modulation of coronary perfusion pressure can reverse cardiac dysfunction after brain death

Modulation of Coronary Perfusion Pressure CanReverse Cardiac Dysfunction After Brain DeathGabor Szabo, MD, Thilo Hackert, MS, Christian Sebening, MD,Christian Friedrich Vahl, MD, and Siegfried Hagl, MDDepartment of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany

Background. Brain death results in a rapid decline inleft ventricular function, which has clinical relevance fororgan transplantation. The aim of the present study wasto investigate coronary perfusion changes during braindeath and their role in cardiac dysfunction.

Methods. In an in situ isolated canine heart model,brain death was induced by inflation of a subduralballoon catheter. The heart was perfused separately withthe animal’s own blood by a pressure-controlled rollerpump that was coupled to the measured aortic pressure.Myocardial contractility was estimated by the slope ofthe end-systolic pressure–volume relation.

Results. Induction of brain death resulted in a transienthyperdynamic response, followed by a significant de-

crease in systemic vascular resistance, coronary bloodflow, and the end-systolic pressure–volume relation (p <0.05). However, if coronary perfusion pressure was de-coupled from aortic pressure and elevated to pre–braindeath levels, coronary blood flow and the end-systolicpressure–volume relation were also restored to baselinelevels.

Conclusion. Severe impairment of coronary blood flowmay contribute to decreased contractility after braindeath that can be reversed by modulation of coronaryperfusion pressure.

(Ann Thorac Surg 1999;67:18–26)© 1999 by The Society of Thoracic Surgeons

During the past few years, an increasing number ofpatients with end-stage heart disease have been

registered on the waiting lists for heart transplantation.Although in 1996 10% fewer transplantations could beperformed worldwide [1], primarily because of a shortageof suitable donor organs, a considerable number ofpotential donor hearts must be rejected because of he-modynamic instability and poor cardiac function. More-over, the major cause of early postoperative mortalityand morbidity is graft failure. Many studies [2–6] de-scribe a hemodynamic deterioration after brain death inpotential donors, the exact mechanisms of which are yetnot clearly understood. Several possible etiologies havebeen proposed, including direct cardiac myocyte injury,catecholamine-induced myocardial damage, and impair-ment of the b-adrenoceptor–adenylyl cyclase system, aswell as hormone depletion. In a recent study, there wasno correlation between the occurrence of hemodynamicinstability and severity of histologic changes after rapidinduction of brain death [7]. Galinanes and associates [8]found no improvement in cardiac function in brain-deadanimals if full blood replacement was performed withblood from non–brain-dead blood donors. Vice versa, ifthe blood of healthy animals was replaced by blood frombrain-dead animals, cardiac function did not deteriorate.These data indicate that humoral and blood-borne fac-

tors, including hormone depletion after brain death, mayhave a less important effect on cardiac function thansuggested in earlier studies.

The possible pathophysiologic link between alteredloading conditions, organ perfusion with special refer-ence to the heart, and cardiac function after brain deathhas not yet been investigated. Using the microspheretechnique, Meyers and colleagues [4] and Herijgers andassociates [9] showed a significant decrease in myocar-dial blood flow after brain death. However, in theirstudies, no conclusion could be made as to how fardecreased myocardial blood flow contributes to de-creased cardiac function. Therefore, the role of coronaryperfusion changes in cardiac dysfunction after braindeath was investigated in the present study. We used amodified model of the neurohumorally intact “in situisolated heart” [10] with extracorporal circulation to an-alyze cardiac function independent of actual loadingconditions. In this model, coronary perfusion could beexamined as an independent determinant of left ventric-ular function.

Material and Methods

Study AnimalsTwelve dogs (foxhounds) weighing 24 to 35 kg (mean,27.4 6 2.9 kg) were used in these experiments. Allanimals received humane care in compliance with the“Principles of Laboratory Animal Care” formulated bythe National Society for Medical Research and the“Guide for the Care and the Use of Laboratory Animals”

Presented at the Thirty-fourth Annual Meeting of The Society of ThoracicSurgeons, New Orleans, LA, Jan 26–28, 1998.

Address reprint requests to Dr Szabo, Department of Cardiac Surgery, ImNeuenheimer Feld 110, 69120 Heidelberg, Germany (e-mail:[email protected]).

