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J Thorac Cardiovasc Surg 1999;118:1068-1077
© 1999 Mosby, Inc.
SURGERY FOR CONGENITAL HEART DISEASE |
From the Brain Research Laboratory, Joseph Stokes Research Institute, Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia,a and the Department of Anesthesia and Pediatrics,b Department of Pediatrics,c Department of Pathology,d and Department of Neurosurgery,e University of Pennsylvania School of Medicine, Philadelphia, Pa.
Address for reprints: C. Dean Kurth, MD, Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, 34th St & Civic Center Blvd, Philadelphia, PA 19104 (E-mail: kurth{at}email.chop.edu).
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Abstract |
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Introduction |
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1,2 Neurologic sequelae appear to result from global ischemia (circulatory arrest), with cardiopulmonary bypass (CPB), deep hypothermia, hemodilution, postoperative care, and pre-existing disease as contributing factors.
After a global ischemic insult, certain neuronal subpopulations are known to die whereas others do not. 3,4 This phenomenon, referred to as selective vulnerability, occurs in adult and neonatal brain. Neurons in the hippocampus, cerebellum, striatum, amygdala, lateral thalamic nucleus, and third to fifth layers of the neocortex are selectively vulnerable to ischemia in adults. Loss of neurons in these regions is responsible for the impairment of memory, cognition, emotional state, and motor function seen in adults after cardiac arrest. Selective vulnerability appears to differ between adults and neonates and between normothermic and hypothermic ischemia. 3-8
Recent work indicates that some selectively vulnerable neurons in adults and neonates die after ischemia by a process called apoptosis (programmed cell death). 3,9 In apoptosis, cell death is orchestrated, involving the activation of specific genes and enzymes, through which cells neatly commit suicide, breaking up into membrane-packaged bits for removal by resident macrophages. 10,11 Cell death by necrosis, on the other hand, is uncontrolled, involving energy failure, catalysis, and membrane rupture, spilling cellular contents to elicit inflammation and secondary injury. Apoptosis occurs during normal brain development and helps shape brain architecture through the death of specific cell populations during fetal and early postnatal life. 12,13 Apoptosis also plays a role in neuronal cell death after hypoxia-ischemia, brain trauma, and neurodegenerative diseases, although its role relative to necrosis remains unsettled. 3,9-11 In neonates, apoptosis may be favored over necrosis as a cell death process after hypoxia-ischemia. 9 Whether apoptosis plays a role in neuronal cell death after DHCA in neonates is unknown.
In the present study, we sought to characterize brain injury after DHCA in a newborn pig model to determine the selectively vulnerable cell populations and the contribution of apoptosis to cell death.
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Methods |
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Through an incision in the right side of the neck, the carotid artery and external jugular vein were exposed. After intravenous heparin (200 units/kg) was administered, cannulas (Medtronic Bio-Medicus) were advanced to the aorta and right atrium for CPB. The CPB circuit used a bubble oxygenator (Bio-2, Baxter Cardiology), a 40-µm arterial filter (Kol Bio-Medical Instruments), and a nonpulsatile roller pump (RS 7800, Renal Systems) flowing at 100 mL · kg–1 · min. The pump prime contained pig whole blood, heparin 2000 units, fentanyl 50 µg, pancuronium 2 mg, calcium chloride 500 mg, dexamethasone 30 mg, cephazolin 25 mg/kg, and sodium bicarbonate 25 mEq. Electrolyte solution (Plasma-Lyte A, Travenol Laboratory) was added to yield a hematocrit value of 20% to 25% during CPB. Blood gases were managed by alpha-stat principles.
During CPB cooling, the perfusate was kept 5°C to 10°C less than body temperature. At 19°C (brain), DHCA lasting 90 minutes was induced and confirmed by asystole and no arterial pressure. Ice bags were positioned around the head to maintain the brain temperature at 19°C. During CPB reperfusion, arterial perfusate was kept 5°C to 10°C greater than body temperatures, the maximum being 38°C. After 15 minutes’ reperfusion, the heart was defibrillated. When all temperatures were more than 33°C, CPB was stopped, cannulas were removed, protamine 4 mg/kg was injected intravenously, and incisions were closed.
