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Ann Thorac Surg 2003;75:1288-1293
© 2003 The Society of Thoracic Surgeons

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Original article: cardiovascular

Direct visualization of minimal cerebral capillary flow during retrograde cerebral perfusion: an intravital fluorescence microscopy study in pigs

^a Department of Cardiac Surgery and Biostatistics, Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
^b Department of Thoracic and Cardiovascular Surgery, University Hospitals of Saarland, Homburg, Germany

^* Address reprint requests to Dr Jonas, Department of Cardiac Surgery, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USA.
e-mail: richard.jonas{at}tch.harvard.edu

Presented at the Poster Session of the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2002.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
BACKGROUND: Retrograde cerebral perfusion (RCP) is used in some centers during aortic arch surgery for brain protection during hypothermic circulatory arrest. It is still unclear however whether RCP provides adequate microcirculatory blood flow at a capillary level. We used intravital microscopy to directly visualize the cerebral capillary blood flow in a piglet model of RCP.

METHODS: Twelve pigs (weight 9.7 ± 0.9 kg) were divided into two groups (n = 6 each): deep hypothermic circulatory arrest (DHCA) and RCP. After the creation of a window over the parietal cerebral cortex, pigs underwent 10 minutes of normothermic bypass and 40 minutes of cooling to 15°C on cardiopulmonary bypass ([CPB] pH-stat, hemocrit 30%, pump flow 100 mL · kg^-1 · min^-1). This was followed by 45 minutes of DHCA and rewarming on CPB to 37°C. In the RCP group the brain was retrogradely perfused (pump flow 30 mL · kg^-1 · min^-1) during DHCA through the superior vena cava after inferior vena cava occlusion. Plasma was labeled with fluorescein-isothiocyanate-dextran for assessing microvascular diameter and functional capillary density (FCD), defined as total length of erythrocyte-perfused capillaries per observation area. Cerebral tissue oxygenation was determined by nicotinamide adenine dinucleotide hydrogen (NADH) autofluorescence, which increases during tissue ischemia.

RESULTS: During normothermic and hypothermic antegrade cerebral perfusion the FCD did not significantly change from base line (97% ± 14% and 96% ± 12%, respectively). During retrograde cerebral perfusion the FCD decreased highly significantly to 2% ± 2% of base line values (p < 0.001). Thus there was no evidence of significant capillary blood flow during retrograde cerebral perfusion. The microvascular diameter of cerebral arterioles that were slowly perfused significantly decreased to 27% ± 6% of base line levels during RCP. NADH fluorescence progressively and significantly increased during RCP, indicating poorer tissue oxygenation. At the end of retrograde cerebral perfusion there was macroscopic evidence of significant brain edema.

CONCLUSIONS: RCP does not provide adequate cerebral capillary blood flow and does not prevent cerebral ischemia. Prolonged RCP induces brain edema. However, there might be a role for a short period of RCP to remove air and debris from the cerebral circulation after DHCA because retrograde flow could be detected in cerebral arterioles.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
Hypothermic circulatory arrest (HCA) is used in complex operative interventions such as aortic arch surgery or congenital heart surgery to provide an uncluttered and bloodless operative field. But even with deep hypothermia the maximal safe duration of circulatory arrest is limited. The brain is particularly sensitive to ischemic damage. To protect the brain during HCA additional techniques have been proposed. One of them is retrograde cerebral perfusion (RCP) through the superior vena cava (SVC) during circulatory arrest. RCP was introduced clinically as an adjunct to cerebral protection more than a decade ago [1]. However, the reported clinical results vary from beneficial [2, 3] to neutral or detrimental [4–6]. In addition the experimental data regarding RCP are not uniform [7–10]. It is generally agreed that RCP improves cerebral cooling [11] and that RCP has the potential to flush emboli and debris from the cerebral circulation. In fact, RCP was first used to flush out massive air embolism during CPB [12]. It still remains a matter of debate whether RCP provides adequate capillary flow in the brain. Additionally RCP may result in cerebral edema and consequent brain damage during retrograde perfusion and antegrade reperfusion [13].