© 1999 by The Society of Thoracic Surgeons 0003-4975/99/$20.00Published by Elsevier Science Inc PII S0003-4975(98)01330-7

prepared by the National Academy of Sciences andpublished by the National Institutes of Health (NIHpublication 86-23, revised 1985).

Brain Death ModelExperimental brain death was induced by creating intra-cranial hypertension [3]. A Foley catheter was introducedinto the subdural space through a parietal burr hole inthe skull. A rapid injection of 25 mL of saline inflated theballoon of the catheter, which caused an acute increase inintracranial pressure. Brain death occurred within fewminutes in all dogs, and cerebellar herniation causedinterruption of neurologic pathways between the mid-brain and the spinal chord. Brain death was confirmedneuropathologically at the end of the experiments.

Surgical Preparation and Experimental DesignThe dogs were anesthetized with a bolus of pentobarbital(Nembutal; Abott) (12 mg/kg intravenously), paralyzedwith pancuronium bromide (Pancuronium; Organon,Teknikka, Boxtel, the Netherlands) (0.1 mg/kg as a bolus,then 4 mg z kg21 z min21 intravenously), and endotrache-ally intubated. The level of anesthesia was maintainedwith the synthetic opiate piritramide (Dipidolor; Janssen-Cilag, Neuss, Germany) (1 mg/kg as a bolus and then 15mg z kg21 z min21 intravenously). The dogs were venti-lated with a mixture of nitrous oxide and oxygen (40%:60%) at a frequency of 12 to 15 breaths/min and a tidalvolume starting at 15 mL z kg21 z min21. The settings wereadjusted by maintaining arterial partial carbon dioxidepressure levels between 35 and 40 mm Hg. The leftfemoral artery and vein were cannulated to record aorticpressure, and blood samples were taken for analysis ofblood gases, electrolytes, and pH. The animals received500 U/kg of heparin.

Basic intravenous volume substitution was carried outwith Ringer’s solution at a rate of 1 mL z kg21 z min21. Ifnecessary, the rate of volume substitution was modifiedaccording to the continuously controlled input–outputbalance to maintain perfusion volumes at baseline levels.According to the values of K1, HCO3

2, and base excess,substitution included administration of potassium chlo-ride and sodium bicarbonate (8.4%). No catecholaminesor other hormonal or pressor agents were administered.Rectal temperature and the standard peripheral electro-cardiogram were monitored continuously.

The right femoral artery was prepared for arterialcannulation of the extracorporal circulation. After lateralthoracotomy in the fourth intercostal space, the pericar-dium was incised. The great vessels of the hearts wereisolated. A 14F retroplegia balloon catheter with a secondsmall lumen was introduced into the ascending aortathrough the left subclavian artery. The left pulmonaryartery was cannulated to collect coronary sinus effluent.The superior and inferior vena cavas were cannulated forthe venous return of the extracorporal circulation, andthe azygos vein was ligated. The extracorporal circuitconsisted of a heat exchanger, a venous reservoir, a rollerpump, and a membrane oxygenator.

Figure 1 shows the in situ isolated heart model. After

cannulation of all vessels, extracorporal circulation wasinitiated. Arterial perfusion was performed through theright femoral artery and the retroplegia balloon catheter,which was placed in the ascending aorta. Perfusionvolume was adjusted to achieve the same mean aorticpressure measured before extracorporal circulaton. Per-fusion volume was within the range of 2.0 to 2.5 L/min.After a 5-minute equilibrium period, the balloon of theretroplegia catheter was inflated with 5 to 7 mL of fluid,which led to total occlusion of the aortic root. The heartswere perfused through the aortic root in a retrogrademanner with the animal’s own blood by a second pres-sure-controlled roller pump separately from the organ-ism. Through the small lumen of the catheter, coronaryperfusion pressure was monitored continuously and keptat the same level as mean aortic pressure.

