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Eur J Cardiothorac Surg 2001;20:170-176
© 2001 Elsevier Science NL
Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg, 69120, Germany
Received 6 November 2000; received in revised form 21 February 2001; accepted 30 March 2001.
Corresponding author. Tel.: +49-6221-566111; fax: +49-6221-565585
e-mail: dzsi{at}hotmail.com
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Abstract |
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 Top Abstract 1. Introduction2. Material and methods3. Results4. DiscussionReferences |
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Key Words: Brain death • Contractility • Afterload • Ventriculo-arterial coupling
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1. Introduction |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionReferences |
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On the base of our previous studies [8–10], we hypothesized that altered loading conditions play a key role in the changes of cardiac function after brain death. In the first part of the study cardiac function was assessed in the previously developed [2] in situ isolated heart model. In this model the hearts are completely separated from the systemic circulation and thereby independent from loading conditions. In the second part of the study, the hearts were investigated in vivo allowing the interaction between left ventricular contractility and arterial load. Cardiac function was described by relatively load-independent means such as the slope of the end systolic pressure–volume relationship. Additionally, the interaction between left ventricular contractility and arterial load was described by ventriculo–arterial coupling ratio and mechanical efficiency [11].
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2. Material and methods |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionReferences |
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2.2. Brain death model
Experimental brain death was produced by creating intracranial hypertension. A Foley catheter was introduced into the subdural space through a parietal burr hole in the skull. A rapid injection of 25 ml of saline inflated the balloon of the catheter, which produced an acute increase in intracranial pressure. Brain death occurred within a few minutes in all animals and cerebellar herniation caused interruption of neurological pathways between the midbrain and the spinal chord. Brain death was confirmed neuropathologically at the end of the experiment.
2.3. Surgical preparation and experimental design
2.3.1. General management
The dogs were anesthetized with a bolus of pentobarbital (Nembutal–Abott 12 mg/kg i.v.), paralyzed with pancuronium bromide (Pancuronium–Organon 0.1 mg/kg as a bolus and then 4 µg/kg per min i.v.) and endotracheally intubated. The level of anesthesia was maintained with synthetic opiate piritramid (Dipidolor–Janssen 1 mg/kg as a bolus and then 15 µg/kg per min i.v.). The dogs were ventilated with a mixture of N2O and O2 (40:60) at a frequency of 12–15/min and a tidal volume starting at 15 ml/kg per min. The settings were adjusted by maintaining arterial partial carbon dioxide pressure levels between 35–40 mmHg. The femoral artery and vein were cannulated for recording aortic pressure (AoP) and taking blood samples for the analysis of blood gases, electrolytes and pH. Basic intravenous volume substitution was carried out with Ringer's solution at rate of 1 ml/min per kg. If necessary, the rate of volume substitution was modified according to the continuously controlled input-output balance in order to maintain cardiac output at baseline levels. According to the values of potassium, bicarbonate and base excess, substitution included administration of potassium chloride and sodium bicarbonate (8.4%). Neither catecholamines nor other hormonal or pressor substances were administered. Rectal temperature and standard peripheral electrocardiogram were monitored continuously.
2.3.2. In situ isolated heart (n=6)
The experimental model was described in detail elsewhere [2]. Briefly, after lateral thoracotomy in the fourth intercostal space the pericardium was incised. The great vessels of the hearts were isolated. A 14F retroplegia balloon-catheter with a second small lumen was introduced into the ascending aorta via the left subclavian artery. The left pulmonary artery was cannulated to collect coronary sinus effluent. The superior and inferior vena cava were cannulated for the venous return. The right femoral artery was cannulated for arterial perfusion. After cannulation of all vessels, extracorporal circulation including a heat exchanger, a venous reservoir, a roller pump and a membrane oxygenator was initiated. Arterial perfusion was performed via the right femoral artery and venous return was collected due to the caval cannulas. Perfusion volume was adjusted to achieve the same mean aortic pressure measured before extracorporal circulation. Perfusion volume was 2.34±0.27 l/min. After a 5 min stabilization period, the balloon of the retroplegia catheter was inflated and the donor heart was perfused with the animal's own blood by a second parallel pressure-controlled roller pump with a constant perfusion pressure of 80 mmHg. In this setting, the hearts were separated from the systemic circulation and, therefore, loading conditions and coronary perfusion pressure could be kept constant independently from the changes of the peripheric circulation throughout the experiments. A latex balloon was fixed on a 7F Millar catheter tip manometer with an internal lumen and placed in the left ventricle through an incision of the left atrium. The compliance of the balloon was negligible within a volume range of 0–50 ml. The mitral valve and the left atrium were closed with a 4-0 suture. The thebesian blood flow was vented via a 14F vent catheter. After baseline measurements, brain death was induced in the donor animal and the observation continued up to 2 h.