We developed a porcine model of fluorescence microscopy to directly visualize and quantify cerebral capillary flow during RCP. Nicotinamide adenine dinucleotide hydrogen (NADH) autofluorescence was used to monitor tissue oxygenation of the brain before, during, and after deep hypothermic circulatory arrest (DHCA) with and without RCP.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Animals and surgical preparation
Twelve Yorkshire piglets (Parsons Farm, Hadley, MA) with a mean body weight of 9.7 ± 0.9 kg were divided into two groups (n = 6 each): DHCA and RCP. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Science and published by the National Institutes of Health (National Institutes of Health publication No. 86-23, revised 1985).

After premedication with ketamine and xylazine, the piglets were intubated and ventilated with 50% oxygen. After induction with fentanyl (25 µg/kg intravenously [IV]) anesthesia was maintained with continuous IV infusion of fentanyl (25 µg · kg^-1 · h^-1), midazolam (0.2 mg · kg^-1 · h^-1), and pancuronium (0.2 mg · kg^-1 · h^-1). Rectal and esophageal temperature probes were placed. An arterial catheter was inserted through the left femoral artery into the thoracic aorta for blood pressure monitoring and blood gas analysis. Venous catheters were inserted into the femoral vein and jugular bulb for administration of drugs and jugular vein pressure monitoring, respectively. After administration of heparin (300 IU/kg IV) and a median sternotomy bypass cannulas were placed into the ascending aorta (10F Bio-Medicus cannula), SVC (18F Harvey cannula), and right atrium (26F Harvey cannula). The right atrial cannula and SVC cannula were connected using a Y connector. Only the venous line from the Y connector to the reservoir was clamped, therefore allowing blood to drain from the SVC through the Y connector into the right atrium before the start of cardiopulmonary bypass (CPB). The azygos and hemiazygos veins were ligated. After placement of a band around the superior vena cava the SVC cannula was tightly snared. Next the venous and arterial cannulas were secured to the chestwall to prevent any kinking and the animals were turned from a supine into a prone position under careful observation of jugular vein and arterial pressure.

The piglets were positioned prone in a stereotactic frame and cranial windows (10 x 20 mm) were created over the right and left parietal cerebral cortex before institution of cardiopulmonary bypass. After sealing of the bone edges with bone wax and incision of the dura the cerebrocortical microvessels were visualized.

CPB management
The prime of the CPB circuit (including a hardshell reservoir, a Minimax membrane oxygenator, and 40 µm arterial filter) consisted of 800 mL blood freshly drawn from an adult donor pig on the morning of each experiment. Methylprednisolone (25 mg/kg), cephazolin (25 mg/kg), sodium bicarbonate 7.4% (10 mL), and furosemide (0.25 mg/kg) were added to the prime before starting CPB and upon reperfusion. CPB flow was set at 100 mL/kg per minute. The pH stat strategy was employed (oxygenator gas 5%CO₂ and 95%O₂). The hematocrit aimed for on CPB was 30%. After base line recordings of the cerebral microcirculation all piglets were placed on normothermic CPB (esophageal temperature 37°C) for 10 minutes. Piglets then underwent 40 minutes of cooling on CPB to an esophageal temperature of 15°C. This was followed by 45 minutes of deep hypothermic arrest (DHCA group). In the RCP group, the pigs were retrogradely perfused with oxygenated blood (temperature 15°C) during circulatory arrest through the SVC cannula after IVC occlusion. A pump flow rate of 30 mL · kg^-1 · min^-1 was applied during RCP. After 45 minutes of DHCA all piglets were slowly rewarmed on CPB more than 40 minutes to 37°C.

