12, 15, 16], the ECG-triggered SSR system was modified by adding a pressure regulation of retrograde blood flow (Fig. 1). This was achieved by replacing the mechanical pumping device of the previous SSR system [12]by a high-pressure reservoir of arterial blood and an ex-center valve regulating blood flow to the infusion line of the retroinfusion catheter during each retroinfusion period (Fig. 1). The high-pressure reservoir (150 ml Autovent-SV, Pall, UK) was filled with arterial blood by a roller pump. The pressure in the reservoir was kept at approximately 2.5 atm (±0.2 atm) by a pressure-controlled activator of the roller pump. The 4 lumina of the retroinfusion catheter were connected to (1) the high-pressure reservoir, (2) to the suction pump (–0.8 atm), (3) to the pressure monitoring device for the coronary vein, and (4) to the pressure-controlled balloon pump. When ECG-triggered (1:2) SSR was activated by the operator, the balloon at the tip of the retroinfusion catheter was first inflated up to a pressure of 150 mmHg. At the same time the suction valve was opened, reducing coronary venous pressure to near zero values (Fig. 1). 150–200 ms before end of systole the ex-center valve for pressure-regulated retroinfusion was opened, allowing retrograde delivery of arterial blood from the high-pressure reservoir until the preset coronary venous pressure was reached. In order to keep coronary venous pressure within the preset pressure range, retrograde blood flow was regulated by the ex-center valve within milliseconds (Fig. 1). At the end of the pumping period the suction valve was opened again and the cycle repeated. After retroinfusion during ischemia the balloon was deflated and the pumping line of the retroinfusion catheter flushed at low flow rates.
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After a bolus injection of heparin (300 IU/kg i.v. followed by 100 IU/kg/h i.v.), the high-pressure reservoir was filled with arterial blood obtained from the right femoral artery. For catheterization of the anterior ventricular vein a 7F catheter (Cournand or left Amplatz, Cordis, USA) was introduced through the left jugular vein into the coronary sinus under fluoroscopy. A 0.018 I guide wire (‘roadrunner’, Cook, USA) was advanced through the catheter placed in the coronary sinus into the anterior interventricular vein. The 7F catheter was then replaced by the 7F 4-lumen retroinfusion catheter (Pro-Med, Mödling, Austria). Before each pressure-regulated retroinfusion the correct position of the catheter was confirmed by injection of contrast agent into the anterior interventricular vein under fluoroscopic control.
Before ischemia, the balloon of the SSR catheter was inflated for 30 s to measure the individual systolic plateau of venous occlusion pressure of the anterior interventricular vein. The retroinfusion pressure during pressure-regulated SSR treatment was set 20 mmHg higher than the systolic venous occlusion pressure [16]. Drug application with SSR was realized by connecting a perfusor (Braun, Melsungen, Germany) through an unidirectional valve to the retroinfusion catheter. Dobutamine (Hexal, Holzkirchen, Germany) was administered at 0.1 µg/kg/min and glyceryl trinitrate (Pohl-Boskamp, Hohenlockstedt, Germany) at 0.03 mg/kg/min. Because SSR operates with bidirectional blood flow, glyceryl trinitrate was administered in a local dose (0.03 mg/kg/min) approximately twice as high as that used in investigations in which this substance was injected into the coronary arteries [21, 22]. In pilot experiments on 3 pigs excluded from further analysis, dobutamine doses of 0.2 µg/kg/min were given with SSR, which resulted in systolic early relaxation (‘SERP’). The contractile dysfunction occurring with the ‘systolic early relaxation phenomenon’ is the earliest indicator of a mismatch between inotropic stimulation and blood supply in dobutamine stress echocardiography [23–25]. Since at 0.1 µg/kg/min no systolic early relaxation was observed in our experiments, this dose was considered to be suitable for selective inotropic stimulation of the ischemic myocardium by retroinfusion without causing additional stress on the challenged ischemic myocardium.