2.3.3. In vivo model (n=6)
Six dogs were anesthetized and thoracatomized as described above. After pericardiotomy and isolation of the great vessels a perivascular electromagnetic flow probe was attached to the ascendent aorta. A combined 6F Millar pressure-conductance catheter with 6 mm spacing was inserted into the left ventricle via the apex. Aortic pressure and right atrial pressure were monitored by 5F Millar catheter tip manometers.
2.4. Data acquisition and analysis
Heart rate (HR) and aortic pressure (AoP) were monitored continuously.
In the in situ isolated hearts, left ventricular pressures were measured during isovolumic contraction at different balloon volumes and systolic and diastolic pressure–volume relationships were constructed. Systolic function was evaluated by the maximal peak systolic pressure (LVSP), maximum pressure development (dP/dtmax) and the slope of the peak systolic pressure–volume relationship (Emax). Diastolic function was characterized by minimum pressure development (dP/dtmin) and end-diastolic pressure (LVEDP) at a volume of 16 ml. Coronary blood flow (CBF) was measured by an electromagnetic flowmeter, which was connected to the arterial cannula. All hemodynamic parameters were registered on a Gould multichannel monitor unit and recorded on a PC computer for further off-line analysis. Hemodynamic measurements were performed before and 2 h following brain death induction.
In the in vivo model, left ventricular systolic pressure (LVSP), maximum pressure development (dP/dtmax), end-diastolic pressure (LVEDP) and cardiac output (CO) as the equivalent of aortic flow were monitored continuously. Stroke volume (SV) was calculated from the integrated flow signal and was used to calibrate the volume signal from the conductance catheter. Systemic vascular resistance (SVR) was calculated as: SVR=(AoP-RAP)/CO.
The volume signal provided by the conductance catheter using dual field excitation was registered continuously (Sigma F5, Leycom, Leiden, The Netherlands) and computed by the Conduct PC software (Leycom, Leiden, The Netherlands). Pressure–volume loops were constructed on-line. Vena cava occlusions were performed at different time points before and up to 4 h after brain death induction to obtain a series of loops for calculation of the slope (Ees) and intercept (V0) of the end-systolic pressure–volume relationship according to the equation Pes=Ees(Ves-V0). Arterial elastance (Ea) was calculated as Ea=Pes/SV. Ventriculo–arterial coupling was described by the quotient of Ea and Ees [11]. According to Sunagawa et al. [11], stroke work (SW) was calculated as the area within the pressure–volume loop and pressure–volume area (PVA) was calculated as the area circumscribed by the endsystolic pressure–volume line, the enddiastolic pressure–volume relation curve and the systolic pressure–volume trajectory. SW/PVA ratio was defined as mechanical efficiency [11].
All values were expressed as mean±standard error (SEM). Paired t-test was used to compare two means within groups. A probability value less than 0.05 was considered statistically significant.
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3. Results |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionReferences |
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3.2. In vivo model
Brain death induction led to the well-known initial hyperdynamic reaction (Table 2) with a significant increase of most hemodynamic variables except LVEDP and RAP. Immediately after the acute phase, AoP, SVR, SW and PVA decreased significantly followed by a slower decrease of LVSP and dP/dtmax. CO returned to baseline level and remained constant. Representative pressure volume loops and endsystolic pressure volume relationships are shown before and 4 h after brain death induction (Fig. 2)
. Ees and Ea showed a parallel decrease (Fig. 3)
. The ventriculo-arterial coupling ratio did not show any significant changes (Fig. 4)
. Similarly, the parallel decrease of SW and PVA (Fig. 3) resulted in an unchanged mechanical efficiency (Fig. 4).
