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Ann Thorac Surg 1999;67:1065-1069
© 1999 The Society of Thoracic Surgeons

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Original Articles

Distribution of cerebral flow using retrograde versus antegrade cerebral perfusion

^a Departments of Cardiovascular Surgery, Wolfson Medical Center, Holon, and Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
^b Anesthesiology, Wolfson Medical Center, Holon, and Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
^c Nuclear Medicine Institute, Wolfson Medical Center, Holon, and Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
^d Angiology Unit, Wolfson Medical Center, Holon, and Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel

Accepted for publication September 29, 1998.

Address reprint requests to Dr Cohen, Department of Cardiovascular Surgery, Wolfson Medical Center, Holon 58100 Israel

	Abstract

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Background. This study compared flow to the brain with retrograde and antegrade cerebral perfusion during circulatory arrest.

Methods. Twenty-four rabbits were injected with 5 mCi of technetium-99 macroaggregated albumin, a tracer trapped in the capillaries. Group I (n = 6) were maintained normothermic, and the tracer was injected into the ascending aorta. Group II (n = 6) were maintained normothermic, and underwent cannulation of the superior vena cava (SVC), exsanguination through the aorta, and injection of the tracer into the SVC, which was proximally occluded. In group III (n = 6), the animal was cooled to 25°C. The animal was exsanguinated through the aorta and tracer was injected into the ascending aorta. In group IV (n = 6), animals were cooled to 25°C. The animal was exsanguinated through the ascending aorta and tracer was injected into the SVC. Three animals (group V) were exsanguinated through the ascending aorta and a retrograde venogram of the SVC was performed. Scintigraphy of groups I to IV was carried out on a digital gamma camera. Brain trapping of tracer was graded from 0 to 5, with 0 being no tracer in the brain and 5 being dominant tracer trapping in the brain.

Results. Tracer trapping in the brain showed group I, 3.67 ± 0.82; group II, 0; group III, 4.67 ± 0.41; group IV, 0.17 ± 0.41 (p < 0.0001). Retrograde venogram of the SVC showed flow into the cerebral veins.

Conclusions. Retrograde flow through the SVC reaches the cerebral venous system. Flow arriving in retrograde fashion does not go through the capillary system.

	Introduction

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Circulatory arrest is a technique commonly used in cardiac operations. Its use continues to be associated with significant morbidity and mortality. One of the major causes for these complications is neurologic damage during circulatory arrest [1, 2]. Adjunctive techniques, including profound hypothermia and selective antegrade perfusion of the great vessels, have reduced morbidity during these operations [2, 3]. However, these operations continued to be associated with neurologic morbidity. Furthermore, the technique of selective antegrade perfusion has proved to be technically cumbersome.

Recently, the technique of retrograde cerebral perfusion during circulatory arrest, as an adjunct to deep hypothermia, has been introduced clinically in adults [2, 4]. Both clinical and experimental studies evaluating this technique have been inconclusive [1, 2, 5, 6]. Controversy exists regarding the amount of blood that reaches the brain using this technique. Little data are available as to whether blood flow that reaches the brain in a retrograde fashion flows into the capillary bed or is shunted within the brain [7–10].

Technetium-99 macroaggregated albumin (Tc-99m-MAA) is a radioactive tracer, with an average particle size of 15 to 30 µm (Pamphlet 511931-0694, June 1994; DuPont Merck Pharmaceutical Co, Billerica, MA) [11]. Ninety percent of the particles are between 10 and 90 µm and none are greater than 150 µm. As such, Tc-99m-MAA will only be trapped in the capillaries, postcapillary venules, or collecting venules of an organ, which are sized between 5 and 50 µm [12]. It will not be trapped in an organ if there is venovenous or venoarterial shunting around the capillary bed, as these shunts are throughout vessels larger than 300 µm in diameter [12]. Thus, the trapping of Tc-99m-MAA represents capillary flow through a given organ.

We used Tc-99m-MAA in a rabbit model to study the distribution of capillary blood flow to the head and brain during retrograde cerebral perfusion with circulatory arrest.

