Different impact of normo- and hypotensive brain death on renal macro- and microperfusion—an experimental evaluation in a porcine model

Arianeb Mehrabi1, Markus Golling1, Michael Körting1, Bahram Hashemi2, Rezvan Ahmadi2, Arash Kashfi3, Peter Schemmer1, Carsten N. Gutt1, Payam S. Pahlavan3, Jan Schmidt1, Markus W. Büchler1 and Thomas W. Kraus1

1 Department of General, Visceral and Transplant Surgery, 2 Department of Neurosurgery and 3 Department of Experimental Surgery, University of Heidelberg, Germany

Correspondence and offprint requests to: A. Mehrabi, MD, Department of General, Visceral and Transplant Surgery, University of Heidelberg, INF 110, 69120 Heidelberg, Germany. Email: arianeb_mehrabi{at}med.uni-heidelberg.de



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Despite the growing use of kidneys from living donors, organs harvested from brain dead donors are the dominant graft types used in renal transplantation. It is accepted that brain death (BD) has a damaging effect on the renal allograft, with a lower graft survival. Amongst various causes, changes in renal microperfusion could be responsible. Renocortical microperfusion was assessed during BD using thermal diffusion in a porcine model.

Methods. Two types of BD were induced in two groups of pigs [hypotension (Hypo-BD): n = 11; normotension (Normo-BD): n = 10] and compared to controls (n = 5) over a period of 210 min. We analysed systemic parameters [heart rate (HR), mean arterial blood pressure (MAP)], aortic blood flow (ABF) and renal perfusion [renal artery blood flow (RABF) and renocortical blood flow (RCBF)].

Results. Following the two distinct forms of BD induction, a stable normo- or hypotension was observed. Haemodynamic parameters were only slightly changed (control group: MAP, 62±2 mmHg; HR, 95±3/min; Normo-BD: MAP, 56±4 mmHg; HR, 104±8/min; Hypo-BD: MAP, 43±3 mmHg; HR, 112±7/min). Solely dependent on systemic haemodynamics, RABF and RCBF decreased in the Hypo-BD (RABF: 142±19 to 94±9 ml/100 g/min; RCBF: 80±4 to 52±2 ml/100 g/min), while in Normo-BD group RABF mildly changed (158±13 ml/100 g/min) and RCBF decreased slightly from 76±3 to 70±6 ml/100 g/min. As opposed to the Normo-BD group, animals with Hypo-BD showed a significant decrease in RABF (reduction of 34%) and RCBF (reduction of 35%) with a sharp drop of MAP (reduction of 25%), however ABF remained relatively constant.

Conclusions. In this model, a reduction of renocortical microperfusion in brain dead pigs was only found during haemodynamic instability (hypotension) and could not be attributed to BD as such. Our findings would support intensive cardiocirculatory stabilization for potential BD donors in order to minimize kidney preservation damage.

Keywords: brain death; kidney transplantation; renal microperfusion; thermal diffusion



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Brain death (BD) as an essential part of prepreservation damage is still poorly understood [1]. The discussion on the influence of BD on transplant function was recently revived in animal experiments that showed an increase in nonspecific cell–cell interaction and cytokine m-RNA Th1 expression in the tissues [1,2]. This is supported by clinical results showing significantly better results from living donation in comparison to organs from brain dead donors, which could not be attributed to a shorter ischaemia time or HLA compatibility [3,4]. Cardiovascular instability is a well-known risk factor and potential variable during BD [1,2]. This may secondarily result in marked disturbances of parenchymal microperfusion of donor organs [5], which in the case of prolonged ischaemia can lead to organ (graft) damage and subsequent failure [2,6]. An incidence of up to 50% of acute tubular necrosis has been described when renal grafts from donors with haemodynamic instability following BD were transplanted [7].

Despite the fact that living donors still contribute a limited proportion of organs in current transplant programmes, most experimental studies only investigate models of living organ donation. Experimental BD models in organ transplantation are designed to simulate the standard clinical situation and can thus focus on the type of BD and its related pathophysiology. The extent of BD, which can induce changes in renocortical microperfusion and can affect graft quality, has not been yet sufficiently investigated in a large animal model.