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4. Discussion |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionReferences |
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In the second part of the study the ventriculo-arterial coupling was described by means of ventricular and arterial elastance (Ees and Ea) in an in vivo model. In this series, myocardial contractility decreased parallel to the decrease of afterload, whereas the ventriculo-arterial coupling ratio remained constant. The findings of the two series indicate that hemodynamic instability after brain death rather reflects to altered loading conditions than primary cardiac dysfunction.
The observed hyperdynamic reaction after induction of brain death is in agreement with the literature [1–10,12–14]. This Cushing type reaction can be explained by a sympathetic nervous discharge and an activation of the sympatho-adrenal system with significant increase of plasma catecholamines [1,15].
A very important finding of the present study is that in the in situ isolated heart model no cardiac dysfunction occurred after the initial reaction. This partly contradicts previous studies [1,12–14] where deterioration of cardiac function was suggested to be responsible for hemodynamic instability after brain death.
Cardiac dysfunction was explained by the initial hyperdynamic reaction associated with extensive catecholamine release and the frequently observed hormone depletion [1,12,15]. A catecholamine-associated histologic damage of the myocardium was reported in experimental studies of brain death [1,5,6,12,13]. However, an increasing number of recent studies questioned the causal relationship between catecholamine damage and hormone loss on one hand and cardiac dysfunction and hemodynamic instability. Bruinsma et al. [5] demonstrated in a cat model that no relationship is given between the acute increase of myocardial workload, the occurrence of hemodynamic deterioration and myocardial histologic changes after rapid induction of brain death. Baroldi et al. [6] found myocardial necrosis in all types of brain injury in a human pathomorphologic study. However, the extent of myocardial damage was always minimal and should therefore not jeopardize cardiac function if hearts from those donors are transplanted. Moreover, Galinanes et al. [4] and we [8] showed previously that if donor hearts were evaluated ex vivo, no differences were found between hearts harvested from brain dead and non-brain dead donors.
To explain the discrepancies of the above mentioned studies we hypothesized that altered loading conditions may have a crucial role in hemodynamic instability. Shortly after brain death systemic vascular resistance and aortic, mainly diastolic aortic pressure decreases significantly due to the loss of the sympathetic tone [1–5,8–10,12,16]. This may have an influence on the evaluation of the donor hearts in two terms. First, if cardiac function is evaluated by load-dependent parameters altered loading conditions may mask ‘true’ myocardial function [7]. Second, altered loading conditions themselves may have a significant effect on contractile performance due to the homeometric (Anrepp effect) and heterometric (Frank–Starling mechanism) autoregulation and due to the alteration of coronary perfusion pressure independently from direct brain death related changes of cardiac function.
Therefore, we used a new unique in situ isolated heart model which, however, may have some limitations. The use of extracorporal circulation may cause hemolysis and activation of cytokines which may have an influence on heart function. As we showed in our previous study [2], these effects are negligible within a 2 h observation period in normal control animals. In the present cross-circulated heart model, increased myocardial workload due to increased afterload during the acute phase is excluded, which may have an impact on later impairment of cardiac function. However, Bruinsma et al. [5] showed that there is no relationship between initial increase of myocardial workload and subsequent cardiac dysfunction. On the other hand the main advantage of this model that significant determinants of myocardial function could be differentiated in an independent manner. In the present setting, the hearts under constant loading conditions and coronary perfusion pressure were affected by the two main proposed potential cardiodepressant effects of brain death (1) the hyperdynamic initial reaction in association with the so called ‘catecholamine storm’; (2) hormone depletion. However, under these circumstances no cardiac dysfunction occurred after brain death induction. These results indicate that neuro-humoral changes may have less impact on cardiac performance following brain death than thought before and cardiac function may be load-dependent. Herijgers et al. [16] has already speculated that the frequently observed hemodynamic collapse is primarily related to decreased afterload but not primary cardiac dysfunction. To our best knowledge, this is the first study which showed that maintenance of loading conditions may prevent cardiac dysfunction after brain death. Furthermore if afterload conditions were allowed to interact with left ventricular contractility in the second series, the brain-dead related decrease of afterload resulted in a downregulation of myocardial contractility (homeometric autoregulation).
