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Eur J Cardiothorac Surg 1998;13:449-458
© 1998 Elsevier Science NL
a Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany
b Department of Cardiac, Thoracic and Vascular Surgery, Hannover Medical School, Hannover, Germany
Received 29 September 1997; received in revised form 29 December 1997; accepted 14 January 1998.
Corresponding author. Tel.: +49 6221 566111; fax: +49 6221 565585; e-mail: szabo@novsrv1.pio1.uni-heidelberg.de
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Abstract |
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Material and methodsResultsDiscussionReferences |
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Key Words: Brain death • Right ventricle • Contractility • Regulation • Frank-Starling mechanism • Transplantation
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Introduction |
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TopAbstractIntroduction
Material and methodsResultsDiscussionReferences |
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To evaluate the possible role of brain death in early allograft failure after cardiac transplantation, numerous experimental and clinical studies have been investigated. In the past, many possible causes of cardiac dysfunction after brain death were discussed, as there might be direct cardiac myocyte injury, catecholamine induced myocardial damage [2] and impairment of the ß-adrenergic receptor/adenylyl cyclase system [3] in association with the initial Cushing type reaction, as well as hormone depletion during the further time course [2]. The changes of loading conditions [5] and coronary perfusion [6] may also play a role in cardiac dysfunction in the brain dead organ donor. Although right ventricular dysfunction has a greater clinical relevance, the majority of the previous studies assessed only left ventricular performance. In recent reports of Bittner and his colleagues [3] [4], simultaneous measurements of left and right ventricular function were performed and both ventricles showed decreased contractility at 4–6 h after brain death induction. Furthermore, the right ventricle was more vulnerable against ischemia/reperfusion injury in their study. However, the ability of the right ventricle of hearts from brain dead donors to adapt to an acute increase in right ventricular afterload has not yet been investigated. The present study was designed to characterize right ventricular function after brain death in dogs in vivo and to examine the adaptation potential of the right ventricle to the increase in RV afterload. The functional testing of the right ventricle after afterload elevations was performed in the brain dead donor to avoid additional injury by ischemia/reperfusion and transplantation and to describe direct brain-death related changes of right ventricular adaptation potential.
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Material and methods |
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TopAbstractIntroduction
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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 15 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 interuption of neurological pathways between the midbrain and the spinal chord.
Preparation
The dogs were anaesthetized with an intravenous bolus of pentobarbital (Nembutal-Abott, 12 mg/kg), paralyzed with pancuronium bromide (Pancuronium-Organon 0.1 mg/kg as a bolus and then 4 µg/kg per min) and endotracheally intubated. The level of anesthesia was maintained with morphine intravenously (Dipidolor-Janssen 1 mg/kg as a bolus and then 15 µg/kg per min). After lateral thoracotomy in the 4th intercostal space, the pericardium was incised.
Cannulas were inserted to monitor pulmonary arterial pressure (PAP), right ventricular peak systolic pressure (RVSP) and its first derivative (dP/dt), right ventricular end-diastolic pressure (RVEDP), right atrial pressure (RAP) and left ventricular pressure (LVP). Blood pressures were recorded by Gould pressure transducers which were connected to an analog strip chart recorder (Astromed). Cardiac output (CO) was measured by an electromagnetic flow probe on the ascending aorta. Stroke volume (SV) was estimated from the integrated flow signals. Ultrasonic crystal transducers were implanted subendocardially parallel to the minor axis in the anterolateral wall of the right ventricle to assess segment length shortening. This pair of crystals provide a segment length along the right ventricle’s principal directions of shortening [5]. The outputs from the ultrasonic and RV pressure transducers were plotted continuously and simultaneously as an X–Y plot on a memory oscilloscope to obtain a pressure-length loop for the myocardial segment. All these data were recorded on a magnetic tape for subsequent computer analysis.