A latex balloon was fixed on a 7F Millar catheter-tippedmanometer with an internal lumen and placed in the leftventricle through an incision of the left atrium. Thecompliance of the balloon was negligible within a volumerange of 0 to 50 mL. The mitral valve and the left atriumwere closed with a 4-0 suture. The thebesian blood flowwas vented through a 14F vent catheter. Left ventricularpressures were measured during isovolumetric contrac-tion at different balloon volumes, and systolic and dia-stolic pressure–volume relations curves were con-structed. Systolic function was evaluated by the maximalpeak systolic pressure, maximal rate of left ventricularpressure development (dP/dtmax), and the slope of thepeak systolic pressure–volume relation (Emax). Diastolicfunction was assessed by the end-diastolic pressure andthe end-diastolic pressure–volume relation. Coronaryblood flow and coronary perfusion pressure were mea-sured by an electromagnetic flowmeter and a Stathampressure transducer, respectively, which were connectedto the arterial site of the perfusion apparatus. Coronaryvascular resistance was estimated by dividing perfusionpressure and coronary blood flow. Coronary perfusionpressure–flow relations were determined from a perfu-

Fig 1. Experimental model (see Material and Methods). (A. 5 arte-ria; LV 5 left ventricular; V. 5 vena.)

19Ann Thorac Surg SZABO ET AL1999;67:18–26 CORONARY PERFUSION AFTER BRAIN DEATH

sion pressure of 40 to 100 mm Hg in 10-mm Hg steps atbaseline and at the end of the experiment. Myocardialoxygen consumption was calculated as the product ofcoronary blood flow and arteriovenous oxygen contentdifference. All measured hemodynamic variables wereregistered on a Gould multichannel monitor unit andrecorded on a personal computer for further off-lineanalysis.

Coronary artery and venous lactate concentrations andmyocardial lactate contents were measured with stan-dard photometric methods.

Perfusion–Contractility Matching/Closed-LoopAnalysisWe measured myocardial contractility (Emax) and coro-nary perfusion pressure independently of each other(“open-loop analysis”). Under physiologic conditions,the ventricle perfuses itself through the coronary circu-lation. In intact situations, the coupling between leftventricular and coronary perfusion pressures forms afeedback loop that can affect ventricular contractility.According to Sunagawa and colleagues [11], we con-structed a so-called closed-loop analysis from the open-loop data in which feedback between left ventricular andcoronary pressures was simulated. We used the corre-sponding left ventricular pressure points from the open-loop–estimated systolic pressure–volume relations ateach coronary perfusion pressure assuming a couplingratio of 1. That is, we selected the pressure–volumecoordinates as follows: At a coronary perfusion pressureof 40 mm Hg, we used the left ventricular pressure–volume point where left ventricular pressure was equalto 40 mm Hg; at a coronary perfusion pressure of50 mm Hg, we used the left ventricular pressure–volumepoint where left ventricular pressure was equal to50 mm Hg; and so forth, up to 100 mm Hg of coronaryperfusion pressure.

Experimental ProtocolAfter 10 minutes of equilibrium after the final prepara-tion, baseline measurements were performed to obtainsystolic and diastolic function and coronary perfusionvariables and biochemical data. Then the dogs were

divided into two groups. Six animals with sham opera-tion served as the control group. In the other 6 animals,brain death was induced as previously described. Aftersham operation or induction of brain death, measure-ments were performed after 5, 15, 30, 60, and 120 minutes.Coronary perfusion pressure was kept at the same levelas the actually measured mean aortic pressure. After 120minutes, perfusion pressure was decoupled from aorticpressure and set at baseline levels, and after 5 minutes ofequilibrium, all measurements were repeated.

Statistical AnalysisResults are expressed as mean 6 standard error of themean. The paired t test was used to compare two meanvalues within the groups. An unpaired t test and one-wayanalysis of variance were used for between-group com-parisons. A probability value less than 0.05 was consid-ered statistically significant.

Results

Variables in the control animals remained stable duringthe entire observation period. Hemodynamic variablesare shown in Table 1 and coronary circulation variablesin Table 2. Because none of the variables assessedchanged significantly during the 2-hour observation pe-riod, only the average of the entire observation period isshown.