Videomicroscopy system
A Leica MZFL III epi-fluorescence microscope (Leica, Heerburge, Switzerland) on a surgical stand was used. It was equipped with a rapid filter exchanger which included two sets of filters: a blue filter set (450 to 490 nm excitation per >515 nm emission wavelength) for visualization of fluorescein fluorescence and a UV filter set (340 to 380 nm excitation per >420 nm emission wavelength) for monitoring NADH autofluorescence. The microscopic images from the charge-coupled device (CCD) video camera (Dage-300-RC) were transferred to a high resolution 12-inch monitor (Dage HR-1000; Dage-MTI, Michigan City, IN), and recorded by a professional S-VHS videocassette recorder (Panasonic AG 7350). For subsequent offline analysis of microcirculatory measurements a Scion LG-3 frame grabber card (Scion Corporation, Frederick, MD) and a computer-assisted image analysis system (National Institutes of Health-Image, Bethesda, MD) were used.

Measurements
Hemodynamics and biochemical measurements
The arterial pressure and jugular vein pressure were monitored continuously throughout the experiments and recorded every 5 minutes. Blood samples were taken every 10 minutes on CPB from the arterial line and right atrium for measuring hemoglobin, hematocrit, glucose, lactate, pO₂, PCO₂ and pH. During RCP blood samples were taken every 10 minutes from sideports of the SVC and ascending aortic cannula. All samples were measured using a blood gas analyzer (Stat Profile 9, Nova, Waltham, MA).

Microcirculatory measurements
For measurement of microvascular diameter (MVD) the plasma was labeled with 1 mL fluorescein-isothiocyanate-Dextran 5% (150 kD, Sigma) before each measurement. This also allowed the assessment of functional capillary density (FCD), defined as total length of erythrocyte-perfused capillaries per observation area. To visualize the tissue oxygenation, NADH fluorescence was used. NADH fluoresces blue upon ultraviolet epi-illumination. NADH, the reduced form of NAD⁺, is one of the main means to transport energy from the tricarboxylic acid cycle to the respiratory chain in mitochondria. In case of tissue hypoxia the respiratory chain is inhibited and therefore intracellular NADH levels increase. For evaluation of NADH fluorescence the automatic brightness and contrast control of the video camera was disabled and the optical densities were evaluated densitometrically [14].

Microcirculatory measurements were performed at base line, at 10 minutes normothermic CPB, at 20 minutes cooling, at end of cooling, and at 5, 10, and 40 minutes of rewarming. In addition to these time points NADH fluorescence was recorded every 15 minutes during DHCA with retrograde perfusion (RCP group) and without retrograde perfusion (DHCA group). Microvascular diameter and FCD were measured at 5, 15, 30, and 45 minutes during RCP.

Statistics
Data are expressed as mean ± SD. No skewness was detected in any of the variables using the Kolmogorov-Smirnov test. RCP and DHCA groups were compared at base line with respect to hemodynamic, biochemical, and microcirculation variables using the two-sample Student’s t test. Two-way repeated-measures analysis of variance (ANOVA) was used to evaluate time-related changes in microvascular diameter, FCD, and NADH fluorescence and to compare rates of change between the RCP and DHCA groups. Paired t tests were used for specific time point comparisons within an experimental group. A two-tailed p value less than 0.05 was considered significant.

	Results

Top Abstract Introduction Material and methods Results Comment References

 
At base line (before CPB) there were no statistically significant differences between the two experimental groups regarding blood gases, whole body lactate, hematocrit, and body temperature (p = NS).

Hemodynamics
The mean arterial pressure was not significantly different between the two groups at base line (before CPB) and during the cooling and rewarming phase of the experiment (Fig 1). During cooling, a decrease in MAP relative to base line was documented in both groups (p < 0.01). In the RCP group the jugular venous pressure was 28 ± 7 mm Hg during the RCP phase. The mean arterial pressure during retrograde cerebral perfusion reached 8 ± 2 mm Hg. During rewarming on CPB the mean arterial pressure increased gradually to base line values in both groups.

View larger version (25K): [in this window] [in a new window]   Fig 1. Pressure: MAP DHCA (diamonds), MAP RCP (squares), and JVP RCP (triangles). Jugular venous pressure during RCP was 28 ± 7 mm Hg. (MAP = mean arterial pressure; DHCA = deep hypothermic circulatory arrest; JVP = jugular venous pressure; RCP = retrograde cerebral perfusion [cooling phase]; Rewarm = rewarming phase.)

