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J Thorac Cardiovasc Surg 1998;115:1047-1051
© 1998 Mosby, Inc.

SURGERY FOR CONGENITAL HEART DISEASE

Endothelial dysfunction in cerebral microcirculation duringhypothermic cardiopulmonary bypass in newborn lambs

Read at the Seventy-seventh Annual Meeting of The American Associationfor Thoracic Surgery, Washington, D.C., May 4-7, 1997.

Received for publication May 12, 1997. Revisions requested July 2, 1997. Revisions received Dec. 18, 1997. ccepted for publication Dec. 23, 1997. Address for reprints: L. Craig Wagerle, PhD, Department ofCardiothoracic Surgery, Allegheny University of the Health Sciences, Broad andVine Sts., M.S. 469, Philadelphia, PA 19102.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix: Discussion References

 
Objectives: Inflammatory stimuli ormechanical stresses associated with hypothermic cardiopulmonary bypass couldpotentially impair cerebrovascular function, resulting in inadequate cerebralperfusion. We hypothesize that hypothermic cardiopulmonary bypass is associatedwith endothelial or vascular smooth muscle dysfunction and associated cerebralhypoperfusion. Therefore we studied the cerebrovascular response toendothelium-dependent vasodilator, acetylcholine, endothelium-independent nitricoxide donor, sodium nitroprusside, and vasoactive amine, serotonin, in newbornlambs undergoing hypothermic cardiopulmonary bypass (nasopharygeal temperature =18° C).
Methods: Studies were performedon 13 newborn lambs equipped with a closed cranial window, allowing for directvisualization of surface pial arterioles. Six animals were studied whileundergoing hypothermic cardiopulmonary bypass, whereas seven served asnonbypass, warm (37° C) controls. Pial arteriolar caliber (range = 111to 316 µm diameter) was monitored using video microscopy.
Results: Topical application of acetylcholine caused adose-dependent increase in arteriolar diameter in the control group that wasabsent in animals undergoing hypothermic cardiopulmonary bypass. Hypothermiccardiopulmonary bypass did not alter the vasodilation in response to sodiumnitroprusside. Furthermore, the contractile response to serotonin was fullyexpressed during hypothermic cardiopulmonary bypass.
Conclusions:The specific loss of acetylcholine-induced vasodilation suggests endothelialcell dysfunction rather than impaired ability of vascular smooth muscle torespond to nitric oxide. It is speculated that loss of endothelium-dependentregulatory factors in the cerebral microcirculation during hypothermiccardiopulmonary bypass may enhance vasoconstriction, and impairedcerebrovascular function may be a basis for associated neurologic injury duringor after hypothermic cardiopulmonary bypass. (J thorac Cardiovasc Surg1998;15:1047-54)

	Introduction

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Cerebral vasoparesis is believed to play a major role in causing cerebralinjury in patients undergoing hypothermic cardiopulmonary bypass (HCPB). ^1,2During HCPB, autoregulation, usually preserved at temperatures greater than 22°C, is lost with profound hypothermia. This is an important consideration ininfants and children in whom hypothermia in the range of 16° to 18° C iscommonly achieved. In addition, reduced cerebral perfusion persistent afterrewarming/reperfusion, "no-reflow," has been described in patientsexposed to HCPB. ^3,4 These reports are suggestive ofHCPB-associated derangements of cerebrovascular regulatory mechanisms.Nevertheless, the mechanism(s) by which HCPB induces cerebrovascular dysfunctionis not known.

Studies of noncerebral arteries suggest that endothelium-dependentresponses are specifically impaired in animals undergoing HCPB. ^5,8However, similar data for the cerebral circulation are lacking because of theunique characteristics of the cerebrovascular bed, which make it difficult tostudy (i.e., its anatomic inaccessibility and the presence of the blood-brainbarrier). ⁹ In this regard,the closed cranial window technique circumvents some of these problems, allowingdirect assessment of function of cerebral resistance arterioles in vivo. Thisstudy used the closed cranial window technique to investigate specificfunctional aspects of the pial circulation in a neonatal lamb model undergoingHCPB, testing the hypothesis that HCPB is associated with impaired endothelialfunction in cerebral resistance vessels.

	Methods

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All animals received humane care in compliance with the "Guide forthe Care and Use of Laboratory Animals" prepared by the National Academyof Sciences and published by the National Institutes of Health (NIH publicationNo. 96-03, revised 1996), and the experimental protocol was approved by theInstitutional Animal Care and Use Committee at the Allegheny University of theHealth Sciences. Animals were preassigned to one of two groups as describedbelow; in brief, one group would be studied while undergoing HCPB and thecontrol group would be instrumented for HCPB but not connected to the bypasscircuit. However, this selection was subject to hazard distribution (i.e.,dependent on availability of perfusionists). Thus the selection of animals wasnot random but, nevertheless, there was no possibility of investigator bias inanimal selection.