Effects of Brain DeathBaseline values of the brain-dead group were similar tothose of the control group (Table 1). After induction ofbrain death, characteristic hemodynamic changescould be observed. Within 40 seconds, progressivetachycardia and hyperdynamic responses occurredthat reached a maximum 5 minutes after induction ofbrain death. Heart rate increased by 129% (p , 0.001).Transient and spontaneously reversible supraventric-ular and ventricular arrhythmias were observed inmost of the dogs. Left ventricular systolic pressure(177%; p , 0.001), dP/dtmax (1473%; p , 0.001), andmean aortic pressure (136%; p , 0.01) increased sig-nificantly. As depicted in Figure 2 (left panel), the

Table 1. Hemodynamic Variablesa

Variable

Brain Death Group (n 5 6)

Control Group(n 5 6) Baseline t5 t120 t1201

HR (beats/min) 124 6 8 126 6 7 224 6 7b,c 138 6 8 137 6 8AoPmean (mm Hg) 88 6 8 92 6 5 168 6 17b,c 52 6 4b,c 52 6 4b,c

SVR (Wood unit) 40 6 8 42 6 6 53 6 5 28 6 3b,c 28 6 3b,c

LVSP (mm Hg) 141 6 11 125 6 9 222 6 11b,c 81 6 7b,c 159 6 18dP/dtmax (mm Hg/s) 2,567 6 198 2,413 6 279 4,813 6 387b,c 1,477 6 187b,c 2,385 6 211LVEDP (mm Hg) 9.31 6 1.41 8.91 6 1.43 7.21 6 1.11 7.10 6 1.24 7.41 6 0.98

a Data presented are mean 6 standard error of the mean. b p , 0.05 versus baseline. c p , 0.05 versus control group.

AoPmean 5 mean aortic pressure; BD 5 brain death; dP/dtmax 5 maximal rate of left ventricular pressure development; HR 5 heartrate; LVEDP 5 left ventricular end-diastolic pressure; LVSP 5 left ventricular systolic pressure; t5 and t120 5 5 and 120 minutes afterinduction of brain death; t1201 5 coronary perfusion pressure decoupled from aortic pressure and elevated to pre–brain death levels.

20 SZABO ET AL Ann Thorac SurgCORONARY PERFUSION AFTER BRAIN DEATH 1999;67:18–26

systolic pressure–volume relation showed a significantleftward shift, and the slope of the relation Emax

increased significantly (p , 0.01), indicating a highercontractility. Left ventricular end-diastolic pressureand pressure–volume relations did not change (Fig 2,right panel). By protocol, coronary perfusion pressurewas coupled to mean aortic pressure. Coronary bloodflow increased significantly by 80% (p , 0.05), whereascoronary vascular resistance remained unchanged.Myocardial oxygen consumption showed a significantincrease of 108% (p , 0.05) (Table 2).

The initial hyperdynamic phase lasted approximately15 minutes. Thereafter, hemodynamic variables de-creased within 15 to 30 minutes and remained stable untilthe end of the experiments (Tables 1, 2). Mean aorticpressure and systemic vascular resistance showed a sig-nificant decrease compared with baseline values ( p ,0.05). By protocol, coronary perfusion pressure was setlower, parallel to aortic pressure. Left ventricular pres-sure and dP/dtmax declined significantly ( p , 0.05)below baseline values. The systolic pressure–volume

relations showed a significant rightward shift (Fig 2, leftpanel), and Emax decreased significantly ( p , 0.05) (Fig3). Left ventricular end-diastolic pressure and pressure–volume relations remained unchanged (Fig 2, right panel).Coronary blood flow decreased significantly ( p , 0.05),whereas coronary vascular resistance and myocardialoxygen consumption remained unchanged (Table 2).Coronary artery and venous lactate concentrations (Table2) were stable over the entire observation period.Myocardial lactate content was similar in control andbrain-dead animals at the end of the experiment (30.5 67.7 and 27.9 6 5.9 mmol/g dry weight, respectively; notsignificant).

One hundred twenty minutes after induction of braindeath, coronary perfusion pressure was decoupled frommean aortic pressure and elevated to baseline levels(80 mm Hg). After 5 minutes of equilibrium, measure-ments were repeated. Coronary blood flow increased andreached baseline levels (Table 2). Left ventricular systolicpressure and dP/dtmax also increased to baseline levels(Table 1). The systolic pressure–volume relation showed

Table 2. Variables of Coronary Circulationa

VariableControl Group

(n 5 6)

Brain Death Group (n 5 6)

