Retrograde perfusion and true reverse brain blood flow in humansq

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European Journal of Cardio-thoracic Surgery 17 (2000) 597±601
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     Retrograde perfusion and true reverse brain blood ¯ow in humans q
                                                   Carl Wong, Robert S. Bonser*
         Department of Cardio-thoracic Surgery, University Hospital Birmingham, Queen Elizabeth Medical Centre, Birmingham B15 2TH, UK
                           Received 8 September 1999; received in revised form 17 January 2000; accepted 22 February 2000

Abstract
   Objective: Reversal of brain blood ¯ow is necessary for retrograde cerebral perfusion (RCP) to have any metabolic bene®t, but RCP is
commonly used with little clinical evidence of the true incidence of reverse brain blood ¯ow and impact. S-100B is exclusive to the brain and
spinal cord and released during hypothermic circulatory arrest (HCA). True reverse brain blood ¯ow (tRBBF) during RCP may be
determined by demonstrating an excess of S-100B in the ef¯uent blood from the common carotid artery compared to blood entering the
brain. Methods: Simultaneous blood samples were drawn from the jugular bulb and left common carotid artery during RCP at 5 min intervals
in ten patients undergoing aortic surgery, utilizing HCA and subjected to blood gas, glucose and S-100B quanti®cation. RCP was instituted at
maximum pressure of 25 mmHg. Trans-cranial Doppler (TCD) continuously monitored the middle cerebral artery velocity (MCAV).
Results: The mean HCA and RCP durations were 31 min (20±50 min). Reversal of MCAV was demonstrated in only 6/10 cases (mean,
6 cm/s). Veno-arterial (V-A) extraction of oxygen and glucose occurred in all cases (P , 0:001), with the mean ef¯uent pO2 falling to 14
mmHg. V-A S-100 gradients greater than 5% were demonstrated in 8/10 cases and correlated with higher oxygen extraction (P , 0:01). In
patients with and without MCAV reversal, the S-100 gradients were 1.7 and 0.3 mmol/l, respectively (P , 0:01). Conclusions: tRBBF
occurred in nearly all patients. MCAV reversal appears to be a speci®c but insensitive guide to reverse perfusion. The de-saturation of
ef¯uent blood is not a reliable guide to true brain perfusion, and despite RCP, the brain remains ischaemic. q 2000 Elsevier Science B.V. All
rights reserved.
Keywords: Retrograde cerebral perfusion; S100 protein; Trans-cranial Doppler

1. Introduction                                                                (SVC), non-brain tissue may be responsible for oxygen
                                                                               extraction [2].
   Retrograde cerebral perfusion (RCP) has been used as a                         Antegrade brain blood ¯ow can be directly measured in
putative brain protective adjunct to hypothermic circulatory                   animals using a number of methodologies, including laser
arrest (HCA) in aortic surgery [1]. Theoretically, RCP may                     ¯ow Doppler, direct maxillary vein and internal carotid
provide substrate supply and catabolite removal. In order to                   cannulation. These techniques are all highly invasive and
do so, true reverse brain blood ¯ow (tRBBF) is required.                       are not applicable to clinical RCP monitoring [3±6].
   The issue of de-saturated blood from the common carotid                        In canine models, true reversal of brain blood ¯ow has
arteries during RCP has been interpreted as evidence of                        been described with demonstrable metabolic bene®t [7].
brain metabolic extraction. If metabolic support is provided                   However, the techniques used to institute RCP are not clini-
by RCP, then this infers that ischaemia during HCA is not                      cally applicable, and they bypass the jugular venous valves
absolute and that HCA duration could be safely extended.                       known to be present in almost all patients [8]. In the baboon,
However, venting of deoxygenated blood from the extra-                         RCP via the SVC produces no signi®cant reverse brain
cranial arteries during RCP may not be con®rmation of                          blood ¯ow or metabolic bene®t [6].
brain oxygen consumption. As blood may also ¯ow to the                            In humans, the demonstration of tRBBF during RCP is an
upper limbs, extra-cranial tissue and lower body via the                       important issue, and if tRBBF does occur, then it is impor-
azygos vein during RCP via the superior vena cava                              tant to determine its incidence and its ability to meet the
                                                                               metabolic demands of the ischaemic brain during HCA [9].
                                                                                  The S100B protein is a large, charged, dimeric protein,
  q
    Presented at the 13th Annual Meeting of the European Association for       made up of two b-subunits with a combined molecular
Cardio-thoracic Surgery, Glasgow, Scotland, UK, September 5±8, 1999.
  * Corresponding author. Tel.: 144-121-472-1311; fax: 144-121-627-
                                                                               weight of 22 000 kDa [10]. It is found almost exclusively
2542.                                                                          in astrocytes. S100B has been used as a marker of brain
  E-mail address: r.s.bonser@bham.ac.uk (R.S. Bonser)