Postoperatively, inspired oxygen concentration and minute ventilation were adjusted to maintain arterial PCO 2 at 35 to 45 mm Hg and arterial PO 2 greater than 75 mm Hg. Dextrose 5% in lactated Ringer solution was infused intravenously (4 mL · kg–1 h–1). When purposeful movements, airway reflexes, and regular breathing had returned, the trachea was extubated. The animals were inspected frequently after DHCA. If they were unable to feed from the trough, bottle feeding or intravenous fluids were initiated.
Experimental protocol
Piglets were randomly assigned to control, surgery, CPB, and DHCA groups. The control group (n = 3) received no intervention (healthy animals put to death for histologic analysis). The surgical group (n = 3) received the surgical preparation without CPB. The CPB group underwent deep hypothermic CPB (n = 3) without DHCA (cooling to deep hypothermia followed by rewarming). Surgery and CPB groups survived 2 days. The DHCA groups survived either 6 hours (n = 6), 2 days (n = 6), or 1 week (n = 6). Physiologic data were recorded before CPB, during deep hypothermic CPB (before DHCA), during warm CPB (after DHCA), and 15 minutes and 2 hours after ending CPB.
Neurologic outcome
A neurologic performance score was performed in the 2-day and 1-week survivor groups. 14 The score consists of a physical examination with points given for specific deficits in level of consciousness (range 0-25), cranial nerve function (range 0-6), sensory function (range 0-14), gait (range 0-25), and behavior (range 0-20). The score is weighted between categories to reflect the components of the neurologic examination and degree of functional disability associated with that category. 14 The scores from each category were summed. The minimum score, 0, represents no deficits (normal examination results), whereas the maximum score, 95, indicates severe damage.
Brain histology
After survival for the designated intervals, piglets were re-anesthetized, given anticoagulants (intravenous heparin 300 units/kg), and put to death (intravenous pentobarbital 100 mg/kg). Chilled saline solution 0.9% (1 L) followed by 4% paraformaldehyde in 0.1 mol/L phosphate-buffered saline solution (1 L, pH 7.4) were infused into the aortic root to fix the brain in situ. The brain was removed in toto, immersed in 4% paraformaldehyde, and stored at 4°C in phosphate-buffered saline solution. After a superficial cut was made along the undersurface of the right hemi-brain to identify it from the left, the whole brain was cut coronally into 5-mm blocks. The tissue blocks were dehydrated in ethanol and xylene (Citadel 2000, Shandon-Lipshaw) and embedded in paraffin (Histoembedder 1160, Leica). Two 8-µm sections cut from each tissue block (Microtome 2155, Leica) were mounted onto slides. One section was stained with hematoxylin and eosin to characterize cell damage; the other section was prepared for terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end labeling (TUNEL) to detect in situ DNA fragmentation. The TUNEL assay was performed as described. 15 Each assay included positive and negative control slides (mouse breast tissue (Oncor) and brain tissue without the terminal deoxynucleotidyl transferase, respectively).
Histologic outcome
All slides were scored by a neuropathologist blinded to the experimental group. Brain regions evaluated included the neocortex, hippocampus, striatum (caudate-putamen), thalamus, amygdala, cerebellum, and brain stem (pons and medulla), chosen for their known vulnerability to hypoxia-ischemia. Cell damage was categorized as either necrotic or apoptotic according to classic morphologic criteria. 16 Although these criteria are not absolute indicators of the cell death process, they serve as a useful first step to elucidate it. Further, these categories are not always mutually exclusive and may not represent the only possible modes of cell death. Apoptotic cells were defined by the presence of nuclear karyorrhexis (fragmented, rounded, dense chromatin) and minimal cytoplasmic change, whereas necrotic cells were identified by a pyknotic nucleus or no nucleus (ghost neuron) along with a swollen, eosinophilic cytoplasm. In addition to nuclear and cytoplasmic changes, sections were evaluated for inflammation, hemorrhage, and infarction. TUNEL(+) cells were identified by a red-stained, condensed nucleus with apoptotic bodies, along with a diminutive or absent cytoplasm.