Baseline t5 t120 t1201

CPP (mm Hg) 90 ('AoP) 90 ('AoP) 170 ('AoP) 50 ('AoP) 90 (ÞAoP)CBF (ml z min21 z 100 g21) 66 6 9 61 6 10 110 6 17b,c 33 6 7b,c 70 6 8CVR [kPa z mL21 z s21 8.31 6 0.95 9.21 6 0.81 5.55 6 0.46b,c 9.47 6 0.75 8.98 6 0.44Mvo2 (mL z beat21 z 100 g21) 0.0142 6 0.0031 0.0133 6 0.0040 0.0277 6 0.0022b,c 0.0161 6 0.0019 0.0155 6 0.0037Lactate arterial (mg/dL) 21.7 6 3.0 22.9 6 3.7 23.8 6 2.5 24.3 6 5.6 24.6 6 6.0Lactate venous (mg/dL) 22.6 6 1.6 19.6 6 2.9 24.8 6 4.6 21.3 6 5.7 23.8 6 3.1

a Data presented are mean 6 standard error of the mean. b p , 0.05 versus baseline. c p , 0.05 versus control group.

BD 5 brain death; CBF 5 coronary blood flow; CPP 5 coronary perfusion pressure; CVR 5 coronary vascular resistance; Mvo2 5myocardial oxygen consumption; t5 and t120 5 5 and 120 minutes after induction of brain death; t1201 5 coronary perfusion pressure decoupledfrom aortic pressure and elevated to pre–brain death levels; 'AoP 5 approximately equal to aortic pressure.

Fig 2. Left ventricular systolic (LVSP) (leftpanel) and end-diastolic (LVEDP) (rightpanel) pressure–volume relations. Valuesshown are mean 6 standard error of themean. (BDb 5 baseline, induction of braindeath; BDt5 and BDt120 5 5 and 120 min-utes after induction of brain death; BDt1201

5 after decoupling of coronary perfusionpressure from aortic pressure and elevation topre–brain death levels; Co 5 control [averagevalues for the 2-hour observation period];LVV 5 left ventricular volume.)


a significant leftward shift compared with that obtained120 minutes after induction of brain death and wassimilar to baseline values when perfusion pressure wasequal to mean aortic pressure (Fig 2, left panel). The slopeof the relation Emax was also comparable to that atbaseline (Fig 3). End-diastolic pressure–volume relationsdid not change (Fig 2, right panel).

Coronary Perfusion Pressure–FlowRelations/Perfusion–Contractility MatchingThe coronary perfusion pressure–flow relations, deter-mined from 40 to 100 mm Hg of perfusion pressure in10-mm Hg steps, did not differ between the groups.Figure 4 depicts the matching of coronary perfusionpressure and contractility (Emax) at the end of the exper-iment. The relation between the relative changes incoronary perfusion pressure and Emax was nearly identi-cal in control and brain-dead dogs. In both groups therelation could be described by a typical inverse J-shapedcurve. For each animal a “critical coronary perfusionpressure” could be identified, which was between 60 and80 mm Hg (75.0 6 2.23 mm Hg in control and 73.3 63.33 mm Hg in brain-dead animals; not significant).While above this critical pressure, a change in coronaryperfusion pressure led to only a small change in Emax ;below this critical pressure, a further decrease in coro-nary perfusion pressure led to a significant (p , 0.05)decrease in contractility. We did not find any differencebetween coronary perfusion pressure–flow relations andperfusion–contractility matching before and 120 minutesafter brain death induction. End-diastolic pressure–volume relations remained unchanged.

According to the method of Sunagawa and colleagues[11], we constructed a so-called closed-loop analysis fromthe “open-loop” data in which feedback between leftventricular and coronary pressure was simulated. Figure5 shows a representative example of this closed-loopanalysis in a brain-dead dog. We did not find anysignificant differences between curves constructed beforeand after brain death. Similarly, there was no differencebetween control and brain-dead animals. The systolic

Fig 3. Slope of the peak systolic pressure–volume relation (Emax).Values shown are mean 6 standard error of the mean. (BDb 5brain death; Co 5 control [average values for the 2-hour observationperiod]; t5 and t120 5 5 and 120 minutes after induction of braindeath; t1201 5 after decoupling of coronary perfusion pressure fromaortic pressure and elevation to pre–brain death level; * 5 p , 0.05versus baseline; † 5 p , 0.05 versus control group.)

Fig 4. Perfusion–contractility matching as relation between percen-tile changes in coronary perfusion pressure (DCPP) and slope of thepeak systolic pressure–volume relation (DEmax). Values shown aremean 6 standard error of the mean. (BD 5 brain death; Co 5control.)

