Immediate-early gene expression in ovine brain after hypothermic circulatory arrest: effects of aptiganel.

BACKGROUND: Altered gene expression occurs in the brain after global ischemia. We have developed a model to examine the effects of cardiopulmonary bypass and hypothermic circulatory arrest (HCA) on the induction of the immediate-early gene c-fos in the brains of neonatal lambs. We then tested the effects of the noncompetitive N-methyl-D-aspartate antagonist, aptiganel hydrochloride (Cerestat), on c-fos expression and neuronal injury. METHODS: Neonatal lambs (weight, 4 to 6 kg) anesthetized with isoflurane were supported by cardiopulmonary bypass, subjected to 90 or 120 minutes of HCA at 15 degrees C, and rewarmed on bypass to 38 degrees C. One hour after cardiopulmonary bypass was terminated, the brains were perfusion fixed and removed for in situ hybridization and immunohistochemical analysis. Some animals survived 3 days before their brains were removed to examine for neuronal necrosis. One group of lambs (n = 20) received aptiganel (2.5 mg/kg). A second group (n = 25) received saline vehicle only. RESULTS: Increasing duration of HCA induced a corresponding increase in c-fos messenger RNA expression throughout the hippocampal formation and cortex. However, Fos protein synthesis peaked after 90 minutes of HCA and decreased significantly (p < 0.01) after 120 minutes of HCA. Aptiganel administration caused a significant decrease in (p < 0.001) c-fos messenger RNA expression and Fos protein synthesis after 90 minutes of HCA and preserved Fos protein synthesis after 120 minutes of HCA. Neuronal necrosis was observed in the brains of vehicle-treated lambs after 120 minutes of HCA but was significantly decreased (p < 0.05) in the lambs given aptiganel. CONCLUSIONS: These experiments indicate that the transcriptional processes of immediate-early genes remain intact, whereas translational processes are impaired after prolonged HCA. The inability to synthesize Fos proteins after 120 minutes of HCA was associated with neuronal degeneration. Aptiganel preserved translational processes and caused a significant improvement in the neurologic outcome.

Pneumostasis of experimental air leaks with a new photopolymerized synthetic tissue sealant.

Air leak is a major contributor to increased length of stay and postoperative morbidity following pulmonary surgery. The effectiveness of a new photopolymerized synthetic hydrogel (FocalSeal, Focal, Inc., Lexington, MA) as a sealant for pulmonary air leaks was determined in 10 mongrel dogs (20-35 kg). The animals were anesthetized and underwent left-sided anterolateral thoracotomy with amputation of a 2 x 3-cm segment of the lung apex. Hemostasis was achieved and terminal bronchial openings of 1.5 to 3 mm with vigorous air leaks were identified. After successful injury, the dogs were randomly assigned to sealant (n = 5) or control (n = 5) groups. In treated animals, the sealant was applied by brushing the solution to the cut parenchymal surface and solidified while briefly interrupting ventilation (40-60 seconds) using visible illumination (450-550 nm) from a xenon light source. Controls received no sealant. A single chest tube was maintained at the injury site with a continuous negative pressure of 20 cm of water. All dogs were extubated and allowed to breathe spontaneously under sedation for 24 hours. Chest radiographs were taken postsurgery and presacrifice. All control animals (n = 5) showed persistent vigorous air leak for the duration of the 24-hour observation period. All treated air leaks resolved immediately, and four of five remained sealed throughout the observation period. One leak reappeared after 17 hours due to inadequate sealant thickness over a 3-mm terminal bronchus. Gross evaluation of the treatment group at the end of 24 hours demonstrated intact sealant well adherent to the parenchyma. No evidence of atelectasis or excessive edema was seen, and no sealant-related complications or toxic effects were noted. Radiologically, lungs were fully inflated. Histologic evaluation at 24 hours revealed no evidence of a strong cellular response to the synthetic sealant, and no fibrosis or adhesions were seen, the onset of the healing process was favorable, indicating good biocompatability. In conclusion, this material was found to be an effective means for sealing bronchial and parenchymal air leaks in this model and warrants clinical evaluation.

Coronary artery bypass and valve replacement in octogenarians.