	Material and methods

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Study population
Adult white New Zealand rabbits, weighing between 3 and 4 kg, were used for the study. The animals were treated in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and "The Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985). All animals were anesthetized with an intraperitoneal injection of pentobarbital sodium 50 mg/kg (Parke-Davis, London, UK) and 30 mg/kg ketamine hydrochloride (Abbott, SpA, Italy). Electrocardiogram and blood pressure (Life Scope, Nihon Konden, Tokyo, Japan) were monitored; blood pressure was measured with a catheter in the femoral artery. Oxygen saturation was measured with an oxygen monitor (Oximeter, Nellcor, Hayward, CA) on the left ear, and rectal temperature was monitored. A tracheostomy was performed, an endotracheal tube inserted, and manual ventilation maintained constantly with 60% oxygen. A median sternotomy was performed and a pericardial pocket was created. The right pleural space was opened, the ascending aorta, the proximal innominate artery, and the superior vena cava (SVC) were isolated. The animals were anticoagulated by injection of 300 U/kg of heparin (Kamada, Kibbutz Beit Kama, Israel) to the right atrium.

All animals were injected with 5 mCi of Tc-99m-MAA (Pulmolite; DuPont Merck) diluted in 20 mL of normal saline over 5 minutes using an automated injector and a 1.7 by 45 mm catheter (Ohmeda, Helsingborg, Sweden). This dose was chosen based on pilot studies that showed it to be optimal for normal brain scans in these rabbits. The injection of the radiotracer was randomized according to four different protocols defining four study groups.

In group I (n = 6, warm antegrade group), the animals were maintained under normothermic conditions with the heart beating. They underwent injection of the tracer to the ascending aorta proximal to the innominate artery.

In group II (n = 6, warm retrograde group), the animals were maintained under normothermic conditions, underwent cannulation of the SVC, and exsanguination through an incision in the ascending aorta. The proximal SVC was occluded to prevent backflow of the tracer to the right atrium and the tracer was injected into the SVC.

In group III (n = 6, cold antegrade group), the whole body of the anesthetized animals, including the head, was cooled to less than 25°C in a bath of ice. The ascending aorta proximal to the innominate artery was cannulated with the same catheter, and when the heart rate decreased to less than 20 beats/min or the rabbit developed ventricular fibrillation, the animal was exsanguinated through an incision in the ascending aorta proximal to the injection side. The radiotracer was injected into the ascending aorta with the proximal part occluded.

In group IV (n = 6, cold retrograde group), the anesthetized rabbits were cooled as described in group II. The SVC was cannulated. When the heart started to fibrillate or reached bradycardia less than 20 beats/min, the ascending aorta was incised and the animal was exsanguinated. The tracer injection was performed as in group II.

The injection protocol was considered inadequate and animals were excluded from the study if: (1) initiation of the injection could not be performed within 2 minutes of opening the aorta; (2) there was extravasation of the injectate; or (3) after the creation of a pericardial pocket, the animal appeared unstable. This was defined as ventricular fibrillation, multiple arrhythmias, bradycardia less than 60 beats/min, or systolic blood pressure less than 60 mm Hg that lasted more than 2 minutes.

Eight animals were excluded from the experiment for the above reasons, and were replaced with others so that 24 animals were included in the four study groups.

Group I animals were sacrificed by interrupting the mechanical ventilation 1 minute after the tracer injection, group II to IV animals were sacrificed by exsanguination during the injection protocol.

Scintigraphy of the animals was carried out on a digital gamma camera (Apex SP-4, Elscint, Haifa, Israel) equipped with a low-energy high-resolution collimator (APC-45). For each animal, 2-minute posterior, right, and left lateral views were acquired in 256 by 256-pixel matrix and word mode to avoid pixel overflow. The scans were interpreted and scored visually by a nuclear medicine practitioner (AS).

The tracer trapping in the brain was graded based on a scale of 5 to 0 as follows: 5 = dominant brain trapping. The trapping in soft tissue of the head and upper extremities was insignificant compared with the brain, or not visualized (Fig 1A). 4 = good brain trapping. There is much more trapping in the brain than in the soft tissues of the head and upper extremities (Fig 1B). 3 = fair brain trapping. There is more brain trapping than in the soft tissues of the head and upper extremities. 2 = poor brain trapping. There is equal trapping in both the brain and the soft tissues of the head and upper extremities. 1 = very poor brain trapping. There is less brain trapping than in the soft tissues of the head and upper extremities (Fig 1C). 0 = no brain trapping at all (Fig 1D).

View larger version (39K): [in this window] [in a new window]   Fig 1. Scintigrams of animal models. Artist’s impression of rabbit’s outline was added for easier identification of body parts. (A) Dominant brain trapping (grade 5) from group III. (B) Good brain trapping (grade 4) from group I. (C) Very poor brain trapping (grade 1) from group II. (D) No brain trapping (grade 0) from group IV.