Fig 5. Representative “closed-loop” analysis of left ventricular sys-tolic pressure (LVSP)–volume (LVV) relations in a brain-dead ani-mal constructed according to Sunagawa and colleagues [10] from theleft ventricular systolic pressure–volume relations (straight lines)obtained for each coronary perfusion pressure (CPP) by simulationof feedback between left ventricular and coronary pressure (see Ma-terial and Methods for details).


pressure–volume relation became curvilinear, and theslope of the systolic pressure–volume relation becamenegative at lower pressures.

Comment

In the present study, the effects of brain death on cardiacfunction were analyzed with special reference to coro-nary perfusion changes. We applied a modified model ofthe neurohumorally intact in situ isolated heart in whichleft ventricular function could be determined indepen-dently of actual loading conditions, and coronary perfu-sion pressure could be varied independently of aorticpressure. In this setting, brain death resulted in animpairment of coronary perfusion with concomitant de-terioration of myocardial contractility. However, if coro-nary perfusion pressure was restored to baseline levels,myocardial function showed full recovery.

Potential Pathologic Mechanisms of BrainDeath–Related Hemodynamic InstabilityThe initial acute hyperdynamic response was supposedto cause a direct cardiomyocyte injury with subsequenthemodynamic deterioration [6]. However, the hyperdy-namic cardiocirculatory reaction is only transient, withreturn of the elevated hemodynamic indices to the phys-iologic range within a few minutes, and is thereforeunlikely to cause persistent myocardial dysfunction.

A correlation between extreme catecholamine releaserelated to the Cushing reaction [2, 3, 6, 12] and histologicmyocardial damage was reported by Shivalkar and col-leagues [13]. In contrast, Bruinsma and associates [7]refuted a relation between acute increase in myocardialworkload, occurrence of hemodynamic deterioration,and myocardial histologic changes after rapid inductionof brain death. Baroldi and coworkers [14] demonstratedmyocardial necrosis in all types of brain injury in ahuman pathomorphologic study, but always to a minimalextent, which should not jeopardize cardiac function aftertransplantation.

Brain death–related hormone depletion [2, 3, 6, 15], andespecially loss of thyroid hormones, was assumed to playan essential role because of a direct effect on myocardialcontractility and anaerobic conversion of myocardial me-tabolism. Administration of thyroid hormones wasshown to reverse hemodynamic and metabolic conse-quences of experimental brain death by Novitzky andcolleagues [15]; however, in other experimental [4] andclinical [16] studies, no benefit of such therapy could bedocumented. In the present study, no evidence of anaer-obic conversion of myocardial metabolism was observedwith respect to blood and myocardial lactate content,although the hearts were subjected to the brain death–associated neurohumoral response, including catechol-amine storm and hormone depletion. At identical coro-nary perfusion pressures and loading conditions, nosignificant differences in left ventricular function werefound between control and brain-dead animals as well asbefore and after induction of brain death. These findingssuggest only a minor importance of neurohumoral

changes in hemodynamic instability after brain death inthe potential donor, which is in agreement with thepreviously mentioned study of Galinanes and colleagues[8]. Therefore, we hypothesized that mechanisms otherthan neurohumoral mechanisms must be at least partlyresponsible for the observed cardiac dysfunction.

Coronary Perfusion and Myocardial Function AfterBrain DeathAs described in previous reports [2, 3, 6] and observed inthe present study, systemic vascular resistance showed amarked decrease after brain death as a consequence ofthe loss of sympathetic tone. The subsequent decrease inaortic and coronary perfusion pressure as well as coro-nary blood flow may have contributed to the decrease inmyocardial performance. Using the microsphere tech-nique, a significant decrease in myocardial blood flowwas demonstrated in a porcine [4] and a rat [9] model ofbrain death. Both studies underlined an apparent corre-lation between the impairment of myocardial blood flowand the observed deterioration of left ventricular func-tion. Although there was no histologic evidence formyocardial ischemia [4], the data obtained did not allowdetermination of whether the decreased coronary flowwas still sufficient to fulfill the actual needs of themyocardium. In the present study, myocardial oxygenconsumption and lactate production did not change afterthe acute phase of brain death, indicating that the de-crease in contractility was unlikely to be caused by globalischemia of the myocardium.

