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Ann Thorac Surg 1999;68:4-12
© 1999 The Society of Thoracic Surgeons
a Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
Address reprint requests to Dr Langley, Department of Cardiothoracic Surgery, Southampton General Hospital, Southampton, Hampshire, SO16 6YD, United Kingdom
e-mail: stephenlangley{at}dial.pipex.com
Presented at the Forty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 12–14, 1998.
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Abstract |
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Methods. Fifteen neonatal piglets were placed on CPB and cooled to 18°C. Each animal then underwent either: (1) 60 minute continuous CPB (control), (2) 60 minute uninterrupted DHCA (UI-DHCA), or (3) 60 minute DHCA with intermittent perfusion (1 minute every 15 minutes) (I-DHCA). All animals were then rewarmed and weaned from CPB. Measurements of CBF and CMRO2 were taken before and after CPB. A further 9 animals underwent CPB without DHCA (2 animals) or with DHCA (7 animals), under various conditions of arterial blood gas management, intermittent perfusion, and reperfusion time.
Results. UI-DHCA resulted in significant impairment to recovery of CMRO2 after CPB (p < 0.05). Regardless of the blood gas strategy used, the EM after UI-DHCA revealed extensive damage characterized by perivascular intracellular and organelle edema, and vascular collapse. I-DHCA, on the other hand, produced a pattern of normal CMRO2 recovery identical to controls, and the EM was normal for both these groups.
Conclusions. Intermittent perfusion during DHCA is clinically practical and results in normal cerebral metabolic and ultrastructural recovery. Furthermore, the correlation between brain structure and CMRO2 suggests that monitoring CMRO2 during the operation may be an outstanding way to investigate new strategies for neuroprotection designed to reduce cerebral damage in children undergoing correction of congenital cardiac defects.
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Introduction |
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In the majority of previous studies investigating cerebral dysfunction after DHCA, the marker for cerebral injury has been either the rate of recovery of cerebral metabolic rate of oxygen (CMRO2) or of cerebral high-energy phosphates. It has been known since the 1960s, however, that the use of DHCA is accompanied by histologic evidence of anoxic brain damage [8, 9]. Despite the widespread use of DHCA for almost 30 years and the fairly intensive investigation in this area more recently, no previous studies have examined the histology of the cerebral vasculature in detail after DHCA and reperfusion. In particular, the cellular ultrastructure of the cerebral vascular endothelium as viewed under the transmission electron microscope (EM) has yet to be described under these conditions. This is perhaps surprising, as the abnormal cerebral perfusion that follows a period of DHCA must be a vascular phenomenon of some kind.
The following study in the neonatal piglet was designed to investigate the effects of intermittent perfusion during a 60-minute period of DHCA. The initial part of the study utilized the xenon 133 (133Xe) clearance technique for determination of cerebral blood flow (CBF) and metabolism. Subsequent experiments incorporated perfusion fixation with Karnovsky’s solution at the end of CPB and examination of the cerebral microcirculatory bed with transmission EM. Correlation of cerebral metabolic findings with ultrastructural microvascular appearance is demonstrated for the first time.
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Material and methods |
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The heart was exposed through a median sternotomy. Cardiac instrumentation consisted of a 3-F micromanometer (Millar Instruments Inc, Houston, TX) inserted into the superior vena cava for central venous pressure monitoring, placement of an 8-mm flow probe (Transonic Systems, Ithaca, NY) around the proximal pulmonary artery for cardiac output monitoring, and insertion of a left atrial catheter for 133Xe injection.
Sagittal sinus access
The animals were anticoagulated with intravenous heparin (500 IU/kg) before access of the sagittal sinus. A 1-cm strip of scalp was raised in the midline over the vertex of the skull. Two separate 2-mm burr holes were made over the superior sagittal sinus for repeated sagittal sinus venous blood sampling and continuous sagittal sinus venous pressure monitoring with a 3-F micromanometer (Millar Instruments Inc).