We followed the hypothesis that BD may cause impairment in renocortical blood flow (RCBF). The aim of this experimental study was to assess the impact of BD-induced normo- and hypotension on renocortical blood flow in a porcine model.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Anaesthesia
Landrace pigs (mean weight: 27.4±5.6 kg) were used in our experiments (n = 26). All studies were performed in deep anaesthesia. After premedication with azaperon (1–2 mg/kg i.m.) and midazolam (0.5–0.7 mg/kg i.m.), narcosis was induced with midazolam (1–1.5 mg/kg i.v.) and ketamine (10 mg/kg i.v.). After tracheal intubation, anesthesia was continued with an isoflurane enriched O2/air mixture. Fentanyl (500 mg/h i.v.) was applied for analgesia. Ringer lactate solution was infused during the observation period (20 ml/kg/h). No further drugs were given in order to avoid interference with the spontaneous haemodynamic situation. Stabilization of body temperature at 37°C was achieved by placement of animals on a heated blanket. Temperature was monitored by a rectal thermometer.

Systemic cardiocirculatory monitoring
The common carotid artery and internal jugular vein were catheterized and connected to membranous pressure transducers for continuous measurement of mean arterial pressure (MAP) and central venous pressure (CVP), respectively. Heart rate (HR) and its rhythm were continuously monitored by a surface electrocardiogram.

Experimental design
After median laparotomy the right renal artery was freed from local connective tissue. The subdiaphragmatic aorta (segment IV) was surgically prepared. Size-adjusted ultrasonic flow probes were placed around aorta and renal artery (Transonic System Inc.; Ithaca, NY, USA) for continuous measurement of aortic blood flow (ABF) and renal artery blood flow (RABF). Using post-autopsy kidney wet weight, RABF values (ml/min) were converted to ml/100 g/min. This allowed the comparison of the results with RCBF measured by a thermal diffusion (TD) probe (Thermal Technologies Inc.; Cambridge, MA, USA), which was implanted in the renal cortex. TD electrodes were always inserted in the kidney corpus (never in the pole areas) at a depth of 8–10 mm at a 45° angle to the kidney surface. Measurement of the local tissue temperature conductivity ascertained adequate positioning of TD probes in the renal cortex. Details of TD technology, validation and principles of probe placement have been already described [8].

Animal groups
Control group (n = 5)
A cardiocirculatory stabilization period of 90 min was allowed after median laparotomy and probe insertion. HR, MAP, CVP, ABF, RABF and RCBF were measured in 30 min intervals. No further manipulations were performed during the observation phase of 210 min (Figure 1).



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Fig. 1. Experimental design, time course and modes of brain death induction.

 
Brain death group (n = 21)
A controlled and standardized herniation of the porcine brain stem with consecutive BD was induced by placement of a balloon catheter (8 Fr) in the epidural space (Foley catheter; Kendall Co., Germany). For intracranial catheter placement, the skin covering the skull was locally removed and three drill holes (left temporal, right temporal, left frontal) were created (Ø 8 mm). A measurement probe for detection of intracranial pressure (ICP) (Codman MicroSensor Basic Kit; Codman & Shurtleff Inc., UK) was inserted through the left temporal hole. The balloon catheter was inserted into the epidural space through the right temporal hole and a TD probe was placed into the brain tissue through the left frontal hole. ICP was then elevated in a standardized fashion by stepwise filling of the balloon with 6–10 ml of saline. After documentation of a 60 min period with constant ICP elevation above 100 mmHg and documentation of persisting brain ischaemia [cerebral blood flow (CBF) <10 ml/100 g/min], BD was confirmed and measurements according to the protocol were started during the observation period (Figure 1). BD resulting in two different forms of systemic haemodynamic situation was induced via slow or fast expansion of intracranial balloon volume.

Normotensive brain death (Normo-BD) group (n = 10)
In this subgroup, brain stem herniation was achieved by slow saline injection (1 ml/3 min over 30 min). In these animals, BD was always associated with a normotensive MAP (Figure 1).