Even if a decrease in coronary perfusion pressure andflow does not lead to major ischemia, it may have animpact on myocardial contractility. Sunagawa and asso-ciates [11] demonstrated in cross-circulated isovolumetri-cally working hearts that neither the slope nor the vol-ume intercept of the end-systolic pressure–volumerelation changed so long as coronary perfusion pressurewas higher than a “critical perfusion pressure.” However,ventricular function deteriorated below a mean pressureof 67.0 6 22.1 mm Hg. In the present study a similarcritical perfusion pressure was found. The finding thatmean aortic and coupled coronary pressures in brain-dead animals were below this range suggests that hemo-dynamic instability in the potential donor may not reflectthe direct cardiac effects of brain death; rather, it mayreflect altered loading conditions and coronary perfu-sion. A further important finding is the reversibility ofcardiac dysfunction after brain death when coronaryperfusion pressure was elevated to pre–brain deathlevels.

A possible pathologic mechanism leading to decreasedcontractility may be the so-called garden hose effect,which postulates a relation between systolic function andcoronary perfusion pressure based on solely mechanicaleffects [17, 18]. This concept could be supported by ahistologic study demonstrating lengthened sarcomeresin isolated guinea pig hearts as a result of increasingcoronary perfusion pressure [19]. In a range where cor-onary autoregulatory reserve is exhausted [11, 20, 21], thereduction of intravascular pressure decreases the stretch-


ing of the intramyocardial vessels and, in turn, thesurrounding myocardium. Under these conditions, thelack of evidence of myocardial ischemia may not besurprising. The reduction in contractility as a conse-quence of decreased coronary perfusion pressure re-duces myocardial oxygen demand and therefore myocar-dial oxygen consumption, and lactate production canremain unchanged even at a lower coronary perfusionpressure and flow.

The closed-loop analysis [11] may also explain whychanges in coronary perfusion pressure could play acentral role in donor heart dysfunction. In a model of thephysiologic situation in which left ventricular and coro-nary perfusion pressures are coupled, we observed acurvilinear systolic pressure–volume relation with a neg-ative slope in the lower pressure region. It can beassumed that in the potential donor, coronary perfusionpressure falls into the negative slope region of the sys-tolic pressure–volume relation because of an excessivereduction in afterload (loss of the sympathetic vasomotortone) and preload (diabetes insipidus) [2, 3, 6]. Then, thelow coronary perfusion pressure reduces contractility,which tends to further lower coronary perfusion pressurein the setting of increasing end-systolic volume anddecreasing ventricular pressure. Once this vicious cycleis triggered, the ventricle is unable to recover on its own.

We did not observe any effects of coronary perfusionpressure on diastolic function and chamber stiffness, inagreement with the studies of Abel and colleagues [10]and Templeton and associates [22].

Direct Effects of Afterload on Myocardial ContractilityThe possible direct participation of decreased afterloadin the decline of cardiac contractility independent ofcoronary perfusion pressure remains to be clarified.Using brain death as a model for the totally denervatedheart, Suga and colleagues [23] found increased leftventricular contractility by a separate increase in aorticpressure. In an in vivo canine model, Asanoi and associ-ates [24] observed that under autonomic blockade,changes in afterload were followed by parallel changes incontractility. They postulated the existence of a controlsystem that maintained optimal stroke work over a widerange of afterload conditions by mechanisms other thanneural reflexes. According to this hypothesis, the reducedcontractile state after brain death might also be seen asa response to decreased afterload for stroke workoptimization.

Study LimitationsTo allow a separate analysis of coronary perfusion of theneurohumorally intact heart independent of the actualloading conditions, we had to use extracorporal circula-tion with isolated perfusion of the heart. In previous pilotexperiments [25], extracorporal circulation was shown tocause coronary and peripheral vasodilation after 3 hours.Later, hemolysis and a decrease in hemoglobin concen-trations could be observed. Moreover, extracorporal cir-culation can cause activation of cytokines, which maylead to deterioration of cardiac function. Therefore, in the

present study we limited the observation period to 2hours. During this time, the preparation remained stable,as shown in the control animals.

