Retrograde perfusion and true reverse brain blood flow in humansq
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European Journal of Cardio-thoracic Surgery 17 (2000) 597±601 www.elsevier.com/locate/ejcts 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 unknown. References In this study, the detection of a signi®cant trans-cranial S100B gradient implies that true brain perfusion occurs in [1] Ueda Y, Miki S, Kusuhara K, Okita Y, Tahata T, Yamanaka K. Deep the majority of patients undergoing RCP. The correlation of hypothermic systemic circulatory arrest and continuous retrograde cerebral perfusion for surgery of aortic arch aneurysm 42 (discussion). the S100 gradient (V-A) with MCAV signal reversal Eur J Cardio-thorac Surg 1992;6:36±41. suggests that TCD may be a speci®c, but perhaps insensi- [2] Coselli JS. 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Retrograde perfusion through the superior vena cava perfuses the brain in human beings. J Thorac Cardiovasc Surg 1996;111:270±272. Appendix A. Conference discussion [18] Burtis CA, Ashwood ER. Tietz textbook of clinical chemistry, 2nd ed. Philadelphia, PA: W.B. Saunders, 1994. pp. 2326. Dr H. Borst (Munich, Germany): I think this is quite a provocative [19] Svensson LG, Crawford ES, Hess KR, Coselli JS, Raskin S, Shenaq paper, con®rming what many surgeons working on the thoracic aorta SA, Sa® HJ. Deep hypothermia with circulatory arrest. Determinants always have been suspecting. What is your practical conclusion from of stroke and early mortality in 656 patients 28±31 (discussion). J this? Are you still using RCP? Thorac Cardiovasc Surg 1993;106:19±28. Dr Wong: Yes, we are using RCP in the context of having completed a [20] Okita Y, Takamoto S, Ando M, Morota T, Yamaki F, Kawashima Y, prospective trial. We are also investigating the possibility of potentiating Nakajima N. Predictive factors for postoperative cerebral complica- RCP, since a number of reports suggest that pharmacological manipulation tions in patients with thoracic aortic aneurysm. Eur J Cardio-thorac can increase the ¯ow, augmenting perfusion. Surg 1996;10:826±832. Dr Borst: Do you think it has a protective effect in keeping the tempera- [21] Pagano D, Boivin CM, Faroqui MH, Bonser RS. Surgery of the thor- ture down, for instance, or in washing out metabolites, debris and things of acic aorta with hypothermic circulatory arrest: experience with retro- that sort you always hear about? grade perfusion via the superior vena cava and demonstration of Dr Wong: Well, this study doesn't address that problem, and that will cerebral perfusion discussion 839. Eur J Cardio-thorac Surg have to be addressed by the study we just recently completed, which is the 1996;10:833±838. prospective randomized trial between RCP and HCA only. We have yet to [22] Ganzel BL, Edmonds Jr HL, Pank JR, Goldsmith LJ. Neurophysio- analyze that data fully, but we will be presenting some of our results in the logic monitoring to assure delivery of retrograde cerebral perfusion Atlanta meeting of the American Heart Association. discussion 755±757. J Thorac Cardiovasc Surg 1997;113:748±755. Dr D. Blyth (Durban, South Africa): Could I ask you, do you know of a [23] Wahr JA, Tremper KK, Samra S, Delpy DT. Near-infra-red spectro- study that shows anything with regard to uniformity of distribution of blood 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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