How decreased afterload exactly leads to cardiac dysfunction, is not completely understood. One possible mechanism may be, that decreased afterload results in a decreased coronary perfusion pressure which may compromise cardiac contractility. Indeed, some authors reported a significant fall of myocardial blood flow in a rat [17] and in a pig [18] model of brain death using the microsphere technique. Both studies underlined an apparent correlation between the impairment of myocardial blood flow and the observed deterioration of left ventricular function. Though there was no histologic evidence for myocardial ischemia, the obtained data did not allow to decide whether the decreased coronary flow was still sufficient to fulfill the actual needs of the myocardium. In our previous study [2], we demonstrated that decreased coronary perfusion is an important contributing factor to cardiac dysfunction after brain death. Coronary perfusion pressure of brain-dead animals fell below a so-called ‘critical perfusion pressure’, where coronary autoregulatory reserve is exhausted. It is tempting to presume that the deterioration of left ventricular function after brain death is related to a loss of autoregulatory reserve of the coronary vessels. The low coronary perfusion pressure reduces the contractility which tends to further lower coronary perfusion pressure in the face of increasing end-systolic volume and decreasing ventricular pressure. Once this vicious cycle is triggered, the ventricle can hardly recover by its own ability. The fact that critical perfusion pressure, coronary pressure-flow relationships and perfusion-contractility matching were almost identical in control and brain dead animals in our previous study [2] also suggests that hemodynamic instability in the potential donor may not reflect to direct cardiac effects of brain death, but rather to altered loading conditions and coronary perfusion.
A possible direct participation of decreased afterload independently from coronary perfusion pressure in the decline of cardiac contractility remains to be clarified. Suga and his coworkers [19] used brain death as a model for the totally denervated heart to investigate the effects of afterload changes on left ventricular contractility in the absence of neural regulation. They found that left ventricular contractility was increased by a separate increase of aortic pressure. Klautz et al. [20] demonstrated an interaction between afterload and contractility in the newborn heart via the homeometric autoregulation. Asanoi et al. [21] observed in vivo in dogs that under autonomic blockade changes in afterload were followed by parallel changes in contractility. They postulated the existence of a control system, which maintained optimal stroke work over a wide range of afterload conditions by mechanisms other than neural reflexes. A potential explanation for the interaction between contractility and afterload in the absence of neuro-humoral regulation could come from the consideration that a change in endsystolic pressure, even without changes in ventricular volume, implies a change in wall tension. It could be hypothesized that the signal for homeometric regulation lies in mechanical stress activated channels [22]. Even if left ventricular volume and thereby myocardial cell length remain stable (as also in the present study, see Fig. 2), the deformation of cell membrane by stress or distress caused by an increase or decrease of the transmembrane pressure gradient is sufficient to evoke an increase or decrease in calcium activation, respectively. Another endogenous stimulus for the adjustment of contractile performance could originate from the endocardial endothelium. Demer et al. [23] showed that mechanical stimulation of aortic endothelial cells led to increased calcium concentrations in neighboring cells.
Independently from the cellular mechanism, the downregulation of left ventricular contractility via intact ventriculo-arterial coupling has some energetic consequences. At a lower afterload level, reduced stroke work is sufficient to maintain physiological cardiac output and thereby the perfusion of peripheric organs. Cardiac contractility kept at a ‘normal’ level would lead to a mismatch between stroke work and total mechanical energy (PVA) with a proportionally higher oxygen demand in a situation where coronary perfusion is limited. On the other hand decreased myocardial performance requires a reduced oxygen supply and results in an unchanged mechanical efficiency. Tanaka et al. [24] described in a mathematical model that optimal contractility and minimal oxygen consumption exist for constant stroke work. The existence of a such optimal contractility has been expected as a balance of the opposing effect of contractility on myocardial oxygen consumption: myocardial tension that decreases with increasing contractility and the oxygen wasting effect that increases with increasing contractility. Experimental data [11,21] confirmed this hypothesis. Therefore, reduced contractile function after brain death at a decreased afterload may contribute to stroke work optimization.
The findings of the present study might have some clinical implications. If cardiac dysfunction after brain death is related to altered loading conditions and not to neuro-humorally mediated primary cardiomyocyte damage, a part of the rejected donor hearts may be suitable for organ transplantation. Therefore, cardiac function, especially if characterized by load-dependent parameters, should be carefully evaluated. Optimization of donor management may also contribute to unmask ‘true’ cardiac function [7] and to increase the donor heart pool.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstract1. Introduction2. Material and methods3. Results4. DiscussionReferences |
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