This short period of brain death, in contrast to signif-icantly longer periods in the clinical situation and inother experimental studies [2, 4, 6–9, 12], might appear tobe a limitation. However, because brain death–associatedcardiac depression occurred within 2 hours in all re-ported studies without any further major hemodynamicchanges thereafter, the 2-hour period of brain death inthe present study seems to be sufficient to achievepotential cardiac effects. Furthermore, during longer ob-servation periods, cardiac function may also be influ-enced in simple in situ preparations by an increasingnumber of factors that are not necessarily brain deathrelated.

ConclusionsThe present data show that the hemodynamic deteriora-tion after brain death is closely related to the changes incoronary perfusion as a consequence of altered loadingconditions. Furthermore, in our model, cardiac dysfunc-tion after brain death could be reversed by elevation ofcoronary perfusion pressure to the physiologic range.The significance of these findings for the clinical man-agement of potential donors needs to be confirmed byfurther studies.

This study was supported by a grant (“ForschungschwerpunktTransplantation”) from the University of Heidelberg and bygrant SFB 414/Q2 from the Deutsche Forschungsgemeinschaft.We thank Dr Susanne Bahrle for critical review and recommen-dations; Lutz Hoffmann and Nicole Stumpf for technical assis-tance; and Karin Sonnenberg for biochemical measurements.

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DISCUSSION

DR EDWARD D. VERRIER (Seattle, WA): This brings me backto my 3 years in the laboratory of Julian Hoffman. JulianHoffman was one of the foremost coronary blood flow physiol-ogists of our era. This is a very difficult model, and the conceptthat you completely lose all autoregulation of coronary bloodflow is a difficult concept. Normally, you can drop the coronaryperfusion pressure of a dog or pig even down to about40 mm Hg, and you maintain a constant flow (ie, autoregulate).At about 40 mm Hg, flow drops off, and the pressure–flowrelation becomes linear. The curves that you show are atminimal resistance, so that pressure and flow follow when thepressure goes up or down. And that is a very difficult concept fora coronary blood flow physiologist to understand, and I thinkthat the data would have to be very, very carefully looked at.

If it is true, it has implications, obviously, for the donor pool.What is it that you postulate is released by the brain that

affects coronary vascular resistance to this degree, isolated fromeffects on other beds? Because that is what it would have to be ifit is going to be uncoupled like this. You are postulatingsomething from the brain that ends up in the heart that dropscoronary vascular resistance so that it is at a minimal level, sothat it becomes a pressure-dependent bed.

DR SZABO: Thank you very much for your question. It is truethat in isolated heart models, and this model is also a type ofisolated heart model, the coronary autoregulation is at leastpartially lost. This may be one explanation why we found alinear relation between coronary pressure and flow at a pressurefrom 40 to 100 mm Hg. However, overlooking the publisheddata, a linear relation between coronary pressure and flow wasalso found below a “critical” pressure of 60 to 80 mm Hg in in

situ ejecting heart models. This linearity of the coronary perfu-sion pressure–flow relation in the lower pressure range mayhave significance in the brain-dead organ donor, where systemicvascular resistance is decreased owing to a loss of sympatheticvasomotor tone, which consequtively leads to a decrease incoronary perfusion pressure. One can expect that even inejecting heart models, the coronary pressure–flow relation be-comes linear at lower perfusion pressures after brain death. Atthe moment when coronary autoregulation is exhausted, it ispossible that myocardial contractility also decreases.

DR VERRIER: If you postulate that the function is tied into this,then you almost have to postulate that there is ischemia (ie, thatis why flow drops). So if you increase perfusion, you would thenrecover the function. One thing that would be interesting is ifyou used radioactive microspheres or something that you couldget at the transmural distribution of blood flow and see if youreally can document that there is some diminution of flow in thesubendocardium.

DR SZABO: There are many possible explanations for contrac-tility–perfusion matching. One of them may be myocardialischemia. We measured myocardial oxygen consumption andlactate release from the heart, and we did not see any differencesbefore and after brain death and in connection with the changesof coronary perfusion pressure. Therefore, I think that cardiacdepression is unlikely to be caused by ischemia.

Another possible mechanism may be the so-called garden-hose effect, which is described in isolated hearts. It postulatesthat an increase in coronary perfusion pressure results in anincreased intramural myocardial stretch and, subsequently, con-


modulation of coronary perfusion pressure can reverse cardiac dysfunction after brain death

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