Cardiopulmonary bypass and circulatory arrest
An 8 F arterial cannula and a 20 F venous cannula (DLP Inc, Grand Rapids, MI) were inserted through purse-string sutures into the ascending aorta and the right atrium, respectively. CPB was commenced at a flow rate of 120 mL/kg/min. The pump-oxygenator system consisted of a nonpulsatile roller pump (Sarns Inc, Ann Arbor, MI) and a hollow-fiber membrane oxygenator (Minimax PLUS; Medtronic Inc, Anaheim, CA). No arterial filter was used. The circuit was primed with heparinized fresh blood from a donor pig. Ringer’s lactate and sodium bicarbonate solutions were added to the prime to achieve a hematocrit of 0.25 and a pH of 7.4 at 37°C. The total prime volume was approximately 450 mL. The temperature of the perfusate was controlled with the integral heat exchanger in the venous reservoir of the oxygenator and a water bath system (BIO-CAL 370; Biomedicus, Minneapolis, MN). Animals undergoing DHCA were cooled to a temperature of 18°C over a standard duration of 20 minutes by the circulation of ice water through the heat exchanger. At the end of the cooling period, DHCA was established and the aortic and right atrial cannulae were clamped. After 60 minutes of DHCA, the aortic and venous cannulae were unclamped. Perfusion was reestablished at 120 mL/kg/min with the perfusate initially at room temperature (20°C to 22°C). Rewarming was accomplished by circulating warm water to the heat exchanger in the venous reservoir. A nasopharyngeal temperature of 36°C was generally reached by 45 minutes of reperfusion. During cooling and rewarming, blood gases were managed according to the "alpha-stat" strategy. The arterial pH was maintained at 7.35 to 7.45, and carbon dioxide tension at 35 to 45 mm Hg measured at 37°C and uncorrected for the temperature of the animal. Arterial oxygen tension was kept between 150 and 250 mm Hg and hematocrit between 0.23 and 0.28. Sodium bicarbonate (8.4%) was given when necessary but not immediately before cerebral blood flow measurements.
Measurement of cerebral blood flow and cerebral metabolism
Cerebral blood flow (CBF) was determined by 133Xe clearance technique in 15 of the animals using a modification of the initial slope index method [10, 11]. Subsequently, the cerebral metabolism (CMRO2), cerebral oxygen delivery (CDO2), and cerebral oxygen extraction (CEO2) were calculated. Arterial and sagittal sinus blood samples were taken at each stage of the experiment for estimation of oxygen tension, carbon dioxide tension, oxygen saturation, pH, and base excess using a blood gas/electrolyte monitor (GEM-Stat; Mallinckrodt Sensor Systems Inc, Ann Arbor, MI). Hemoglobin levels (in g/dL) were measured from arterial blood samples (482 Co-Oximeter; Instrumentation Laboratory Corp, Lexington, MA). This technique of CBF measurement and subsequent determination of CMRO2, CDO2, and CEO2 has been used in a number of studies from our laboratory and was previously described in detail [4]. Sagittal sinus lactate production was measured using a glucose/L-lactate analyzer (model 2300 Stat; Yellow Springs Instrument Co, Yellow Springs, OH).
Preparation of Karnovsky’s fixative
All the animals undergoing EM examination of the cerebral microvascular bed underwent perfusion fixation of the brain with Karnovsky’s solution: a hyperosmolar combined formaldehyde-glutaraldehyde fixative for use in electron microscopy [12]. Karnovsky surmised that as formaldehyde penetrates faster than glutaraldehyde, it temporarily stabilizes structures that are subsequently more permanently stabilized by the glutaraldehyde. The Karnovsky’s fixative was prepared in batches of 2 L. All stages of the preparation were undertaken under a chemical extraction hood. Initially, 700 mL of deionized distilled water was warmed to between 60°C and 70°C over a Bunsen burner, and 80 g paraformaldehyde (Ted Pella Inc, Redding, CA) was added and stirred in thoroughly. After this, 10–20 drops of 1 N sodium hydroxide (JT Baker Chemical Co, Philipsburg, NJ) was added until the solution cleared. The solution was cooled to room temperature, after which 100 mL of 50% glutaraldehyde (Eastman Kodak Co, Rochester, NY), 1.5 g calcium chloride (JT Baker Chemical Co, Philipsburg, NJ), and 1.0 L of 0.2M sodium cacodylate buffer (Ernest Fullam Inc, Latham, NY) were added. The solution was topped up to the 2-L mark with distilled water and then passed through filter paper (No. 4 size; Whatman, England) to remove any precipitation resulting from a supersaturated solution. The filtration was an additional but important modification designed to reduce the likelihood of particulate embolization in the microvasculature of the brain at the time of perfusion fixation. The pH was determined with a pH meter (Model 325; Fisher Accumet, Fair Lawn, NJ) and brought up to a final pH of 7.2 by the addition of 1 N sodium hydroxide, one drop at a time. The osmolality of the final solution was determined with an osmometer (5100 Vapor Pressure Osmometer; Wescor Inc, Logan, UT) and the fixative stored in a cold room or refrigerator at 4°C. The final solution was straw colored and clear with a concentration of 2.5% glutaraldehyde, 4.0% paraformaldehyde, 0.075% calcium chloride, and 0.1 M sodium cacodylate. The pH was 7.2 with an osmolality between 1700 and 2000 mosm/kg. The combination of glutaraldehyde and paraformaldehyde results in a solution that is not only pungent but also extremely irritating to the mucus membranes of the respiratory tract and to the eyes. A surgical gown, gloves, cap, and mask, in addition to eye protection goggles, were worn at all times when handling or delivering the fixative solution.