2.3 Regional myocardial function
Regional myocardial function as the primary efficacy parameter was measured by sonomicrometry with two pairs of 5-MHz ultrasonic crystals (2 mm diameter) [12]. One pair was placed subendocardially in the myocardium supplied by the left anterior descending artery (LAD) and the other pair in the myocardium supplied by the circumflex artery (CX) as described previously in detail [12]. Correct subendocardial position of the ultrasonic crystals was confirmed at necropsy in all animals. End-diastolic (EDL) and end-systolic (ESL) segment lengths were determined using left ventricular dP/dt (EDL before dP/dt upstroke and ESL 20 ms before minimal dP/dt). Segment shortening (SS) was calculated as a percentage of EDL:
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2.4 Coronary venous pressure–flow relationships during retroinfusion
Coronary venous pressure and retrograde transcatheter blood flow were measured continuously during ischemia supported by selective suction and pressure-regulated retroinfusion. Retrograde transcatheter blood flow was measured using an ultrasonic flow probe (Transsonic, USA) which was placed at the beginning of the infusion line of the retroinfusion catheter. Calibration and linearity of the ultrasonic flow probe were checked at the end of each experiment by comparing ultrasonic blood flow measurements with absolute blood flow/min. The difference between the two methods was less than 15% at flow rates between 15 and 50 ml/min. All data were digitized and stored by the SSR system (Pro-Med, Mödling, Austria). The following parameters were derived for pressure–flow analysis: peak and mean retrograde transcatheter blood flow (ml/min), peak and mean coronary venous pressure (mmHg) and the first derivative (dP/dt of coronary venous pressure [mmHg/s]) of coronary venous pressure during retroinfusion.
2.5 Experimental protocol
The left anterior descending artery was occluded proximal to its first diagonal branch 6 times for 90 s with a 3.0 mm PTCA-balloon. Previous experiments had shown that regional myocardial function decreased during the initial 90 s of ischemia and did not change significantly thereafter [12]. Repeat ischemia longer than 90 s might have resulted in ‘myocardial stunning’ and would have interfered with the following occlusions [27]. Reperfusion between the ischemic episodes was allowed for 8.5 min. The first and last occlusion were not supported by SSR (control occlusions). The 2nd to 5th occlusions were supported by pressure-regulated SSR of the anterior interventricular vein with arterial blood without addition of drugs (SSRalone), with dobutamine (SSRDOB), with glyceryl trinitrate (SSRNIT) or with both drugs (SSRDOB+NIT). Pressure-regulated SSR of arterial blood was started immediately after LAD occlusion during all treatments. The drugs were added after 15 s of ischemia and were given at a constant rate until the end of the ischemic period (90 s) supported by retroinfusion. The sequence of treatment was randomized.
Regional myocardial function and systemic hemodynamics were measured at baseline (before each LAD occlusion) and after 90 s of ischemia. Coronary venous pressure and retrograde blood flow during SSR were determined 5–10 s after LAD occlusion and at the end of the ischemic period 5–10 s before reperfusion.
2.6 Statistics
The similarity of baseline variables was assessed with the Kruskal-Wallis test. Differences in regional myocardial function and hemodynamic parameters between the treatments (SSR, SSRDOB, SSRNIT and SSRDOB+NIT) during ischemia were assessed using a two-way ANOVA for repeated measurements. All results are expressed as mean±standard deviation unless otherwise indicated. A P-value of <0.05 was considered to be statistically significant. All data were analyzed with SPSS (SPSS, USA).
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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3.1 Similarity of baseline values
No statistically significant difference was found between baseline hemodynamic variables obtained before each LAD occlusion (Table 1). Regional myocardial function was also comparable in both regions of the left ventricle (LAD and CX) at all baseline time points; ‘myocardial stunning’ did not occur following repeat 90 s ischemia with 8.5 min reperfusion (Table 2).
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3.2 Regional myocardial function and hemodynamics during ischemia
LAD occlusions not supported by retroinfusion resulted in a complete loss of regional myocardial function within 90 s: segment shortening decreased to 0.95±2.3% (first control occlusion) and 0.6±1.6% (second control occlusion) (Fig. 2). Consistent with previous findings [12]segment shortening was preserved at 57.5±9.2% (% of baseline) during ischemia supported by SSR with arterial blood alone. The local application of low-dose dobutamine to the ischemic region together with retroinfusion of arterial blood resulted in further improvement of regional myocardial function (78.0±22.3%, P<0.05) (Fig. 2). A trend towards higher cardiac output and mean arterial pressure was also observed in pigs supported with retroinfusion and dobutamine during ischemia (Table 1).