A two-way analysis of variance was the statistical method used. It was conducted to test the separate and cross-effect of temperature and location of injection on the trapping of the tracer. A value was considered statistically significant when p < 0.05.

	Results

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The scoring of the brain perfusion scans are summarized in Table 1. Group I showed good flow to the cerebral capillary system, besides physiologic trappings found throughout the body. Group III showed all or most of the flow reaching the head and upper extremities with excellent or dominant flow in the cerebral capillaries. In groups II and IV, the Tc-99m-MAA reached the head and upper extremities, but the scan did not demonstrate brain trapping, indicating no flow through the cerebral capillaries.

View larger version (69K): [in this window] [in a new window]   Fig 2. Lateral (A) and posteroanterior (B) projections from a retrograde superior vena cavagram showing reflux of contrast and retrograde filling of the jugular and cerebral veins.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Experimentally, results with retrograde cerebral perfusion (RCP) are also inconclusive. A cadaver study in humans demonstrated that a small percentage of fluid injected into the SVC reaches the central nervous system’s macrocirculation [5]. Studies in pigs showed RCP to reduce neurologic dysfunction and provide superior brain protection [15]. Other pig studies showed RCP during profound hypothermia to be inferior to antegrade selective flow during circulatory arrest for cerebral protection, and similar to circulatory arrest alone [6, 16].

Studies in dogs demonstrated both metabolically and using microspheres that only 2% to 3% of needed cerebral capillary blood flow is available during RCP [7, 9, 17]. In dogs, RCP during circulatory arrest did not provide sufficient flow to the brain to maintain aerobic metabolism [9, 17]. Selective antegrade perfusion was shown to be superior in dogs as well [3]. A baboon study using biochemical markers and colored microspheres showed almost no flow into the cerebral capillary system [10]. The investigators attribute this to venovenous shunting and arteriovenous shunting in the brain.

Our study is the first to use rabbits to evaluate RCP. Rabbit anatomy has a clear connection from the SVC to the cerebral veins [18]. The veins are not valved [18–20]. The connection between the SVC and cerebral veins was demonstrated clearly in the venograms performed in group V. Despite this, there was minimal flow through the capillaries when the flow was retrograde.

It is clear in our study that the flow is reaching the venous system of the brain, but not the capillary system of the brain. Although this has been implied through previous biochemical studies [9, 10], the present study demonstrates this fact by directly examining the flow distribution. We speculate that the cause is venovenous and venoarterial shunting in the brain, as described by Boeckxstaens and Flameng [10]. The exact mediators have not been identified that affect vasomotor activity in the precapillary beds; however, it is clear that the pre- and postcapillary pH as well as the hydrostatic pressure in the pre- and postcapillary beds are critical in this process [12]. The physical effect of retrograde cerebral perfusion during circulatory arrest is to create high pressure in the postcapillary system and low pressure in the precapillary system. In addition, such flow would create a higher (or at least equal) pH in the postcapillary collecting venules. Such a state should physiologically create shunting around the cerebral capillary system through vessels more than 300 µm in size [12]. Such shunting would allow Tc-99m-MAA to pass through the system without being trapped. In the present study, this was shown to be true at normothermic and hypothermic conditions, as demonstrated in groups II and IV.

Such a hypothesis would explain the variable results obtained clinically with retrograde cerebral perfusion. In fact, retrograde cerebral perfusion does flow through the brain, and physically "washes out" any particulate matter that could cause embolic damage during circulatory arrest. However, the metabolic benefit of retrograde cerebral perfusion on the brain should be minimal because of cerebral venovenous and venoarterial shunting during retrograde cerebral perfusion.

A number of limitations must be acknowledged in this study. First, during retrograde injections in this study, methods were not applied to reduce venovenous shunting to the lower body. This was compensated for by demonstrating that the majority of the flow was to the head and by reading the scans such that uptake in the brain was compared only to the head and upper extremities. Second, the sizes of the capillary system and small arteriovenous systems are not available in the rabbit and have been extrapolated from human data. Third, the mediators of vasomotion have been best studied in muscle and skin [12], and it is not known whether the mechanism is the same in the brain. Finally, the mediators of vasomotion have been studied at normothermia. Whether these data can be extrapolated to profound hypothermia are unknown. With these limitations in mind, our findings imply that the metabolic effects of retrograde cerebral perfusion are negligible.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This study was supported by the Schauder Foundation for the Advancement of Experimental Surgery, Tel Aviv University, Tel Aviv, Israel. We thank Sally Esakov for editorial assistance.

	References

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