1010-7940/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved.
PII: S 1010-794 0(00)00407-3
598                        C. Wong, R.S. Bonser / European Journal of Cardio-thoracic Surgery 17 (2000) 597±601

injury after stroke, trauma, intra-cranial haemorrhage and              samples were subjected to blood gas analysis on a Stat
other neurological diseases [11,12].                                    Pro®le 9 (Nova Biochemical, USA). pH, pCO2 and pO2
   A large gradient of S100B protein between the cerebral               were measured at 378C, and later corrected for temperature
spinal ¯uid (CSF) and blood is produced during cardiopul-               using standard formulae [18].
monary bypass (CPB), which is as great as 20 mg/l [13,14].                 Serum was obtained by centrifuging blood at 6000 rev/
S100B is continuously released into the blood during CPB,               min for 5 min. S100B levels were measured using a dual site
and following HCA, all patients have elevated serum levels              monoclonal chemoluminescent assay (LIA-MAT 100,
at the end of bypass [15,16].                                           Sangtec, Cambridge Life Sciences, Bury St Edmunds,
   The high CSF±blood gradient and continuous release of                UK) in pairs calibrated with the control samples supplied.
S100 protein may allow the identi®cation of true reverse                This assay has a co-ef®cient of variation of 5%. The efferent
cerebral blood ¯ow. Afferent blood, traversing the brain                serum S100B protein levels were subtracted from the affer-
circulation, would be expected to partially equilibrate with            ent level. A value greater than 5% of the afferent level was
CSF levels. We, therefore, hypothesized that the determina-             taken as the true difference, in accordance with the limita-
tion of a trans-cranial afferent±efferent S100B gradient                tions of the assay.
during RCP would be indicative of tRCBF. Further, we                       The data were analyzed on an IBM-compatible personal
postulate that such a gradient may correlate with the occur-            computer using standard two-tailed t-tests.
rence of reversal of middle cerebral artery ¯ow and trans-
cranial oxygen extraction.
                                                                        3. Results

2. Material and methods                                                    In the ten patients studied, the mean bypass, HCA and
                                                                        RCP durations were 216, 32 and 30 min, respectively. One
   The study was approved by the Local Research Ethics                  patient died from primary myocardial failure, and one
Committee of South Birmingham Health Authority, and                     patient suffered permanent neurological de®cit manifest
all patients gave informed consent. Ten patients undergoing             by sensory loss over the left maxillary division of the
aortic surgery using HCA and RCP were studied. Aortic                   trigeminal nerve.
root and ascending replacement was performed in six                        During RCP, veno-arterial oxygen and glucose extraction
patients, hemiarch replacement in three, and total arch                 occurred in all cases. The ef¯uent SO2 fell from 99.94 ^
replacement in one.                                                     0.01 to 68.17 ^ 4.6% (P , 0:0001), the pO2 fell from 226 ^
   Standardized anaesthesia, CPB, HCA and RCP techni-                   22.6 to 9.5 ^ 2.9 mmHg (P , 0:001), and the glucose from
ques were used, as previously described [17]. During                    7.7 ^ 0.9 to 6.9 ^ 0.8 mmol/l (P , 0:001; Fig. 1; ^
RCP, the inferior vena caval line was clamped, allowing                 represents ^ SEM).
the pressurization of the inferior vena cava via the azygos                Overall, there was a signi®cant gradient of S100B, (af¯u-
collaterals.                                                            ent, 3.0 mg/l; ef¯uent, 6.0 mg/l; P , 0:001). A V-A S100
   A right retrograde jugular bulb line was inserted for pres-          gradient of greater than 5% occurred in 8/10 cases.
sure monitoring and blood sampling, and its position                       In one patient, MCAV data could not be obtained because
checked later by a skull X-ray in the intensive care unit.              of an inadequate acoustic window. In the remainder, the pre-
Following cooling on CPB, HCA was initiated at a naso-                  HCA mean MCAV was 10 ^ 1.4 cm/s. MCAV reversal,
pharyngeal temperature of 158C. RCP was instituted with                 with a mean velocity of 6.02 ^ 3.5 cm/s was detected in six
the patient in the Trendelenberg position via the SVC, limit-           patients. In patients with and without MCAV reversal,
ing the jugular bulb venous pressure to 25 mmHg, with the               S100B gradients were 1.73 ^ 0.56 and 0.31 ^ 0.6 mg/l,
pressure manometer zeroed at the angle of the jaw.
   Trans-cranial Doppler (TCD) (SciMed 862, Fishponds,
Bristol, UK) monitoring of the right middle cerebral artery
velocity (MCAV) was performed in all patients using a 2
MHz probe, with the focus at 5 cm and an acquisition width
of 1 cm. The probe was positioned to gain the optimum
signal before the start of bypass, and ®xed in place with a
head band. Continuous recording of the MCAV trace was
captured on VHS video tape. The mean MCAV was noted
immediately before HCA, and during RCP.
   Arterial blood samples were drawn at the start of CPB,
just before HCA and at the end of CPB. During the RCP
period, blood samples from the jugular bulb line and directly           Fig. 1. Afferent and efferent oxygen tension and saturation during RCP.
from the common carotid artery using a 15 cm soft, ¯exible              Afferent samples were drawn from the jugular bulb line. Efferent samples
cannula were taken at 5 min intervals. The whole blood                  were drawn from the left common carotid artery.
C. Wong, R.S. Bonser / European Journal of Cardio-thoracic Surgery 17 (2000) 597±601                  599