RV stroke work was calculated as
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RV segmental work was calculated as
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Segment length shortening was calculated as
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Arterial blood samples were taken at regular intervals to determine the levels of the circulating catecholamines epinephrine (EPI) and norepinephrine (NOR). Arterial blood gases and serum electrolytes were measured and, if necessary, corrected to physiologic norms. Intravenous crystalloid solution was administrated to maintain the fluid balance. No pressor or hormonal substances were used.
Experimental protocol
After surgical preparation and instrumentation, steady state baseline (baseline 1) data were recorded and blood samples were taken. Then, in eight dogs, brain death was induced. The other sham-operated five dogs served as controls without brain death induction. Pressure, flow and dimension data were registered on line for 2 h, blood samples were collected at 1, 5, 60 and 120 min after brain death induction. In the control group, a sham-operation was performed and the same protocol was utilized.
To examine the adaptation potential of RV to afterload increase, the pulmonary artery was constricted by tightening a snare around the pulmonary artery 3–4 cm distal to the RV outflow tract. An increase in RV pressure from 25 to 50 mmHg was achieved by progressive constriction of the pulmonary artery. Measurements were taken at all levels directly after pulmonary banding (PB) and in steady state (10, 20, 30 min after PB). After the last PB level (RVP=50 mmHg) the snare was loosened and the dogs were then allowed to return to baseline steady state. The recorded values 2 h after brain death induction served as control (baseline 2) to this series. In the control group, the same procedure was performed. Collection of arterial blood samples was performed during each step of PB.
Statistics
Data were compared over time by a paired t-test. Intergroup statistical analysis was performed with one-way analysis of variance. All results are expressed as the mean±S.E.M. A probability value less then 0.05 was considered significant.
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Results |
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TopAbstractIntroduction
Material and methodsResultsDiscussionReferences |
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Baseline catecholamine levels were similar in both groups. In the control group they remained unchanged during the following 2 h. In the brain death-group, 1–2 min after balloon inflation, a 
100-fold increase in the circulating cathecolamine levels was noted. These high levels began to decrease after 5 min and were almost equal to baseline values after 120 min (Table 2).
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The increase of RVSP led to a characteristic significantly higher increase of RVEDP in the brain death group in comparison to control ( Fig. 2 , right panel). RVEDP was significantly higher at RVSP=30 mmHg in the brain death group and only at RVP=50 mmHg in the control group in comparison to baseline. There was a significant difference between the groups at RVSP=30–50 mmHg. RAP (7.21±0.79 vs. 4.57±0.71 mmHg, P<0.05 at RVSP=50 mmHg) showed similar changes as RVEDP. The left panel of Fig. 2 depicts the changes of peak positive dP/dt. In the control group, peak positive dP/dt increased progressively parallel to the increase of RVSP reaching the level of significance at RVSP=30 mmHg. In contrast, the brain death group showed only a slight increase of dP/dt, which however, did not reach the level of significance even at RVSP=50mmHg. Fig. 3 shows global cardiac function as plot of SW vs. RVEDP. Each point represents a steady state coordinate of one RVSP level from RVSP=20–50 mmHg. The rightward shift of the coordinates in the brain death group in comparison to control indicates lower contractility. This plot clearly demonstrates that at a given RVSP, right ventricular pump performance was similar in both groups (similar SW), however contractility was lower and preload was augmented in the brain death group. It should be noted, that these plots are not the same as the traditional Starling curves, where SW-end diastolic pressure relations are determined by acute primary changes of preload.
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After the last pulmonary banding level (RVSP=50 mmHg), the snare was loosened and the dogs were then allowed to return to baseline steady state. No differences were found between the groups and the values after 2 h of brain death induction.