Perfusion fixation of the brain
At the end of the period of ischemia and reperfusion for each animal undergoing EM, the clamp on the bridge of the CPB circuit was released and the blood drained out of the animal into the venous reservoir. After exsanguination, the aortic cannula was first clamped to prevent air entering the circuit, and then disconnected from the CPB circuit. The aortic cannula was then connected to the stem of a Y connecting tube. A 1-L bag of heparinized normal saline was attached to one arm of the Y connecting tube, and a 1-L bag of Karnovsky’s solution attached to the other arm. Great care was taken to insure that no air entered the circuit during this process. An infusion pressure bag around the heparinized saline was inflated to maintain a constant cerebral perfusion pressure (CPP) of 50 mm Hg during the infusion. The difference between the pressure in the descending aorta and the sagittal sinus venous pressure was used to determine the CPP. The infusate returning to the right atrium was drained out of the venous cannula into a plastic container for disposal. To flush out any residual blood cells and plasma from the vascular space, between 750 and 1500 mL of heparinized normal saline (10,000 IU heparin sulphate/L) was infused via the aortic cannula. The infusion was continued until the color of the returning fluid had changed from red to almost colorless. At this time, the infusion of heparinized saline was stopped and the infusion of Karnovsky’s solution commenced, again at an infusion pressure that resulted in a CPP of 50 mm Hg. After infusion of 1.0 L of Karnovsky’s solution, the aortic and venous cannulae were removed, and the specimen was prepared for examination.
Preparation of the brain for EM
The animal was placed prone, and the scalp and vault of the skull were completely excised. The frontal lobes were then elevated to enable division of the olfactory nerves, optic nerves, and the pituitary stalk. The occipital lobes were then elevated and the tentorium cerebelli was incised to expose the cerebellum. A blunt instrument was then passed posterior and inferior to the cerebellum to transect the medulla at the foramen magnum. The remaining cranial nerves were divided and the whole brain specimen was removed intact. The entire specimen was then placed in Karnovsky’s solution for a minimum of 72 h to allow the fixation process to continue. After this time, the brain was removed from the Karnovsky’s fixative for further processing. To reduce irritation, caused by the vapors of the fixative during handling, the specimen was rinsed with 0.1 M sodium cacodylate buffer containing 7.5% sucrose. This solution was prepared by the addition of 7.5 g sucrose (Mallinckrodt AR, Paris, KY) to enough 0.1 M sodium cacodylate buffer (Ernest Fullam Inc, Latham, NY) to make 100 mL of solution. The solution was stored in a refrigerator at 4°C before use. A 5 x 5-mm block of tissue was carefully dissected from the medial end of the precentral gyrus of the right cerebral hemisphere in each animal. The block was washed for 20 min, initially in 1 M cacodylate buffer containing 3.4% sucrose and then in a solution of 0.1 M veronyl acetate buffer, which was changed twice. This entire washing process was repeated a further two times. The specimen was then fixed on ice in reduced osmium [1% osmium tetroxide in 1 M cacodylate buffer containing K4Fe (CN)4] for 1 hour. Subsequently, the specimen was fixed for 1 hour in 1% uranyl acetate in veronyl acetate buffer. After a brief wash in water, the specimen was dehydrated in a graded series of ethanols, embedded in Spurr resin (Electron Microscopy Sciences, Fort Washington, PA), and baked at 70°C for several hours. Ultrathin sections were cut on an ultramicrotome (Reichert Ultracut E; Leica, Deerfield, IL) and picked up on 200-mesh copper grids (Electron Microscopy Sciences). A minimum of six grids were prepared with one to two sections per grid. The specimen was then viewed in one of two electron microscopes (EM300; Philips; or 100B JOEL). With blinding to the perfusion protocol, each grid was viewed in its entirety. Regions thought to be most representative of the entire grid were photographed. The EMs that best displayed the relevant features present in the individual study groups were selected for final review.