Animal preparation.
Experiments were carried out on 13 newborn lambs 1 to 7 days of age.After induction of anesthesia (20 mg/kg ketamine + 1 mg/kg diazepam,intramuscularly), a vertical incision was made in the groin and the femoralartery and vein were cannulated for continuous sedation (6 mg/kg per hourketamine + 0.15 mg/kg per hour diazepam) and intravenous fluid administration (5%glucose at 12 ml/hr). A vertical incision was made in the midline of the neck,and the right carotid artery was dissected free and encircled with 2-0 silksuture. A transverse incision was made between the second and third trachealrings, and a 4 to 5 cm endotracheal tube was inserted and secured with umbilicaltape ties. The animal was mechanically ventilated, positive end-expiratorypressure = 3 to 4 cm water and inspired oxygen fraction = 0.21 to 0.60to ensure end-expired carbon dioxide was maintained between 35 and 40 mm Hg andarterial oxygen tension (PO₂) morethan 200 mm Hg. Nasopharyngeal temperature was monitored using thermocouples inall cases and, in some preparations, a thermocouple was placed into the subduralspace to monitor brain temperature. Arterial blood was sampled periodically fromthe femoral artery cannula and checked for pH, carbon dioxide tension (PCO₂), PO₂,and electrolytes by use of conventional electrodes (NOVA Biomedical, Waltham,Mass.).

A cranial window was inserted over the left cerebral hemisphere(contralateral to the side of carotid artery cannulation) as previouslydescribed. ¹⁰ The animal'shead was placed into a stereotaxic device and the scalp removed to expose theleft parietal portion of the skull. A hole approximately 2 cm in diameter wasmade in the parietal plate, and the dura was carefully removed to expose thecerebral cortex. A cranial window was inserted into the hole, the edges weresealed with bone wax, and the device was cemented into place with dental acrylicas illustrated in Fig. 1. The space under the window was filledwith artificial cerebrospinal fluid (CSF) of the following composition (mmol/L):KCl (2.9), MgCl₂ (1.4), CaCl₂ (1.2), NaCl (132), NaHCO₃(24.6), urea (6.7), and glucose (3.7), equilibrated with 6% carbondioxide, 6% oxygen, at 37° C (control group) or 20° C (HCPBgroup). Pial arteries were visualized with a trinocular stereomicroscope (modelM3Z, Wild, Heerbrugg, Switzerland) attached to a high-resolution CDC videocamera (model LX-450A, Optronics Engineering, Goleta, Calif.). The video imagewas recorded on video tape and intraluminal diameter (red cell column width)measured directly from the television screen after calibration with a stagemicrometer. The pial arteries studied ranged in size from 111 to 316 µm indiameter. One arteriole was studied in each animal.

View larger version (48K): [in this window] [in a new window]   Fig. 1. Schematic diagram of aclosed cranial window.

Experimental protocols.
The pial arteriolar response to acetylcholine (ACh), anendothelium-dependent vasodilator, sodium nitroprusside (SNP), anendothelium-independent vasodilator, and serotonin, a vasoconstrictor amine, wasevaluated as follows. Once the animal had achieved a steady state (i.e.,stabilized blood pressure, blood gases, core temperature, and pial arteriolardiameter) the cortical surface under the window was suffused with artificial CSF(1 to 2 ml) by flushing into one port in the window and out another port,filling the space under the window without changing intracranial pressure. Theports were then closed and arteriolar diameter recorded. After 5 minutes,artificial CSF was replaced sequentially by increasing concentrations of ACh (10⁷mol/L, 10⁶ mol/L, and 10⁵ mol/L in artificial CSF) for 5minutes each. After this, the cortical surface was washed repeatedly (three tofour times each 5 minutes) with artificial CSF. After recovery, dose-responsecurves to subsequent compounds (SNP or serotonin) were determined in similarfashion. The order by which the respective vasoactive compounds wereadministered in each animal was randomized. All three compounds were evaluatedin three of the control animals and four of the HCPB animals.

Statistical analysis.
All values are presented as mean ± standard error of the meanFor variables of interest (i.e., pial diameters and their percent changes) 95%confidence intervals were calculated for the individual groups and are presentedas appropriate. The data were analyzed using two-way analysis of variance withone repeated measure (SigmaStat Statistical Software, Jandel Scientific, SanRafael, Calif.). The repeated measure was drug doses because these wereadministered sequentially to each animal. When the F value was significant,Student-Newman-Kuels test was used to test for significant differences betweenindividual means.