View larger version (28K): [in this window] [in a new window]   Fig 2. Functional capillary density (FCD). Note the highly significant decrease of FCD during retrograde cerebral perfusion (RCP) (black bars). (CPB 10' = at the end of 10 minutes normothermic cardiopulmonary bypass; Cool = cooling; DHCA [white bars] = deep hypothermic circulatory arrest; Rewarm = rewarming.)

During the reperfusion phase the FCD gradually increased in both groups. After 40 minutes of rewarming the FCD did not statistically differ from prebypass values in either group.

There were no statistically significant differences between the FCD of the right and left parietal cortex duringcooling and rewarming in either group. The FCD of the right and left parietal cortex were practically identical (right 2.2% ± 2.0% versus left 1.8% ± 2.2%, p = 0.91) during retrograde cerebral perfusion.

Microvascular diameter
The arteriolar diameter increased in both groups during normothermic and hypothermic bypass employing the pH-stat strategy relative to base line (Fig 3) (end of cooling DHCA 131 ± 7 mm Hg versus RCP 128 ± 7 mm Hg). During RCP the microvascular diameter of slowly perfused cerebral arterioles significantly decreased to 27% ± 6% of base line levels (p < 0.01). In the DHCA group, the arteriolar diameter also decreased (23 ± 7 mm Hg) since the venous lines were left open to the reservoir during circulatory arrest for drainage of blood. During antegrade reperfusion the arteriolar diameter gradually increased in both groups. There were no significant differences between the groups during reperfusion.

View larger version (29K): [in this window] [in a new window]   Fig 3. Arteriolar diameter. Arteriolar diameter decreased during retrograde cerebral perfusion (RCP) (black bars) to 27% ± 6% of baseline values. It also decreased in the deep hypothermic circulatory arrest (DHCA) (white bars) group because the venous lines were left open to the reservoir during circulatory arrest (CA). (CPB 10' = at the end of 10 minutes normothermic cardiopulmonary bypass; Cool = cooling; Rewarm = rewarming.)

View larger version (21K): [in this window] [in a new window]   Fig 4. Nicotinamide adenine dinucleotide hydrogen (NADH) fluorescence. NADH fluorescence increases during ischemia and can therefore be used as a marker for tissue oxygenation. Cerebral tissue oxygenation was not significantly greater in the retrograde cerebral perfusion group (diamonds). (DHCA [squares] = deep hypothermic circulatory arrest; Rewarm = rewarming.)

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
For complex congenital heart repair and aortic arch surgery HCA is still used in many centers to achieve ideal operative exposure. However, even with DHCA the safe time before neurologic morbidity occurs is limited. Therefore alternative techniques have been developed that were expected to provide cerebral perfusion during circulatory arrest. Although the routine use of RCP through the SVC was introduced clinically about a decade ago, the RCP protocols used today at different centers still vary enormously. The jugular vein pressure aimed for is as low as 15 to 20 mm Hg [15] and as high as 40 mm Hg in some centers [16]. Perfusion protocols of different centers also involve significantly different pump rates during RCP. In addition the hematocrit and pH management during RCP differ among the centers that apply RCP [17]. Another important detail is the question as to whether the IVC should be occluded during RCP.

In addition to these technical aspects of RCP, it is still a matter of debate whether RCP provides adequate blood flow at capillary level in the brain. It is not certain whether RCP improves brain tissue oxygenation during HCA. Conversely the "unphysiological" venous hypertension during RCP might induce significant brain edema.

We used our established animal model to study these questions. Intravital fluorescence microscopy (IVM) was used to directly visualize and quantify the FCD (length of perfused capillaries per unit area) during cooling, retrograde cerebral perfusion, and rewarming. IVM also allows for the quantification of brain tissue oxygenation by monitoring NADH autofluorescence, which increases during ischemia. We used an "aggressive" model of 45 minutes continuous RCP that included IVC occlusion, a pump flow of 30 mL · kg^-1 · min^-1 that resulted in a jugular bulb pressure of 30 mm Hg, pH-stat management, and a hematocrit of 30% during RCP. The data for FCD and tissue oxygenation were compared with a control group that underwent HCA without RCP.