To describe the extent of damage and apoptosis among the brain regions, we used a semiquantitative score. On each slide, the regions were scored on a scale of 0 to 4. Hematoxylin-eosin slides were scored as follows: 0 = normal neuronal structure; 1 = rare clusters (<5) of damaged neurons; 2 = occasional clusters (5-15) of damaged neurons; 3 = frequent clusters (>15) of damaged neurons; and 4 = diffusely distributed damaged neurons. The corresponding scores for the TUNEL slides were as follows: 0 = no TUNEL(+) apoptotic cells; 1 = rare clusters of TUNEL(+) apoptotic cells; 2 = occasional clusters of TUNEL(+) apoptotic cells; 3 = frequent clusters of TUNEL(+) apoptotic cells; and 4 = diffusely distributed TUNEL(+) apoptotic cells. Histopathologic and TUNEL scores were the average among of the slides: neocortex (7 slides), hippocampus (2 slides), striatum (2 slides), thalamus (2 slides), amygdala (1 slide), cerebellum (2 slides), and brain stem (2 slides).
To assess the density of damaged and apoptotic neurons in a cluster, we estimated the percentage of damaged and TUNEL(+) cells in afflicted areas of the neocortex and hippocampus. Four 2.5-mm2 areas containing damaged or TUNEL(+) neurons were selected in each region. The number of damaged, TUNEL(+), and normal-appearing neurons were counted in the neocortex (from the surface of the gray matter down to the border with the white matter) and in the hippocampus (along the CA1 sector).
Statistical analysis
Data are presented as mean ± SD. Comparisons among groups were made by analysis of variance (ANOVA) for continuous variables or Kruskal-Wallis ANOVA for discontinuous variables. When a significant overall F was found, pairwise multiple comparisons were made with the use of the Tukey or Mann-Whitney test. Pearson correlation coefficients were calculated between neurologic outcome variables (eg, histopathologic score) and perioperative variables (eg, arterial pressure). Multivariable regression was explored between neurologic outcome variables and perioperative variables having correlation coefficients, with .01 level of significance to adjust for the multiple correlation tests.
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, C ). In the fascia dentata, damaged neurons were mainly apoptotic.
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, A ). Outside of the clusters, TUNEL(+) cells were rarely seen. Within a cluster, TUNEL(+) cells were located mainly in superficial gray matter, interspersed among normal neurons. In the hippocampus, TUNEL(+) cells were also seen (Fig 3, B ).
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Discussion |
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In animal models of global ischemia, age and temperature have been shown to influence which cell populations die. 3-8,17 Vulnerable cell populations in adult normothermic ischemia include neurons in the hippocampus, cerebellum, striatum, thalamas, amygdala, and neocortex (third to fifth layers). 3,6 Glia, endothelium, and smooth muscle are relatively resistant to death, as are neurons in other regions. By comparison, neurons in the striatum and neocortex (second and third layers) were vulnerable in newborn normothermic ischemia. 4 Hypothermia does not appear to confer protection equally to all neuronal populations. For example, after hypothermic global ischemia, thalamus, hippocampus, and striatum continued to be damaged even though the other vulnerable regions were protected. 4,17 Although the mechanism of selective vulnerability is not fully understood, the metabolic makeup, trophic factor availability, and synaptic connectivity of the cells in the region appear to play a role.
During normal brain development, neurons in certain regions (eg, the neocortex) are also known to selectively die by a process called apoptosis. 12,13 Apoptosis uses endogenous suicide programs. Certain factors (eg, cytokines, glutamate) activate these programs, which result in a characteristic cell degeneration, in which the cell breaks up into membrane-bound bits, which are engulfed by resident macrophages. 10,11 Consequently, apoptosis lacks the inflammation and secondary tissue damage of necrosis. Several of the pro-apoptotic and anti-apoptotic factors also play a role in cellular proliferation. 10,12 It is not uncommon to see cell division and apoptosis simultaneously in the same region.
Apoptosis has also been found to play a role in neuronal death after ischemia and other neurologic diseases. 3,9-11,15,18,19 Evidence for apoptosis in ischemia includes damaged neurons with apoptotic structure and TUNEL positivity, as well as caspase activity and pro-apoptotic and anti-apototic factor expression in the damaged region. More convincing is the neuroprotection afforded by caspase inhibitors or in animals genetically deficient in caspases. 9,18,19
Previous work described apoptosis in adult and neonatal models of global ischemia. 3,9 In these models, apoptotic neuronal death began within hours of reperfusion and continued for several days. The contribution of apoptosis to ischemic cell death varied with brain region and severity of the insult, being prominent in the neocortex and hippocampus after mild to moderate ischemia. 3,10 In our study, apoptosis displayed a time course and regionality similar to these models, suggesting that anti-apoptotic drugs should be examined for neuroprotection in relation to DHCA.