	Results

Top Abstract Introduction Methods Results Discussion Appendix: Discussion References

 
The control group and HCPB groups had a mean body weight of 6.4 ±0.5 kg and 7.3 ± 1.0 kg, respectively. Table I compares thehemodynamic and blood gas status of control and HCPB groups at the time of therespective dose-response determinations to ACh, SNP, and serotonin. Mean arterial blood pressure, arterial pH, and arterial PCO₂ and PO₂were not different between the two groups with the exception of PCO₂, which was higher in the HCPB groupduring the serotonin administration.

View larger version (22K): [in this window] [in a new window]   Fig. 2. Representative tracingof mean arterial blood pressure (MABP),bottom, and pial arteriolar diameter,top, during topical application ofacetylcholine (ACh) from a control animal andan animal undergoing HCPB procedure. Arrowsindicate application of artificial cerebral spinal fluid (CF)or ACh in cerebral spinal fluid at the indicated concentrations.

View larger version (25K): [in this window] [in a new window]   Fig. 3. Effect of HCPBprocedure on pial arteriolar responses. Data are presented as percent ofbaseline diameter (see Table II). Errorbars represent standard error of the mean; light shaded area represents 95%confidence intervals and dark shading represents their overlap. There was asignificant difference between control and HCPB groups for acetylcholine (p = 0.036), but no significant group effects werenoted for sodium nitroprusside (p = 0.268)or serotinin (p = 0.304)

	Discussion

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This study has used the closed cranial window preparation for analysis ofcerebrovascular reactivity in vivo in a perinatal animal model undergoing HCPB.The advantage of this technique is that it allows direct visualization andcontinuous measurement of caliber of surface pial arterioles. As in this study,it provides a means for direct application of agents onto the perivascularsurface, and thus reactivity of cerebral vessels can be studied without thecomplication of altered hemodynamic effects or possible influence of blood-brainbarrier function that may occur with intravascular administration ofexperimental substances. Pial arterioles are major contributors of resistance toflow, and their responses are generally representative of the cerebralcirculation as a whole. ^9,11 Active regulation ofcerebrovascular resistance is achieved by changes in diameter at the level ofresistance arterioles, where, as predicted by Poiseuille's law, resistance (R)is inversely proportional to the fourth power of the radius (r) of the artery (R1/r⁴).However, when applied in vivo, pial arteriolar diameter more closelyapproximates R1/r³. ¹¹Nevertheless, it can be appreciated that even small changes in diameter willreflect significant changes in resistance to flow. The magnitude of theresponses to ACh (8% to 19% dilation), SNP (5% to 23%dilation), and serotonin (12% to 27% constriction) are similar towhat is noted in a number of species and comparable to the normal physiologicresponse to a 10 to 20 mm Hg increase in arterial PCO₂. ⁹

Cerebrovascular dysfunction (i.e., loss of reactivity or "vasoparesis"during HCPB and/or vasospasm after HCPB) is believed to play a major role in theincreased incidence of central nervous system injury associated with cardiacoperation. ¹ Our laboratoryhas preliminarily reported loss of pial arteriolar reactivity to blood pressurechanges in neonatal lambs undergoing HCPB, ¹²suggesting that impaired reactivity of these important cerebral resistancearterioles contributes to loss of cerebral blood flow autoregulation reported inhuman infants and children during HCPB. ^2,13

This study has attempted to characterize the reported cerebrovasculardysfunction as expressed in cerebral resistance arterioles during HCPB.Accordingly, this study examined the effect of HCPB on cerebrovascularreactivity to three distinct vasoactive stimuli of potential significance duringHCPB, testing the hypothesis that loss of cerebrovascular function is specificto select physiologic or pathophysiologic stimuli whose expression is modulatedby functional endothelium. ACh is widely used as a receptor-mediated stimulus ofendothelium-dependent generation and release of classic endothelium-derivedrelaxing factor (EDRF). There is substantial evidence implicating nitric oxide(NO) or a closely related NO-containing species as the most potent EDRF,although clearly other EDRFs, especially arachidonic acid metabolites, have beenidentified. ^14,15 NO, which is synthesized fromendogenous L-arginine by calcium-dependentactivation of endothelial NO synthase, activates guanylate cyclase in vascularsmooth muscle cells, stimulating cyclic guanosine monophosphate formation, whichinduces relaxation. ¹⁶ SNP isone of the nitrosovasodilators that generate NO directly and thus activatesguanylate cyclase leading to vasodilation independent of endothelial NOsynthase. Serotonin, a vasoactive amine, released by activated platelets is apotent vasoconstrictor of cerebral arteries by means of vascular5-hydroxytryptamine₂ receptors. ¹⁷ However, 5-hydroxytryptaminereceptors on the endothelium may also stimulate EDRF formation and modulate thecontractile response to the amine. Clearly, EDRF/NO through its inhibitoryinfluence on vascular smooth muscle, platelet activation, and adhesionproperties is potentially important to the maintenance of cerebrovascularfunction during or after HCPB.