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In contrast, addition of glyceryl trinitrate to arterial blood did not change regional myocardial function of the ischemic region (56.8±13.7%) compared to retroinfusion of arterial blood alone (57.5±9.2%). Glyceryl trinitrate did not enhance the effect of dobutamine with arterial blood either (75.5±20.1 vs. 78.0±22.3%).
Regional myocardial function of the non-ischemic region (CX) did not change during LAD occlusion during either treatment. In particular, the addition of dobutamine was not associated with hypercontractility (Table 2). There was no evidence from systemic hemodynamics including heart rate for non-selective effects of dobutamine (Tables 1 and 2
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3.3 Coronary venous pressure–flow relationship during ischemia supported by retroinfusion
Mean systolic occlusion pressure of the anterior interventricular vein determined before ischemia (see Section 2) was 71±7 mmHg (range 55–95 mmHg). During ischemia supported by retroinfusion with arterial blood, peak (82.5±12.3 mmHg) and mean (62.0±11.8 mmHg) coronary venous pressures were significantly increased compared to preischemic values (37.1±17.4 mmHg). Between the 4 ischemic periods treated by retroinfusion, there was no difference in peak and mean coronary venous pressure, mean retrograde transcatheter blood flow and maximal dP/dt of coronary venous pressure determined 5–10 s after LAD occlusion (Table 3). Since the addition of drugs to retroinfusion with arterial blood was started after 15 s of ischemia, the same parameters were determined again at the end of the ischemic period. Apparently, dobutamine and glyceryl trinitrate as well as the combination of both drugs had no statistically significant effect on peak and mean coronary venous pressure, mean retrograde transcatheter blood flow or maximal dP/dt of coronary venous pressure (Table 3).
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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4.1 Experimental model
The present experiments, which aimed at investigating the potential of local drug delivery to ischemic myocardium by means of selective suction and pressure-regulated retroinfusion (SSR) were performed in a pig model showing few collaterals of the coronary system [17–19]. Thus, predominant shunting of retrogradely pumped blood through epicardial veins as often observed in dogs was avoided in the pig model. Nevertheless, larger amounts of retrogradely delivered arterial blood are probably shunted away from the capillaries [20], in particular if retroinfusion pressure exceeds the coronary venous occlusion pressure determined before ischemia [16]. Coronary venous pressure during retroinfusion was therefore regulated in each experiment to a preset level dependent on the individual coronary venous occlusion pressure determined before ischemia [16]. A model of repeated brief occlusions of the LAD was chosen because the present investigation aimed at directly comparing the effect of the addition of dobutamine and/or glyceryl trinitrate to SSR in the same animal. Repeat ischemia of longer duration might have produced myocardial stunning, thus influencing baseline conditions of the following occlusions [27]. Previous investigations in pigs showed that regional myocardial function decreased rapidly during the first 90 s of ischemia and did not change significantly thereafter [12]. Hence, after 90 s ischemia, the myocardium was sufficiently jeopardized to show regional akinesia (Table 2, Fig. 2) and to allow the detection of differences in regional myocardial function between treatment conditions (Table 2).
4.2 Effects on regional myocardial function and hemodynamics
The main finding of the present study was that the administration of low-dose dobutamine (0.1 µg/kg/min) together with arterial blood by means of SSR during brief periods of acute coronary ischemia resulted in substantially higher preservation of regional myocardial function of the ischemic myocardium compared with retroinfusion of arterial blood alone (Fig. 2). The inotropic effect of dobutamine was highly selective since no change in regional myocardial function was observed in the non-ischemic myocardium supplied by the circumflex artery (Table 2). Furthermore, there was no evidence of changes in hemodynamics not related to the local effects of dobutamine: heart rate was unchanged, whereas a trend towards stabilization of cardiac output, mean arterial pressure and LVEDP during selective retroinfusion of dobutamine was observed (Table 1). The stabilizing effects of retroinfusion with dobutamine on hemodynamics (Table 1), however, did not reach statistical significance, which was probably due to the short duration of ischemia (90 s) [12].