                                                                             ®c, but relatively insensitive, real-time index of tRCBF. We
                                                                             have also found that despite the evidence of tRBBF, the
                                                                             metabolic impact of RCP is slight.
                                                                                The assessment of tRBBF during RCP in humans is
                                                                             problematic. Previously, using the brain perfusion agent,
                                                                             99m-Technetium-labelled dl-hexamethyl propylene amine
                                                                             oxime ([ 99mTc]HMPAO), we have been able to produce
                                                                             images of radioactive blood ¯ow into the head and brain
                                                                             during RCP [17,21] with the blood ®lling through the inter-
                                                                             nal jugular vein and dural sinuses.
                                                                                Although radio-labelled blood entered the brain in three
                                                                             out of 13 patients, the slow rise in the time-activity curves
                                                                             was compatible with the markedly reduced ¯ow rate
                                                                             compared to antegrade perfusion. In addition, tRBBF
Fig. 2. Box and whiskers plot demonstrating association of signi®cant S100   could not be precisely differentiated from arterialization of
(V-A) gradient with MCAV signal reversal.                                    the brain venous capacitance vessels that contain up to 70%
                                                                             of the brain blood volume. However, this study clearly
respectively (P , 0:01; Fig. 2). The ef¯uent pO2 was lower                   demonstrated that blood could enter the brain past the valves
in those patients with a signi®cant S100 gradient (Fig. 3).                  of the internal jugular vein in some patients, but collateral
                                                                             vessels may be more important. As radio-imaging using
                                                                             brain perfusion agents can not be performed routinely in
4. Discussion                                                                clinical practice, less invasive monitoring techniques are
                                                                             required.
   Surgery requiring HCA has a high incidence of brain                          Ganzel et al., using near infra-red spectroscopy (NIRS),
injury, and there is an undoubted need for improved brain                    reported a slowing of the normal decline in the regional
protection [19,20]. RCP has been used as an adjunct to assist                saturation (rSO2) with the use of RCP during HCA [22].
HCA in many institutions, yet no prospective randomized                      This result is disappointing. Since 70% of the total brain
trials have been performed. Moreover, there is no de®nitive                  blood volume is venous, tRBBF should arterialize this space
evidence that materially signi®cant, tRBBF occurs.                           and result in a higher rSO2 than normal. Additionally, the
   The presence of de-saturated blood ¯owing from the                        path-length of the NIRS beam is unknown. It is critical to
carotid arteries during clinical RCP suggests brain meta-                    the calculation of rSO2 and usually it is assumed to be
bolic extraction. However, as all the blood ¯owing from                      constant [23]. However, changes in the CSF or blood
the cephalic vessels could have come from extra-cranial                      volume during CPB, HCA and RCP will change its value
sources, the effective tRBBF could be insigni®cant.                          and may lead to false results. Thus, the rSO2 before and
   In this study, using a trans-brain S100B gradient as                      during HCA and RCP may not be comparable.
evidence of tRBBF, we have demonstrated that tRBBF                              Direct measurements of the cortical cerebral blood ¯ow
occurs in the majority of patients. Secondly, the reversal                   have been made in a few patients using a sub-dural laser
of the MCAV signal appears to correlate with the S100                        Doppler, but this requires a craniotomy [24]. During RCP,
gradient, inferring that MCAV monitoring may be a speci-                     cortical ¯ows of 10% of that immediately before the start of
                                                                             HCA have been reported. However, the technique is not
                                                                             quantitative, and the ef®cacy of the technique to measure
                                                                             brain blood ¯ow during HCA has not been validated.
                                                                                TCD is a simple, common and safe brain blood ¯ow
                                                                             monitoring technique, and has been used in many studies
                                                                             of moderately hypothermic CPB [25]. During RCP, Ganzel
                                                                             et al. reported reversal of MCAV with some modi®cation of
                                                                             the standard commercial apparatus [22]. However, MCAV
                                                                             reversal has not been correlated with tRBBF by any
                                                                             previous study, and hence, the signi®cance of signal reversal
                                                                             is unknown.
                                                                                It is possible that MCAV reversal may arise from blood
                                                                             bypassing the brain capillary beds during RCP via known
                                                                             veno-arterial shunts [26], and this phenomenon would much
Fig. 3. Box and whiskers plot comparing ef¯uent pO2 in the presence and      reduce the speci®city of TCD as a tRBBF monitor.
absence of a signi®cant S100 (V-A) gradient. Ef¯uent pO2 appears higher in      Other methods of assessing brain blood ¯ow, such as
                                                                             133
the absence of tRBBF.                                                           Xe, Kety±Schmidt and [18] oxygen-positron emission
600                        C. Wong, R.S. Bonser / European Journal of Cardio-thoracic Surgery 17 (2000) 597±601