This study has shown that the vasodilator response to ACh was completelylost in those animals undergoing HCPB, whereas the vasodilator response to SNPwas not affected. This indicates that the injury was at the level of theendothelium, whereas the capacity for vascular smooth muscle to relax inresponse to NO remained intact. At the same time the ability of the cerebralarteries to contract in response to serotonin was fully expressed during HCPB.It may also be concluded that cerebral "vasoparesis" is perhaps amisnomer or requires qualification when applied to HCPB because vasorelaxationas well as vasoconstriction to specific stimuli could be demonstrated. HCPBappears to cause selective loss of functional reactivity, and cerebralautoregulation and endothelium-dependent relaxation appear to be most readilydemonstrable. Finally, we may conclude that cerebrovascular dysfunction duringHCPB is expressed at the level of resistance arterioles visualized by thecranial window method, which may offer a new experimental approach to dissectthe pathologic condition of HCPB.

Various pathologic conditions, including fluid percussion brain injury,acute hypertension, oxidant injury, air emboli, and ischemia/reperfusion, areassociated with loss of relaxation response to ACh and otherendothelium-dependent stimuli. Similarly, vascular pathophysiologic statesassociated with atherosclerosis, diabetes mellitus, immaturity, and aging oftenresult in impaired endothelium-dependent reactivity. Similarly, studies ofisolated femoral arteries and coronary and pulmonary circulation have shown lossof endothelium-dependent responses after HCPB, suggesting that reperfusionand/or rewarming may be associated with endothelium injury as well. ^5,8However, the results of this study showed that endothelium-dependent relaxationto ACh was impaired during HCPB before rewarming/reperfusion and suggests thatrewarming/reperfusion is not necessarily the cause of the associated loss of theendothelium-dependent relaxation.

This study cannot otherwise identify specific factors that may havecontributed to the impaired responses observed. One suggested mechanism isendothelial injury through gaseous microemboli that are frequently producedduring cardiopulmonary bypass operations. ^18,19 However, in one study offemoral arteries, the magnitude of the functional impairment ofendothelium-dependent relaxation was not correlated with the number ofmicroemboli generated. ⁶Another potential cause of impaired endothelium might result from the multitudeof inflammatory mediators released during cardiopulmonary bypass, such asbradykinin, complement, cytokines, and reactive oxygen species, the latter ofwhich is well known to interfere with endothelium-dependent relaxation. ²⁰ Extracorporeal oxygenation alsotriggers platelet aggregation, and platelet aggregation itself may damagecerebrovascular endothelium. ²¹

Another significant factor altering cerebral reactivity may behypothermia. The specific effect of deep hypothermia on cerebrovascular functionis difficult to assess in vivo because of the profound decrease in cerebraloxygen consumption and associated decrease in cerebral blood flow. In isolatedrat jugular vein, tissue cooling to 20° C attenuated the relaxation responseto ACh and enhanced the contraction response to serotonin, showing thatendothelial mechanisms do contribute to a cold-induced modification ofreactivity. ²² Isolatedcerebral arteries from newborn lambs in tissue bath contracted to cooling from37° C to 21° C, where contractile force varied inversely with bathtemperature. ²³ Thecold-induced contraction appears to be mediated by protein tyrosine-dependentpathways. ²⁴ SNP potentlyrelaxed the cold-contracted cerebral arteries. These data suggest that impairedendothelium-dependent NO production may facilitate the contractile response tohypothermia. Furthermore, because cerebral vasoconstrictor responses were notimpaired during HCPB, loss of NO production may set the stage for unmitigatedvasoconstriction to vasoconstrictor amines, which may be especially potent inneonates. ^23,25

It is perhaps notable that NO formation is reportedly essential to thephenomenon of cerebral blood flow autoregulation in some species. For example,cerebral blood flow autoregulation is impaired by NO synthase inhibitors in ratsand cats and the vasodilatation seen with breakthrough of autoregulation dependson release of NO or an NO donor. ^26,27 Furthermore,endothelium-dependent NO formation has been found to play a "permissive"role with respect to cerebrovascular reactivity to elevated arterial PCO₂. ²⁸That is to say that certain vasodilator responses are expressed in the presenceof basal levels of NO synthesis. In this role, rather than directly mediatingvasodilation, NO modulates intracellular second messenger pathways, which permitexpression of the normal vascular reactivity. This concept may provide a basisfor understanding mechanisms by which impairment of endothelial function mayinfluence cerebrovascular reactivity in a broader sense and thus contribute toselective cerebral vasoparesis.