Hypotensive brain death (Hypo-BD) group (n = 11)
In this subgroup, brain stem herniation was achieved by a far rapid crescendo saline injection (1 ml/min over 6–10 min). A systemic arterial hypotension was observed in all animals (Figure 1).

Measurement protocol
Sixty minutes after BD due to complete brain stem herniation HR, MAP, CVP, ABF, RABF and RCBF were measured at standardized intervals (30 min) over a total time period of 210 min (Figure 1).

Statistical analysis
Data are described as mean±standard error of mean (SEM). Statistical calculations were performed using StatView 5.0 and Excel 2000. Statistical significance of differences between sample means was tested with the two-sided Student t-test. A normal distribution of values was confirmed. P-values <0.05 were defined as statistical significance.

Animal rights
Approval for the experimental procedure was obtained from the German Committee on Animal Care, Regierungspräsidium Karlsruhe and the Medical Faculty Ethics Committee, University of Heidelberg. Animals were killed after the experiments in deep anaesthesia with a central venous injection of potassium chloride. During the experiments, all animals received humane care in compliance with the United States National Research Council's criteria for humane care, as outlined in ‘Guide for the Care and Use of Laboratory Animals’ prepared by the National Institution of Health (NIH publication no. 86-23, revised 1985).



   Results
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 Subjects and methods
 Results
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Control group
In the control group, mean baseline MAP was 62±2 mmHg and mean HR 95±3/min (Figures 2 and 3). Mean ABF was 2585±212 ml/min (Figure 4). Mean RABF was 146±6 ml/100 g/min (Figure 5). RCBF averaged 72±1 ml/100 g/min throughout the observation period (Figure 6). All perfusion volumes remained stable during the experiment in this animal group. Upper and lower limits (range) of values in the control group are illustrated in Figures 2–6GoGoGoGo.



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Fig. 2. Mean MAP±SEM after hypo- and normotensive brain death compared to control values (*vs baseline; P<0.05).

 


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Fig. 3. Mean HR±SEM after hypo- and normotensive brain death compared to control values (*vs baseline; P<0.05).

 


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Fig. 4. Mean ABF±SEM after hypo- and normotensive brain death compared to control values (*vs baseline; P<0.05).

 


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Fig. 5. Mean RABF±SEM after hypo- and normotensive brain death compared to control values (*vs baseline; P<0.05).

 


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Fig. 6. Mean RCBF±SEM after hypo- and normotensive brain death compared to control values (*vs baseline; P<0.05).

 
Normotensive brain dead group
In the Normo-BD, MAP and HR values after induction of BD remained stable and did not differ significantly from baseline measurements during the complete observation period (MAP, 56±4 mmHg; HR, 104±8/min) (Figures 2 and 3). Mean ABF showed a continuous decrease of 22% after BD induction from 2271±122 to 1770±120 ml/min (at 210 min). ABF showed a 22% reduction over this time course (Figure 4). Despite this ABF decrease, mean RABF remained constant, except for an initial rise by 16% immediately after BD onset (Figure 5). RCBF also remained constant, except for a slight and temporary decrease from 76±3 to 70±6 ml/100 g/min during the investigation period (Figure 6).

Hypotensive brain dead group
In this group, MAP decreased significantly (by 25%) from a baseline value of 56±2 to 43±3 mmHg immediately after onset of BD (P = 0.02) (Figure 2). Thereafter, MAP remained constant at this hypotensive level during the complete observation period and was significantly lower at all consecutive time points, compared to the Normo-BD group (Figure 2). After BD induction, a compensatory rise of the HR was noted (17%) during the first 90 min of observation (P = 0.002) (Figure 3). Mean ABF was significantly higher after the crescendo-type induction of BD, compared to animals with Normo-BD (2626±363 vs 2213± 143 ml/min). At the beginning, ABF values remained mostly within baseline range (Figure 4). Only at the end of the observation period (210 min after BD onset), did ABF drop significantly to 1822±434 ml/min (P<0.05). Mean RABF dropped continuously by 34% from 142±19 after BD induction to 94± 9 ml/100 g/min at 210 min (Figure 5). In parallel, RCBF decreased significantly by 35% from 80±4 to 52±2 ml/100 g/min at the end of the observation period (P < 0.05) (Figure 6).