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Discussion |
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TopAbstractIntroduction
Material and methodsResultsDiscussionReferences |
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100-fold increase of plasma catecholamines could be observed. Great number of studies
[2]
[5]
[7]
[8]
[14] using experimental models of brain death also reported tremendous increases in the catecholamine levels. Many investigators found a close correlation between the hemodynamic and neuro-hormonal changes during the acute phase
[2]
[5]
[10]
[14]. In the present study, similar changes can be observed in the right ventricle as those already described for the left ventricle. Brain death leads acutely to an increase in right ventricular pump performance associated with a hypercontractile state. Elzinga et al. [15] have shown in isolated ejecting cat hearts, that the higher right ventricular mean pressure influences the performance of the right ventricle in a positive way. This can be due to an increased contractility or to an increased muscle fiber length in the free wall of right ventricle. The analysis of the P–L loops showed, that during the acute response after brain death, the right ventricle reaches a significantly higher contractile state causing an increase in pump function. This could be explained by the acute sympathetic activation in accordance with the higher catecholamine concentrations in plasma. Only sporadic studies [16] [17] describe the acute effects of catecholamines on the function of the right heart. These showed an acute increase in the contractile performance and a subsequent increase in pump function after infusion of norepinephrine or epinephrine.
The pulmonary vasculature seems to be less influenced by the Cushing reaction as the systemic vasculature. Previous studies [2] [3] [4] [5] showed a significant increase of systemic vascular resistance during the acute phase. In the present and in our previous study [5], pulmonary vascular resistance showed no significant changes. The influence of brain death on the pulmonary circulation is a point of controversial discussion. Most of the authors [2] [3] [4] [9] [10] [18] [19] found elevated pulmonary artery pressure after brain death-induction. A reported [2] [18] sequence of events of marked rise in left ventricular filling pressures to exceed—for several seconds during the acute phase—the level of pulmonary arterial pressure leading to the generation of pulmonary edema has not been observed in the present study. Similarly to the study of Brashear et al. [9], increased pulmonary arterial pressure could be explained rather with significantly increased CO then with changes of pulmonary vascular resistance. This is in contrast to changes of the systemic circulation in which a significant increase in systemic vascular resistance could be observe after brain death [2] [5] [10].
There are only few data about the changes of right ventricular function and pulmonary circulation after the acute phase. In the studies of Bittner et al. [3] [4] [19], mean pulmonary arterial pressure remained stable up to 4 h and showed an increase after 6 h. RVEDP and pulmonary flow were also constant during the first 4 h and increased only parallel to mean pulmonary arterial pressure. However, at the same time, pulmonary vascular resistance became significantly lower in their study. In the present study, no significant changes of the pulmonary circulation were observed during the first 2 h after brain death induction which is in agreement with other studies [3] [4] [19]. In a previous study [5], we showed that pulmonary hemodynamics remains stable even up to 5 h. After the acute phase, right ventricular pump performance showed no significant changes during the first 2 h if it was characterized by RVSP, SW and CO. The analysis of the P–L loops and peak positive dP/dt taking account its load-dependency, suggest that not only global performance but also myocardial contractility remains unchanged in comparison to baseline. In the present study, the pulmonary banding protocol was finished at 4.5 h after brain death induction and the animals were evaluated in steady state. There were no differences between the groups and in comparison to baseline (baseline 1 and 2). These data directly contradict the findings of Bittner et al [3] [4] [19], where pump function was maintained at a decreased afterload and contractility. In their study, high output failure developed with an increase of cardiac output and filling pressure. However, it is not clear how far these changes 4–6 h after brain death induction are directly related to brain death or to the applied volume management. Wicomb et al. [20] tested the effects of different types of management on myocardial function after brain death in a cross-circulated heart preparation. They demonstrated that volume loading and inotropic support in the brain dead organ donor increase mean arterial pressure, but may be detrimental for myocardial function. In the study of Mertes et al. [21], volume loading led also to an impairment of cardiac function. Under these aspects, decreased right ventricular contractility in the study of Bittner et al. [3] [4] [19] may rather reflect the management of the donor animal than brain death itself.
Adaptation potential of the right ventricle
While the RV function after brain death during increased afterload has not been studied yet, numerous experimental and clinical investigations characterized the behavior of the normal right heart under different loading conditions.