In summary, this study has shown that HCPB impairs cerebral microvascularfunction (i.e., causes loss of endothelium-dependent vasodilation) but notnonspecific "vasoparesis" because select vasodilator andvasoconstrictor responses are preserved. It is likely that endothelialdysfunction coupled with preserved contractile capability may set the stage forenhanced cerebral vasoconstriction with an increased potential for cerebralhypoperfusion during or after the HCPB procedure.

	Appendix: Discussion

Top Abstract Introduction Methods Results Discussion Appendix: Discussion References

 
Dr. Frank W. Sellke (Boston, Mass.). Autoregulation is determined mainly by endothelium-independent mechanisms. One of those is myogenic contraction. In most species the endothelium really does not play much of a role, so I am not sure you can conclude that the loss of autoregulation is due to endothelial dysfunction. Did you look specifically at loss of autoregulation?

Dr. Russo. Thank you, Dr. Sellke. Clinical and experimental evidence indicate that cerebral autoregulation is lost at 22° C. Loss of cerebral autoregulation, variously defined as "vasoparesis or vasospasm," has been implied in the pathophysiology of cerebrovascular dysfunction, particularly in newborns and infants undergoing HCPB.

The question is whether, indeed, this so-called cerebral vasoparesis occurs as a myogenic phenomenon or is induced by an injury occurring at a different level. We believe that the mechanism underlying this so-called cerebrovascular spasm requires clarification. Better understanding of such mechanism might have potential clinical implications.

Dr. Sellke. Was your examination done during bypass or after bypass?

Dr. Russo. During bypass.

Dr. Sellke. Under hypothermic conditions?

Dr. Russo. We did the studies at 18° C HCPB.

Dr. Sellke. Did you examine the responses under normothermic conditions?

Dr. Russo. Yes. We studied two groups of animals. The control group underwent sham surgery at normothermia. The study group underwent HCPB at 18° C. In the study group cardiopulmonary bypass flow was adjusted so as to maintain a range of mean arterial pressure around 50 mm Hg, a level considered optimal for the evaluation of cerebral autoregulation. One of the goals of the present investigation was to confirm that indeed in our model HCPB was associated with cerebral vasospasm as defined in the literature.

Dr. Sellke. So the way I understand it, you are really doing two things to these animals: you are putting them on bypass and you are decreasing the temperature. Both of these can have effects on vascular regulation. So your control experiments were performed at normothermia versus your experimental group, in which the vessels were examined on bypass and under hypothermic conditions. Is that right?

Dr. Russo. Yes, it is.

Dr. Sellke. I suspect it would be hard to look at just the effects of hypothermia on vascular reactivity with this preparation.

Dr. Russo. This was done in our laboratory. I would refer to our work presented at the Society of Cardiovascular Anesthesia in 1994. In that study we looked specifically at the effect of hypothermia in vivo using this preparation. Indeed, our first slide today is taken from that study and it shows loss of cerebral autoregulation in response to deep hypothermia. In other words, using the cranial window preparation and modifying the mean arterial blood pressure, we were able to confirm loss of cerebral autoregulation in response to deep hypothermia.

Dr. Sellke. I am not saying that you are not losing autoregulation because many investigators have shown that. I am just not sure it is the endothelial dysfunction that is causing it.

Dr. Russo. The objective of this study was not to specifically show loss of autoregulation. We tried to identify the mechanism by which this autoregulation is lost.

Dr. Edward D. Verrier (Seattle, Wash.). I think one of the questions Dr. Sellke is asking, though, is did you have cardiopulmonary bypass as a variable independent of hypothermia?

Dr. Russo. No, we did not have that.

Dr. Verrier. Because cardiopulmonary bypass itself in such settings has also had the ability to affect endothelial cell function and autoregulation. That has been done many years ago.

Dr. Russo. Thank you, Dr. Verrier. That is correct. However, we tried to identify the mechanism underlying the so-called cerebral vasoparesis associated with HCPB.

	Acknowledgments

 
We wish to thank Charles Wacker and Paul Kerins, perfusionistsat St. Christopher's Hospital for Children, and Dr. Xingyi Que, for technicalassistance.

	Footnotes

 
Sponsor:Stanley K.Brockman, MD

	References

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