As reported previously there was maintenance of capillary flow in the brain during deep hypothermic bypass despite the high hematocrit (30%) used in this model [18].

The main finding of this IVM study is that RCP resulted in minimal cerebral capillary flow in this piglet model. However, some retrograde flow in larger arterioles (90 to 150 um) was detectable. These results are in concert with a recent study that indirectly assessed blood flow during RCP through brain capillaries in a pig model. Calculations based on the number of microspheres trapped in the brain showed negligible microcirculatory flow during RCP even after IVC occlusion [19].

Studies using a transcranial Doppler technique have shown inconsistent retrograde flow in the cerebral macrocirculation during RCP [5]. In the transcranial Doppler technique study by Tanoue and coworker [5] using a jugular venous pressure of 15 to 20 mm Hg retrograde signals in the middle cerebral artery were only detected in 3 of 15 patients. Unfortunately this technique is unable to assess flow in the cerebral microcirculation.

An earlier study using nonhuman primates showed that most of the SVC inflow is shunted through venous beds with little resistance [20].

Anttila and coworkers [11] demonstrated in a chronic porcine model that enhanced cranial hypothermia is the major beneficial factor of retrograde cerebral perfusion. They found better survival, neurologic, and histopathologic outcomes in the group undergoing RCP with 15°C relative to 25°C.

In our intravital fluorescence microscopic studies the cerebral tissue oxygenation of the parietal cortex was not significantly greater in the group with retrograde cerebral perfusion in comparison with deep hypothermic circulatory arrest. This indicates indirectly that there was no relevant nutrient RCP flow to the brain. The actual retrograde cerebral flow must have been far too little to meet the metabolic demand of the brain even in the presence of deep hypothermia.

Limitations
Only the superficial parietal cortex was assessed in the present study using intravital fluorescence microscopy. Unfortunately deeper regions of the brain can not be studied owing to the epi-illumination technique of this method.

To directly visualize the capillary flow of the brain using intravital microscopy the animals had to be in a prone position. Therefore opening of the aorta during retrograde cerebral perfusion and closing of the aorta for antegrade reperfusion was technically impossible in this experimental setting. Aortic drainage was achieved through the cannula in the ascending aorta. One of the reasons for the pronounced cerebral edema during RCP observed in our studies might have been the aortic back pressure of about 8 mm Hg during retrograde cerebral perfusion. The pressure gradient between the jugular veins and the systemic arteries was about 20 mm Hg however; that is similar to what is applied during clinical application of RCP.

As in any experimental model this porcine model raises the question whether the species is appropriate for studies of RCP since the anatomy of the cerebral venous and arterial circulation differs among species. In this laboratory RCP study we used a porcine model as others have before because pigs rarely have competent jugular valves.

Summary
The goal of our study was to determine how much of the blood flow during retrograde perfusion delivered through the superior vena cava actually reaches the cerebral microcirculation. Another question was whether this microcirculatory flow is adequate to provide nutritive flow to support cerebral metabolism that is ongoing even in the presence of deep hypothermia. We used intravital fluorescence microscopy IVM to study these questions. Using IVM it was possible to directly visualize and quantify retrograde cerebral perfusion at capillary level. Simultaneously cerebral tissue oxygenation during RCP could be assessed by NADH autofluorescence.

The major findings of our studies are that RCP provides only minimal cerebral capillary blood flow and therefore does not prevent cerebral ischemia.

Thus we conclude from our data that the prolonged use of RCP is questionable as it does not provide relevant nutritive flow to the brain and might induce brain edema. Nevertheless there might be a role for a short period of RCP to remove air and debris from the cerebral circulation after DHCA because slow retrograde flow could be detected in cerebral arterioles.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Christof Stamm Hans-Joachim Schäfers Richard A. Jonas Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Duebener, L. F. Articles by Jonas, R. A. Search for Related Content PubMed PubMed Citation Articles by Duebener, L. F. Articles by Jonas, R. A. Related Collections Cerebral protection