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In general, donor-associated factors implicated in long-term graft dysfunction include age, hypertension, diabetes, ischaemia damage, and the systemic effect of BD [1]. It has been accepted that BD has a negative effect on the renal allograft resulting in decreased graft survival. However, the results of Kunzendorf et al. [4] showed that longer BD did not result in poorer prognosis in comparison to shorter BD. Allografts from living unrelated donors exhibit survival rates that exceed those from cadaver donors with equivalent degrees of human leucocyte antigen (HLA) matching, and approach those of zero-mismatched cadaveric donors [3]. Due to the significantly improved results in living organ donation [9], the pathophysiological influence of BD on systemic circulation, pulmonary function and potentially transplantable organs has been the focus of attention in recent years. BD results in changes of graft immunogenicity, such as increased expression of MHC class II molecules and activation of costimulatory pathways as well as ischaemia/reperfusion injury [1,2,6,10]. Whether these specific and non-specific events are associated with changes in perfusion of potentially transplantable organs is not yet adequately understood. In order to assess the impact of haemodynamic instability as a potential variable of BD, we evaluated RCBF changes as a marker of graft quality [11] in a porcine BD model. By a controlled modification of ICP, a standardized simulation of Normo-BD and Hypo-BD was designed, as observed in the clinical situation. In this study, for the first time RCBF was assessed with implanted TD probes under the BD condition.

In an experimental setting, it has been proposed that slowly rising ICP (compared to a fast increase in ICP) induces less intense secondary cardiovascular and endocrine effects as well as histopathologic lesions of visceral organs [10]. Consequently, systemic haemodynamic changes appear to be less pronounced [12]. Both BD groups showed a comparable reduction of cardiac output. On the other hand, BD induced marked changes in peripheral vascular resistance contributing to the drop in MAP, the second key factor in parenchymal organ perfusion. Cardiocirculatory instability is considered to be an independent variable of BD contributing to prepreservation damage. Determining of several mechanisms that will result in hypotension is unsatisfactory. Even though sympathetic ganglion blocking drugs, haemorrhage and BD will all result in hypotension, they are associated with different sympathetic, hormonal and myogenic responses in the renal cortex and medulla [5,13].

In the Normo-BD group, mean RABF remained constant at a baseline level throughout the observation period while animals in the Hypo-BD group showed a significant reduction in both mean RABF and RCBF of ~35%. The sharp drop in RCBF can possibly be explained by the following factors: a marked decrease in MAP during the hypotensive phase, increase of intrarenal arterio-venous shunt perfusion and severe renocortical vasoconstriction due to the ‘autonomic storm’. In humans, the renal autoregulatory mechanism usually keeps intrarenal perfusion pressures constant in a range between 80 and 180 mmHg [13]. This is the result of an array of resistance vessels and regulatory mechanisms that separate flow to the cortex, the outer and inner medullary regions. Some authors consider autoregulation occurs only in the cortex, and that medullary blood flow is influenced mainly by changes in volume status [14]. Others could show that hypotension results in decreased renocortical pO2 consumption and blood flow, while medullary pO2 consumption and corticomedullary shunting of blood increases [15,16]. Whether placement of a TD probe could influence the RCBF measurement is subject to discussion. Although positioning was performed with the greatest care, it is possible that outer medullary flow was detected as well. Although shunting or shifting might be accentuated due to TD probe insertion, the decreased RCBF in our study reflects systemic haemodynamic changes because it has been shown that medullary flow comprises only 5–10% of total renal flow [13,14,16,17]. The relative importance of these mechanisms for the RCBF decrease, measured in our animals, cannot be differentiated in the current study. In view of the fact that BD occurred in both groups, one might also speculate that the type of induction resulting in two distinct haemodynamic forms [12] could theoretically contribute to changes in renal vascular resistance. It is unlikely, however, that BD induction would result in different forms of renocortical resistance. Since both RABF and RCBF changed in line with the haemodynamic situation, it seems plausible that this is the main cause of renal perfusion changes. In our model, non-specific events, like hypotension-induced changes, resulted in a more profound deterioration of renocortical perfusion than BD itself.