Morphologic and biochemical criteria distinguish apoptosis from necrosis. 10,16 A hallmark of apoptosis is DNA fragmentation into ordered oligonucleosomes with 3'-OH end groups, detectable with in situ labeling (eg, TUNEL). This method, however, is not completely sensitive or specific, as it is possible to see apoptotic cells without TUNEL labeling and necrotic cells with TUNEL labeling. 10,16,20 Moreover, apoptosis and necrosis are not always mutually exclusive processes in ischemia; both may be active in a dying cell. 10,16,20 In our study, the combination of morphology, TUNEL labeling, mitotic figures, and lack of inflammation indicates apoptosis as a process by which many neurons in the neocortex and hippocampus die after DHCA.
The temporal pattern of brain damage and apoptosis after DHCA merits comment. We observed histologic cell death, TUNEL labeling, and apoptosis early (6 hours) in both the neocortex and hippocampus. This rapid cell death is consistent with cell suicide programs, which can kill a cell in 2 to 3 hours. 12,13 Although TUNEL labeling was maximal early, we also observed TUNEL labeling and apoptotic cell death for days after DHCA. This may indicate the continued presence of programmed cell death activators, some programs working slowly, or attempts at repairing injured neurons that were later aborted (then activating apoptosis). We also noted more apoptosis in the neocortex than hippocampus, perhaps indicating different suicide programs or activators to the programs in these regions.
The perioperative factors associated with the DHCA damage provide clues to the mechanism of the injury. Increased arterial pressure, PO 2, and hematocrit value during CPB rewarming and after CPB were associated with improved neurologic outcome, suggesting that local tissue hypoxia during reperfusion may contribute to damage. The role of glucose was conflicting between the neocortex and hippocampus, as increased glucose worsened damage to the former and ameliorated it to the latter. The effect of glucose on ischemic brain damage in neonates is conflicting, 21-23 in contrast to adults, in whom glucose consistently aggravates ischemic brain damage. 24 Brain temperature heterogeneity did not contribute to brain injury as brain temperature gradients are less than 1°C during DHCA in our model. 25
Our results differ from previous work in developing animal models of DHCA. 7,8 The predominant lesion in the 1-month-old pig was selective neuronal necrosis and infarction in the cerebellum, striatum, and neocortex. 8 This difference from our study may reflect brain maturity responses to DHCA between 1-month-old and newborn pigs. The main lesion in the newborn dog was selective neuronal necrosis in the deep neocortex and striatum. 7 This difference from our study may reflect the DHCA models, as the newborn dog study did not use CPB. DHCA without CPB might contain a component of incomplete ischemia during reperfusion, damaging the watershed regions (eg, deep neocortex).
Our model differs from DHCA used in clinical practice. The advantages of our closed-chest CPB model for research include no bleeding, pulmonary dysfunction, or physical disability from surgery, simplifying postoperative care and neurologic assessment. The bubble oxygenator requires less prime volume, given the requirement of blood prime in the newborn pig. The advantage of 90 minutes’ DHCA for research is the consistency of brain damage, minimizing the number of study animals. The distribution of apoptosis and necrosis with varying DHCA durations warrants study, as DHCA in clinical practice is usually briefer. Our model’s disadvantage is the possibility of carotid artery ligation and gaseous emboli contributing to the brain damage. Several observations argue against this possibility. First, ligation of one carotid artery in piglets has no effect on cerebral blood flow during normal or hypoxic-ischemic conditions. 26 Second, the ischemic lesions were not consistent with unilateral carotid artery ligation or emboli because of the symmetry of injury between the hemi-brains, selectivity of cells injured, and lack of injury in the CPB group.
Despite improved surgical results in neonates over the past decade, neurologic sequelae continue to occur. 1,2 Most neuroprotective strategies have been directed intraoperatively to prevent necrotic cell death. Our findings implicate another cell death pathway, apoptosis, suggesting another target for neuroprotective strategies.
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