tomography (PET) techniques, have not been applied to                   signi®cantly lower than the jugular bulb pO2 of 40 mmHg
study tRBBF and may be impractical during RCP. More-                    during antegrade CPB. This approximates the critical neuro-
over, in dogs, Fukae and Furuzawa [3,27] reported a maldis-             nal mitochondrial pO2 of 5 mmHg, and suggests that the
tribution of brain blood ¯ow during RCP, with poorer ¯ows               metabolic impact of RCP, even in those with true perfusion,
in the cortex compared to the medulla. Therefore, the simple            is slight.
determination of ¯ow during RCP may not be a reliable                      One of the limitations of this study is that ef¯uent
guide to its metabolic impact. Thus, the development of a               sampling could be contaminated from extra-cranial sources.
reliable non-invasive technique to detect tRBBF during                  We sought to minimize this by placing a long catheter high
RCP is a desirable ®rst step in assessing its impact.                   in the LCCA from within the open aortic arch.
   S100B protein has potential as a marker of brain perfu-                 Although some contamination of the blood in the LCCA
sion. In cardiac surgery, S100B is released into the serum in           by extra-cranial sources is inevitable, as the brain has the
association with CPB and HCA [28]. Serum S100B protein                  highest metabolic rate of any tissue in the body, brain ef¯u-
levels rise within 5 min of the start of bypass, and rose               ent blood will have a lower pO2 than that of the extra-cranial
continuously up to the end of bypass in all patients studied            tissues. Therefore, if the LCCA blood is a mixture, the
[29]. Thus, even after short periods of bypass, there is a              LCCA pO2 will be an overestimate of the brain extra-cellu-
large ECF±blood S100 gradient, as evidenced by the high                 lar ¯uid pO2, and hence, the true brain metabolic state
CSF levels (up to 20 mg/l) [14].                                        during RCP.
   Therefore, during any period of S100 release, measure-                  The ability to determine tRBBF during clinical RCP is
ment of S100B protein in the blood entering and leaving the             important. Any assumption that the visualization of de-satu-
brain would show higher concentrations in the efferent                  rated blood from the carotid arteries during RCP signi®es
blood. The diffusion of S100B protein into the blood must               signi®cant tRBBF is incorrect. On the contrary, MCAV
occur across the blood brain barrier (BBB) in the capillaries;          reversal is a good real-time monitoring method of determin-
it is expected that this would accompanied by metabolite                ing the ability of RCP to generate tRBBF in patients with a
exchange if there is a signi®cant S100B gradient between                satisfactory acoustic window.
the afferent (jugular bulb) and efferent blood (left common                However, despite evidence of tRBBF, profound ef¯uent
carotid artery (LCCA)).                                                 hypoxaemia implies that RCP, as currently used, is metabo-
   The sensitivity of using S100 as a brain perfusion marker            lically ineffective. Experimental work has suggested that
is theoretically high. At low ¯ows, the blood dwells in the             tRBBF can be increased by physical and pharmacological
capillaries for longer, and hence, has more time to equili-             manipulation [31,32]. The effectiveness of such manoeuvres
brate, thereby amplifying the signal (A-V S100 gradient).               in the clinical situation and the true utility of RCP require
Thus, for a large range of brain blood ¯ows, the afferent±              appropriate investigation.
efferent blood S100B protein difference is maintained, irre-
spective of the direction of ¯ow. However, the measurement
is qualitative, as the rate of brain release of S100B is
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       scopy: theory and applications. J Cardiothorac Vasc Anesth               by this route in the human?
       1996;10:406±418.                                                             Dr Wong: Not in humans. There are two studies in animals, which
[24]   Lin PJ, Chang CH, Tan PP, Chang CN, Lee ST, Wang CC, Chang JP,           suggest that perfusion is maldistributed, which, if the ¯ow is small, is not
       Liu DW, Chu JJ, Tsai KT, Kao CL, Hsieh MJ, Hua MS. Prolonged             an unreasonable result [3,27].
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