A total of 325 patients, aged 80 to 92 (mean 82), underwent cardiac operations with cardiopulmonary bypass over a 4-year period (1991-1995). Hypothermia (22 degrees C) and hyperkalemic cardioplegia were used in each. Coronary bypass procedures only (Group I) were performed in 255 patients with 22 early deaths (8.6%), and the average number of grafts was 3.7 per patient. Single or double valve replacement, with coronary bypass (Group II) was performed in 46 patients, with six early deaths (13%). Single or double valve replacement, without coronary bypass (Group III) was performed in 24 patients, with two early deaths (8.3%). Total hospital mortality was 30 deaths in 325 patients (9.2%). Fifty-six procedures (22%) from Group I and four (9%) from Group II were performed as emergencies, and all operations in Group III were elective. Seventy-two patients (27%) from Group I, 18 patients (39%) from Group II, and nine patients (37%) from Group III had major complications including renal failure, cerebrovascular accident, myocardial infarction, postoperative hemorrhage, sepsis, and ventilatory dependency. Mean hospital stay was 10.5 days for Group I, 13.3 days for Group II, and 15.2 days for Group III, with an overall mean of 13 days (range, 6-52) days. Higher mortality was related to a cardiac index <1.8, cardiogenic shock, emergency operation, creatinine >2.0, and morbid obesity. Mean left ventricular ejection fractions were 0.51 for Group I, 0.45 for Group II, and 0.49 for Group III. Preoperative risk factors associated with a higher mortality included hypertension, smoking, diabetes, and pulmonary hypertension. Two hundred seventy-two of the 299 operative survivors were followed for a mean of 18 (range, 3-52) months. The actuarial survival of octogenarians is 92 per cent, 80 per cent, and 65 per cent at 1, 3, and 5 years, respectively, and of the patients surviving operation it was 85 per cent, 70 per cent, and 55 per cent at 1, 3, and 5 years, respectively. At postoperative follow up, 80 per cent of the survivors reported an active functional status, and there was a low incidence of cardiac-related deaths.

Carotid endarterectomy based on preoperative duplex ultrasound.

Recent studies have suggested that carotid endarterectomy can be performed safely based solely on the noninvasive duplex ultrasound evaluation in selected patients. We have prospectively evaluated 60 consecutive patients who underwent 65 carotid endarterectomies, 48 patients without preoperative angiography and 12 with angiography. Forty-two patients were operated on for symptomatic disease, and 23 procedures were done for critical, asymptomatic stenoses. Long term followup consisted of physical examination and serial duplex scans every 3-6 months postoperatively over a mean followup period of 2.4 years. Clinical management indicated by duplex ultrasound was altered in only one of the 12 patients who had preoperative angiography, a change in the timing of the endarterectomy in a symptomatic patient with an ulcerated lesion seen at angiography. At operation the severity of disease predicted by duplex ultrasound was confirmed in all cases (100 per cent sensitivity), including one > 80% diameter stenosis interpreted by angiography as occluded; no unsuspected anatomic anomalies were found at surgery. The duplex scan also correlated well with intraoperative findings of surface ulceration and gross intraplaque hemorrhage. There was one intraoperative stroke with good recovery in a patient with preoperative angiography; and there were no deaths, for a combined morbidity and mortality of 1.6 per cent. During long term followup, 97 per cent of patients have remained symptom-free. We conclude that clinical assessment with a preoperative duplex ultrasound scan of good technical quality and interpreted in collaboration with the vascular surgeon provides appropriate information on which to base carotid endarterectomy and allows a safe alternative to the routine use of preoperative angiography.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of outcome following open lung biopsy.

The utility of open lung biopsy in the management of patients with acute pulmonary infiltrates and/or progressive respiratory failure remains controversial, particularly in regard to its timing and impact on therapy. We reviewed our most recent 10-year experience with open lung biopsies in 73 patients and evaluated its effect on patient management and outcome. A total of 62 biopsies were done for progressive infiltrating disease, 53 with diffuse bilateral disease, and 9 with more focal infiltrates; 11 biopsies were done for nodular disease. Overall mortality was 25 per cent (18/73), all from the group with infiltrates; there were no deaths in patients with nodular disease (P = 0.034). No patients died who did not have acute respiratory failure (ARF) preoperatively, but mortality was 38 per cent (18/47) in those with ARF (P < 0.001). Immune system status and timing of the biopsy did not affect survival. Clinical management was changed in 40 patients based on biopsy results, but this did not affect survival, with a mortality rate of 20 per cent (8/40) in the group with changed management versus 30 per cent (10/33) for those with no changes (P = 0.457). In those patients with ARF, changes in management based on biopsy results occurred in 31 patients, eight of whom died (26 per cent); no changes in management were made in 16 patients, ten of whom died (62%, P = 0.033).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of intraosseous infusion on the growth plate in a nestling rabbit model.

STUDY OBJECTIVE: The objective of this study was to test the hypothesis that saline or bicarbonate infusion does not damage the growth plate in a nestling rabbit model. SETTING: Animal laboratory. DESIGN: In this prospective study, 22 tibias from nestling rabbits were randomized into control, puncture-only, physiologic saline, or bicarbonate infusion groups and killed three and five days after treatment for evaluation of injury. MEASUREMENTS: Bone injury was evaluated by microradiograph and by decalcified and undecalcified histology. RESULTS: Radiographs demonstrated loss of trabecular (ie, calcified) bone after infusion of both saline and bicarbonate solutions. Although no histologic damage to the cell lines of the growth plate was seen, newly formed bone trabeculae were seen in both infusion groups, suggesting injury and repair at sites of infusion. These findings were absent in control and puncture-only groups. No histologic or radiographic differences were seen between saline and bicarbonate infusions. CONCLUSION: The nestling rabbit provides a good animal model for evaluating the effects of intraosseous infusion on growing long bones and cartilage. Saline and bicarbonate infusions did not damage morphologically the metaphyseal growth plate but did cause loss of bone trabeculae that support the growth plate. The injury appeared to be repaired rapidly in these nestling rabbits.