Several investigators have previously studied the hemodynamic response to a comparable acute increase in pulmonary arterial pressure or right ventricular systolic pressure [22] [23] [24] [25] [26] [27] [28]. The results of these studies are partially controversial. In a few of these studies, a different degree of RV failure developed. Some of the differences in hemodynamic response to similar increases in RV afterload may in part be due to an unphysiologically elevated baseline sympathetic tone, as reflected by marked elevated baseline HR or blood pressure [26] [27]. This might have reduced the adaptation reserve to a further increase in sympathetic tone necessary to compensate for a progressive pulmonary artery constriction [29]. Additionally, a relative hypovolumic state might also have influenced the development of RV failure [26].
In the control group of our study (animals with sham operation without brain death), similar to other experimental and clinical studies [22] [23] [28] [30], the increase of RV afterload did not result in an impairment of the RV function, but to an increase in pump performance. The analysis of the P–L loops as well as the regional and global cardiac function curves showed a higher contractile performance and a complex adaptation process ( Fig. 6 ). The compensatory mechanisms maintaining RV performance during increased afterload are homeometric autoregulation with augmentation of contractility and the Frank–Starling mechanism through increased myocardial stretch. The response of the sympathetic nervous system in this regulatory process can be characterized by the increasing tendency of heart rate in the control group. The increased sympathetic tone due to its positive inotropic effect may play a marked role in this kind of adaptation [23] [29].
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The findings of the present study may be explained by another mechanism: the loss of inotropic adaptation may be due to the denervated state of the heart. In the brain dead animal, the destruction of the central sympathetic pathways excludes the sympathetic regulation. The results of Rose et al. [23] using ß-adrenergic blockade indicate that the ß-adrenergic component of the sympathetic nervous system is important in the right ventricular response to afterload changes. Support for this could be found in the steeper rate of rise in the RVEDP with applied afterload during ß-adrenergic blockade. The parallel increase of RVEDP with increased afterload after ß-blockade was very similar to our observations in the brain death group. Abel et al. [22] showed similar changes after surgical denervation of the heart.
The changes of coronary perfusion pressure may also play a role in the impairment of contractile response to increased afterload. In contrast to pulmonary vascular resistance which remained stable after brain death, systemic vascular resistance decreases significantly resulting in lower aortic, mainly diastolic aortic pressure and therefore, coronary perfusion pressure. Even if coronary autoregulation is satisfactory to cover energy demand to maintain baseline inotropic state, it may be exhausted earlier in the brain dead animals after right ventricular afterload increase, especially at higher elevations. In a preliminary study [6], we showed that coronary perfusion is a major determinant of donor myocardial function. A decrease of left ventricular contractility after brain death could be reversed by restoring coronary perfusion pressure and flow.
At least, it should be stressed, that independently from the possible mechanisms leading to a decreased ability of inotropic adaptation in the brain dead animal, the functional reserve of the right ventricle still remains sufficient to compensate for increased RV afterload by the Frank–Starling mechanism. Sibbald et al. [30] showed that under clinical conditions, the right ventricular pump function could be dissociated from RV contractile function. In patients with depressed right ventricular contractility (right ventricular contusion) or/and severe pulmonary arterial hypertension, they achieved the maintenance of the right ventricular pump function by augmentation of right ventricular preload, thereby utilizing the Frank–Starling mechanism. However, extremely large right ventricular volumes and RVEDP can be associated with impaired right ventricular function due to right ventricular ischemia and septal bulging between the two ventricles [25] [27] [30]. Peak RVEDP >10 mmHg have been described as a critical value in dogs in response to pressure overload [24] [26]. In our study, no RVEDP higher than this value was occurred.