Our data suggest that local administration of low-dose dobutamine into an ischemic myocardium by means of SSR provides the advantage of local inotropic stimulation without undesired systemic effects. Thus, the contractile reserve of the ischemic myocardium was detected by the addition of low-dose dobutamine to SSR in the pig model. At least during brief periods of ischemia (90 s) supported by selective suction and pressure-regulated retroinfusion with the combination of dobutamine and arterial blood, there was no evidence for a mismatch between inotropic stimulation and retrograde arterial blood supply. Nevertheless, extrapolation of the data obtained during brief ischemic periods (90 s) to prolonged ischemia must be made with caution. It remains to be clarified whether, during prolonged ischemia supported by retroinfusion with arterial blood, the addition of dobutamine is as well tolerated as during brief ischemic periods or accompanied by a decrease in high-energy phosphates of the ischemic myocardium.
In contrast to dobutamine, glyceryl trinitrate had no stimulating effect on regional myocardial function during ischemia supported by pressure-regulated retroinfusion, which is in agreement with previous studies using non-selective synchronized retroperfusion [26]. With non-selective retroperfusion combined with glyceryl trinitrate, however, a decrease in regional myocardial function was observed and explained by shunting of arterial blood to non-ischemic regions [26]. In our experiments, regional myocardial function was not influenced by glyceryl trinitrate either in the ischemic or in the non-ischemic myocardium (Table 2), supporting the assumption of a more local application of glyceryl trinitrate to the ischemic myocardium by SSR than by non-selective retroperfusion.
4.3 Effects on retrograde blood flow and coronary venous resistance
Retrograde blood flow and maximal coronary venous dP/dt (dP/dtmax) were repeatedly measured during retroinfusion to investigate whether addition of drugs was associated with changes in the coronary venous pressure–flow relationship. It has to be stressed, however, that regional myocardial blood flow was not measured directly. The application of radioactive or coloured microspheres for determination of regional myocardial blood flow has been established for blood flow measurements during antegrade perfusion [28]. During retroinfusion, however, these methods are of limited value, because blood flow through the capillaries is bidirectional (i.e., retrograde pumping and antegrade collateral blood flow) and leads to unpredictable washout of microspheres already trapped in the capillaries [20]. This effect is probably further enhanced by SSR, which operates with alternate pumping and suction [12, 20]. Since none of the established methods for determination of regional myocardial blood flow was applicable during SSR, we tried to roughly estimate blood flow to the ischemic myocardium by retrograde transcatheter blood flow measurements. Furthermore, we assumed that during retroinfusion with a similar peak and mean coronary venous pressure (Table 3), changes in retrograde transcatheter blood flow or dP/dtmax of the coronary venous pressure rise may reflect changes in coronary venous resistance of the ischemic myocardium. Apparently, the addition either of dobutamine or of glycerol trinitrate had no effect on these parameters (Table 3), suggesting that total coronary venous resistance of the ischemic myocardium was not changed substantially. Whether the proportion of nutritive blood flow, shunted blood flow or antegrade collateral blood flow, which is less than 2% in this pig model [17, 19], was influenced by the drugs cannot be decided on the basis of our data.
4.4 Clinical implications
The present investigation showed that the local application of low-dose dobutamine together with arterial blood during SSR increased regional myocardial function of the ischemic myocardium without affecting non-ischemic myocardium and without causing undesired systemic effects. Thus, in the pig model, detection of the contractile reserve of ischemic myocardium was possible without the drawbacks of systemic dobutamine administration seen in patients [3–5, 8, 9]. Whether selective targeting of dobutamine to ischemic myocardium by means of retroinfusion with arterial blood will help to quantify the contractile reserve of hibernating myocardium in patients more precisely and will be tolerated by the ischemic myocardium, is currently being investigated in a clinical pilot study.
Furthermore, selective pressure-regulated retroinfusion might be a unique approach to deliver inotropics such as dobutamine locally to ischemic myocardium during acute coronary occlusion in order to stabilize hemodynamics. In a small group of high-risk patients who underwent percutaneous angioplasty supported by SSR [13, 14], local delivery of dobutamine to the ischemic myocardium during 120 s of ischemia was well tolerated and associated with a significant stabilization of mean arterial blood pressure compared to retroinfusion with arterial blood alone ([14]and unpublished data). Whether the same holds true for prolonged ischemia, which would have important implications for prevention of or counteracting hemodynamic instability during acute myocardial infarction, is currently under investigation.
Time for primary review 18 days.
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