Experimental protocol and data collection sequence
In the 15 animals undergoing cerebral hemodynamic and metabolic investigation, the data collection was divided into four stages (Fig 1). Prebypass data were collected at 37°C immediately before cannulation for CPB (Pre-CPB). After cannulation and initiation of CPB at 120 mL/kg/min and 37°C, animals were cooled over 20 minutes to a pharyngeal temperature of 18°C, and the first hypothermia data were collected (Pre-DHCA). Animals were then assigned to one of three experimental groups (5 per group). Animals in the control group (CON) were maintained on CPB at 120 mL/kg/min and 18°C without any period of circulatory arrest. A second group of animals (UI-DHCA) received an uninterrupted, 60-minute period of DHCA. A third group (I-DHCA) received intermittent perfusion for 1 minute every 15 minutes at a flow of 50 mL/kg/min during a 60-minute period of DHCA. Upon completion of the respective experimental period, CPB was reinstituted at 120 mL/kg/min and 18°C, and data were collected after stabilization for 10 minutes (Post-DHCA). Animals were then warmed to a pharyngeal temperature of 37°C and weaned from CPB. Measurements were taken immediately after hemodynamic and ventilatory stability was achieved, which was approximately 30 minutes after CPB (Post-CPB). Data collection at each of these stages consisted of pharyngeal temperature, heart rate, blood pressure, cardiac output, arterial and sagittal sinus blood gases, sagittal sinus lactate production, hematocrit, electrolytes, and CBF.
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Statistical analysis
All results are reported as mean ± standard error of the mean and were analyzed by a statistical analysis system (SAS Institute Inc, Cary, NC). An unpaired t test was used to compare variable means between the groups at each time point. A repeated measures analysis of variance was used to compare hemodynamic and blood gas variables between the four measurement time points within each group. When the analysis of variance was significant, multiple paired comparisons were made with the Scheffé F procedure. A paired t test was used to compare data before and after CPB within each group. Analysis of variance was used to compare post-CPB results between groups. Statistical significance was tested at the 95% confidence level.
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Results |
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Comment |
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With cooling to 18°C over 20 minutes, the CMRO2 was reduced by an average of 63%. Therefore, although significantly reduced by cooling to 18°C, cerebral requirements for oxygen still persist at the initiation of DHCA. Clinical data from our institution also demonstrate that CMRO2 in infants remains significant at the time of circulatory arrest [1]. The postbypass value of CMRO2 after a 60-minute period of uninterrupted DHCA was lower than the prebypass values (p < 0.0001). The use of intermittent perfusion during the arrest period, however, significantly improved recovery in CMRO2 after CPB compared with animals undergoing uninterrupted DHCA (p = 0.004). The percentage recovery of CMRO2 with intermittent perfusion was also significantly greater than in the animals undergoing an uninterrupted period of DHCA. Furthermore, there was no difference in the percentage recovery from control animals undergoing hypothermic CPB at 18°C without DHCA.
Data from sagittal sinus blood gas samples obtained immediately before and immediately after the circulatory arrest period demonstrate the possible mechanism of cerebral protection provided by intermittent perfusion. Upon initiation of circulatory arrest, sagittal sinus oxygen saturation averaged 88% for all animals. After 60 minutes of continuous circulatory arrest, sagittal sinus oxygen saturation averaged 16%. With intermittent perfusion, however, sagittal sinus saturation was significantly greater, averaging 55%. This higher sagittal sinus oxygen saturation in combination with the higher pH and a lower lactate production indicate that intermittent perfusion provides metabolic substrates and reduces the ischemia during DHCA.
There is some previous evidence that also suggests that intermittent perfusion reduces the cerebral injury caused by DHCA. Miura and associates [14] demonstrated an improvement in neurobehavioral and histologic outcomes in piglets receiving intermittent blood perfusion during prolonged hypothermic circulatory arrest. The piglets underwent a 100-minute period of DHCA at 15°C, and intermittent perfusion for 5 minutes every 25 minutes at a flow of 50 mL/kg/min with either blood from the pump or a cold asanguineous blood substitute. Cerebral oxygenation was assessed with near infrared spectroscopy. It remained above baseline during the arrest period in the group perfused with pump blood and was significantly higher compared with both the group perfused with blood substitute or a control group with uninterrupted DHCA. In addition, a postoperative daily neurologic evaluation and a neurohistologic score were all better in the group perfused intermittently with pump blood compared with the other groups.
A number of other histologic studies of the brain have been undertaken in the context of CPB, hypothermia, and DHCA, predominantly with the use of light microscopy. Hypothermia during CPB, for example, has been shown to protect against some of the histologic changes that develop during normothermic CPB [15]. After 2 hours of normothermic CPB, changes of cerebral edema with dilatation of the pericapillary space and perivascular swelling of the astrocytic end-feet were observed. These changes were not encountered in the hypothermic (27°C) CPB group. The absence of histologic damage has also been used to try to define a "safe" period of DHCA. The duration of DHCA without histologic injury varies between studies from 30 to 120 minutes [8, 9]. Ultrastructural evidence suggests that the maximum time of DHCA without histopathological or neurophysiologic sequelae should not exceed 70 minutes [16].