Limitations of the study
In the present study, no load-dependent indexes of contractility, such as the slope of the end-systolic pressure-volume/dimension relationship or preload recruitable stroke work were used, since a ‘Starling’ analysis in terms of rapid preload reduction (vena caval occlusion) was not performed for each state of the protocols. However, during the first 2 h after brain death pre- and afterload conditions remained stable, except the transient changes during the Cushing-type reaction and therefore, as indicated by peak positive dP/dt, the contractile state was probably similar in both groups after 120 min and there were no differences in contractility between baseline 1 and baseline 2. During right ventricular afterload elevation, preload and afterload vary, which may also have an effect on peak positive dP/dt independently from inotropic changes. At identical afterloads for each PB level, peak positive dP/dt showed a significant increase in the control group, while it remained unchanged in the brain death group. Even if we do not know exactly which amount of peak positive dP/dt change can be attributed to direct inotropic change and which one to afterload increase, the higher increase in the control group in comparison to brain death reflects higher contractile responses, since afterloads were equal for both groups. Taking into account its load sensitivity, an increase of peak positive dP/dt indicates a significant increase of contractility in the control group and probably, unchanged peak positive dP/dt reflect unchanged contractility in the brain death group.
The qualitative analysis of the steady state P–L loops [32] also indicates that afterload elevation leads to an adaptation primary by increased contractility in the control group and primary by the Frank–Starling mechanism in brain death animals. A mathematical assumption may also suggest indirectly that the right ventricular contractile performance remained unchanged in the brain death group. The P–L relationship as well as SW–end-diastolic length relationship were described as a linear relation and a slope of these relationships as a relatively load-independent index for right ventricular contractile performance [17] [32] [33] [34]. A good correlation with linear regression by the segmental SW–end-diastolic length coordinates was observed in the brain death group. If the segmental SW–end-diastolic length relationship is assumed to be linear, than the steady state segmental SW–end-diastolic length coordinates of the brain death group may represent similar contractile states. On the other hand, the second order polynomial increase of the segmental SW–end-diastolic length relationship in the control group reflects an increase of right ventricular contractility ( Fig. 5).
A further limitation of the present study may be the relatively short period of brain death. However, as discussed above, different management modalities may have a major influence on cardiac performance in the donor during longer observation periods. As we focused on direct brain death related changes of right ventricular performance, we chose a relatively short period of brain death to keep the influence of donor management at the minimum. Furthermore, major hemodynamic changes occur within the first 2 h after brain death in most of the studies [2] [3] [4] [5], therefore longer observation periods would have little influence on the results of this study.
Concluding comments
In the present study, hyperdynamic reaction of the right ventricle and the pulmonary circulation occurred after brain death induction, similarly as previously described in left ventricular studies. After the acute phase, brain death itself acutely does not result in an impairment of baseline right ventricular pump performance and contractility. However, the ability of brain dead hearts to compensate for acute elevations in right ventricular afterload by positive inotropy is impaired in comparison to normal control hearts. In this experimental setting, right ventricular pump function and myocardial contractile performance dissociate in the brain dead animal: progressive increase in right ventricular afterload leads to the increase of RV work by the heterometric regulation (increase of preload), while myocardial contractility do not increase. These findings may also have some relevance for clinical transplantation. First, even if baseline right ventricular function seem satisfactory in the donor, the adaptation to an acute elevation of afterload by inotropic mechanisms may be impaired. Second, under certain circumstances, the augmentation of preload may be useful for maintaining right ventricular pump performance by the Frank–Starling mechanism at increased afterloads. Further studies are necessary to clear the exact mechanisms leading to decreased inotropic adaptation (brain death related damage or denervated state of the heart) and to investigate the effects of additional injury by ischemia/reperfusion and transplantation procedure.
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Footnotes |
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References |
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TopAbstractIntroduction
Material and methodsResultsDiscussionReferences |
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P<0.05 brain death vs. control
, solid line) group in comparison to the controls (
, dotted line). Steeper increase of the SW-RVEDP relation in the control group indicates a higher contractile state than in the brain death group.
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