BD with hypotension most probably has a direct effect on renal perfusion via changes in sympathetic innervation. On the other hand, the observed secondary RCBF perfusion disturbances may also be the sole consequence of systemic arterial hypotension and not of BD per se. Kidney perfusion derangement finally can be induced by a combination of both effects. It therefore has to be noted that a second control group (non-brain-dead group) is missing in our current experimental protocol. We did not investigate the effects of arterial hypotension without an associated or causative BD, i.e. a controlled induction of arterial hypotension. Such an extended experimental protocol will be required in order to allow a more conclusive pathophysiological interpretation of this complex situation and should therefore be investigated in future experiments. Nevertheless, the absence of the second control group was felt acceptable by us because there are not only experimental but also good clinical data available showing that BD-associated factors are probably very relevant and independent pathophysiological factors for renal graft quality. As described by Roodnat et al. [18], superior results of living donated kidney transplantation compared with cadaveric organ transplantation could still be noticed after a retrospective stratification for cold ischaemia time and other clinical variables involved. The functional superiority of non-cadaveric grafts must therefore be caused by pathophysiological factors inherent to the grafts, either directly resulting from the absence of BD-associated factors or the integrated consequences of cardicirculatory instability of the BD donor before graft harvesting.

No histological analysis of kidney grafts has been performed in our study to investigate morphological differences between normo- and hypotonic groups after harvesting. The inclusion of histological data would have potentially increased the scientific value of the study. Nevertheless, we feel that the absence of such data does not invalidate the findings presented here. Most data available in the literature until now, point to mostly functional regulatory pathways after BD, which can severely alter kidney graft function without morphological damage to the transplanted organs. BD causes progressive kidney dysfunction. It was shown previously that BD can be characterized by inflammatory responses that reflect tissue injury. When the haemodynamic instability in BD donors is not rapidly corrected, kidney dysfunction is enhanced and immune activation is more profound [19]. BD can further induce an upregulation of the expression of adhesion molecules and MHC class I and II antigens in renal grafts and can also induce various endocrine changes [1]. These factors may predispose kidney grafts for ischaemia/reperfusion injury and even increase the risk for rejection after transplantation [19]. A further criticism may be that no functional data were collected to reflect kidney viability during the progression of BD in our study. Indeed, our current investigation primarily focused on the detection and quantification of microperfusion disturbances under BD conditions with new and optimized measurement technology. In our eyes, microperfusion can be seen as a pathophysiological entity, which integrates multiple pathophysiological mechanisms as an excellent parameter for estimation of graft quality. We have not yet analysed specific cellular changes or molecular mechanisms, for example, using immunohistochemistry. In future experimental protocols it will be interesting to study the distinct influence of hypotension in combination with BD by immunohistochemistry on gene transcription and endocrine changes. Such investigations have not been performed so far. This will hopefully further illuminate the underlying pathophysiological mechanisms of BD-related graft damage.

By using implanted TD electrodes we could show that marked RCBF disturbances could occur after BD induction in the porcine model. We also demonstrated that the extent of RCBF changes depends on the time course of BD. Since the decrease of RCBF after BD can potentially lead to ischaemic graft damage, intensive medical care must focus on its reduction or prevention. Intensive care of donor patients with hypotensive BD primarily aims at the reconstitution of intravascular volume, achievement of normotensive systemic arterial perfusion pressures and normal cardiac output volumes in order to assure adequate perfusion and oxygenation of organs until graft harvesting [20]. Additionally, clinical therapeutic applications of hormones like thyroxin, insulin, cortisol [21] as well as experimental therapeutic applications of cobalt-protoporphyrin have been suggested [22]. Since it has been shown that dopamine induces the expression of the protective enzyme heme oxygenase-1 in cultured endothelial cells [23], dopamine application needs more attention in the future. It should be also taken into account that aggressive pharmagological donor management, hormonal resuscitation and stabilization of BD donors is associated with a significant increase in transplanted organs. In conclusion, clinical vigilance is required to counteract the often neglected graft-damaging mechanism under BD conditions.

Conflict of interest statement. There is no conflict of interest with any of the authors.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 23. 4.04
Accepted in revised form: 23. 6.04





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