Some of the previous histologic studies have included a fairly detailed study of the neurologic damage in different brain regions after DHCA [17]. Less attention, however, has been given to the possibility that ischemia may injure the blood vessels, with impairment of flow and parenchymal damage occurring as secondary changes. The current study demonstrates, for the first time, the cerebral microvascular bed under various conditions of arterial blood gas management, intermittent perfusion, and reperfusion time.
Previous cerebral blood flow and metabolic studies have demonstrated that the greatest regional reduction in flow after DHCA is in the cerebral hemispheres [13, 18]. It was therefore felt that if microvascular abnormalities were detectable by EM, the greatest area of damage was likely to be in the cerebral hemispheres. In addition, the different sulci and gyri of the cerebral hemispheres can be easily identified on surface inspection of the brain, therefore allowing sampling of the same area in each animal. The precentral gyrus, situated immediately anteriorly to the central sulcus, was chosen for ultrastructural examination, as it proved to be both easy to identify and remarkably consistent between specimens.
The ultrastructural findings should be interpreted in the knowledge that only a small number of vessels can realistically be visualized in an EM study and that the changes observed have only been qualitatively assessed. Furthermore, it is not possible to be certain that morphological signs of damage will continue to improve with reperfusion or whether they will deteriorate. More importantly, however, it is unknown what effects the damage would have if the animals were allowed to survive. Bearing this in mind, a number of important findings have emerged.
The studies in the reperfusion group were undertaken in order to try to differentiate between injury caused by ischemia and that related to an increased duration of reperfusion. The damage was maximal immediately after the arrest period. This suggests that the microvascular injury that results from DHCA develops during ischemia and improves with reperfusion. The improvement in ultrastructural appearance of the microvascular bed with reperfusion is consistent with the improvement in CBF seen with increasing time after DHCA [19, 20]. The damage was characterized by perivascular, intracellular, and organelle edema and vascular collapse. Edema in the perivascular glial cells results from a failure of energy-dependent membrane transport mechanisms. As metabolites of anaerobic cellular respiration build up, the tissue osmolarity increases [21] and water is drawn into the ischemic cells by osmosis. The development of perivascular edema may explain the beneficial effects of modified ultrafiltration in improving cerebral metabolism after DHCA [22].
The management of blood gases during the cooling stage before circulatory arrest remains controversial. Although the alpha-stat strategy is used most frequently in clinical practice, there is some evidence that the pH-stat strategy [23, 24] or even a "cross-over" technique [25, 26] would be of greater benefit. Regardless of the blood strategy used, however, the EM findings after uninterrupted DHCA revealed extensive damage. Intermittent perfusion, on the other hand, produced a pattern of normal ultrastructural recovery that was indistinguishable from the control animals that did not have an ischemic insult. The mode of intermittent perfusion in the histologic studies was slightly longer than in the metabolic studies. After the positive outcome with intermittent perfusion in the metabolic studies, it was decided to increase the interval between the periods of intermittent perfusion with the hope of a creating a more clinically practical technique.
In summary, this study has demonstrated that intermittent perfusion during DHCA significantly improves the recovery of cerebral blood flow and metabolism in neonatal piglets. In addition, the EM appearance of the cerebral microvascular bed was normal when intermittent perfusion was used. Intermittent perfusion during DHCA is clinically practical and results in normal cerebral metabolic and ultrastructural recovery. Furthermore, although the brain is the most susceptible organ to an ischemic injury, the use of intermittent perfusion during DHCA may be advantageous to other organs such as the lungs, kidneys, and the gut.
The finding in the current study of improved cerebral microcirculatory ultrastructure when intermittent perfusion is used during DHCA, in conjunction with the findings of improved cerebral metabolism, suggests a correlation between brain structure and CMRO2. As the CMRO2 can be monitored perioperatively using the xenon clearance technique [3], it may be an outstanding way to investigate new strategies for neuroprotection designed to reduce cerebral damage in children undergoing correction of congenital cardiac defects.
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Acknowledgments |
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Footnotes |
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The Hawley H. Seiler Resident Award is presented annually to the resident with the oral presentation and manuscript deemed the best of those submitted for the competition. This Award was inaugurated in 1997 to honor Dr. Seiler for his contributions and dedicated service to the Southern Thoracic Surgical Association. 
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