Hemoptysis from bronchial varices associated with pulmonary vein stenosis: role of surgical repair.

We present the case of a 6-year-old child who presented with an episode of life threatening hemoptysis. Investigations revealed multiple areas of endobronchial varices and abnormal pleural vessels as well as severe left pulmonary vein stenosis and an atrial septal defect (ASD). After extensive work up and consultation he underwent repair of the left pulmonary vein using a sutureless technique and ASD closure. This resulted in a marked improvement in the appearances of the left lung. The bronchial varices in the right lung remain unchanged. No further hemoptysis has occurred and the child continues to be monitored.

Favorable effect of immunomodulator therapy on bone mineral density in multiple sclerosis.

BACKGROUND: Osteoporosis is a complication of multiple sclerosis (MS), especially if corticosteroid therapy is given. Little is known about the effect on bone of immunomodulatory therapy (IMT) for MS. AIM: We sought to evaluate bone mass in patients with MS on IMT. METHODS: We measured bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) in 37 patients with MS who received IMT. Different IMTs were administered: interferon beta-1a in 70%, interferon beta-1b in 27% and Glatiramer in 3%. High-dose pulse corticosteroid therapy (intravenous methylprednisolone 500 mg) was given to 81% ranging from 1 to 17 courses. RESULTS: Both mean BMD Z-score at spine of 0.53 (CI, 0.15-0.92; P = 0.0084) and mean BMD Z-score at femur of 0.72 (CI, 0.42-1.01; P < 0.0001) were significantly greater than zero. CONCLUSIONS: IMT may have a favorable effect on bone in patients with MS even in the presence of pulse steroid therapy.

Understanding the inflammatory response to cardiac surgery.

The systemic inflammatory response to cardiac surgery is common, and resultant impairment of multiple organ function is generally mild or subclinical due to physiological reserve within organ systems. Unfortunately, the changing profile of patients referred for surgery suggests that the systemic inflammatory response may prominently influence surgical outcome in the future. Older, co-morbid patients with more limited physiological reserve are being referred for complex lengthy procedures, and paediatric surgery has witnessed a shift to earlier complex primary correction or palliation involving long cardiopulmonary bypass times or a period of suboptimal organ perfusion using circulatory arrest or low flow cardiopulmonary bypass. Unique to cardiac surgery is the predictability of the inflammatory response, but prophylactic therapies have not translated into clinical benefit, which the preconditioning phenomenon may address.

Myocardial protection using an omega-3 fatty acid infusion: quantification and mechanism of action.

OBJECTIVES: Omega-3 fatty acids exhibit anti-inflammatory, antithrombotic, and antiarrhythmic properties. We investigated the extent and underlying mechanism of protection conferred by a pre-emptive omega-3 infusion in a model of regional cardiac ischemia-reperfusion injury. METHODS: New-Zealand White rabbits received either the omega-3 infusion or a control infusion of 0.9% saline (n = 14 in each group). The large marginal branch of the left coronary artery was occluded for 30 minutes, cardiac function was assessed during 3 hours of reperfusion, and infarct size was measured. Pretreatment-induced alterations in myocardial membrane fatty acid composition and intramyocardial heat shock protein 72 were additionally assessed (n = 5 in each group). Serum markers of myocardial membrane oxidative stress, malonaldehyde and 8-isoprostane, were also determined. Results are expressed as means +/- standard error of the mean and significance was tested with analysis of variance. RESULTS: Pretreatment increased myocardial membrane omega-3 fatty acid content 5-fold, from 0.94% +/- 0.07% in controls to 5.38% +/- 0.44% in the omega-3 group (P < .01), and it produced a 225% elevation of levels of heat shock protein 72 (P = .019) before ischemia-reperfusion. This was associated with a 40% reduction in infarct size (P < .01). Whereas the reperfusion-induced rise in malonaldehyde levels was higher with omega-3 pretreatment, 10.2 +/-1.5 micromol/L versus 6.1 +/- 0.7 micromol/L in controls (P = .04), 8-isoprostanes showed a 9-fold reduction, 679 +/- 190 pg/mL in controls vs 74 +/- 45 pg/mL in the omega-3 group (P = .0077). CONCLUSIONS: A pre-emptive omega-3 infusion significantly reduces infarct size through the dual mechanisms of upregulation of heat shock protein 72, a key preconditioning protein, and a dramatic increase in the omega-3 content of myocardial membranes, which appears to facilitate a shift in oxidant ischemia-reperfusion injury. Further study to optimally shorten the pretreatment regimen for this potentially acceptable infusion will now be pursued.

Pharmacologically induced preconditioning with diazoxide: a novel approach to brain protection.

BACKGROUND: Ischemic preconditioning is an endogenous mechanism whereby brief periods of ischemia render neurons resistant to subsequent lethal insults. This protection appears to alter cellular apoptosis and can be induced by potassium channel openers acting on the inner membrane of the mitochondria (mitoK(ATP)). To test the hypothesis that pharmacologic preconditioning could provide neuroprotection, the mitoK(ATP) opener diazoxide was used in a canine model of brain injury induced by hypothermic circulatory arrest (HCA). METHODS: Seventeen dogs were placed on cardiopulmonary bypass (CPB) and cooled to 18 degrees C. After 2 hours of HCA, animals were rewarmed and weaned from CPB. Six dogs received intravenous diazoxide (2.5 mg/kg bolus 15 minutes prior to CPB, then 0.5 mg/min until circulatory arrest, then restarted for the first hour of rewarming). Six animals received vehicle only. Five received diazoxide and the mitoK(ATP) blocker 5-hydroxydecanoate (5-HD). Using a modified Pittsburgh Canine Neurological Scoring System (0 = normal, 500 = brain death), animals were evaluated every 24 hours for 3 days. The brains were removed and histologic sections of four regions characteristically injured in this model were scored (0 = no injury, 4 = infarction) by a neuropathologist in a blinded fashion. RESULTS: Clinical scoring showed marked improvement in the diazoxide group at 48 hours (101 +/- 10.5 vs 165 +/- 14.8, p < 0.01) and 72 hours (54 +/- 9.3 vs 137 +/- 12.1, p < 0.01). This neuroprotection was attenuated when 5-HD was concomitantly administered. Three of four brain regions typically injured in this model (cortex, hippocampus, and entorhinal cortex) had significant neuron preservation in the diazoxide group. Likewise, combined region scores were significantly improved in the treatment group (1.18 +/- 0.2 vs 2.46 +/- 0.2, p < 0.01). CONCLUSIONS: Pretreatment with diazoxide resulted in significant improvement in both clinical neurologic scores and histopathology in our model of HCA. This suggests that pharmacologic preconditioning with the mitoK(ATP) channel opener diazoxide may offer effective neuroprotection during HCA.

Chronic toxicity and oncogenicity studies of ingested 1, 3-dichloropropene in rats and mice.

Fischer 344 rats and B6C3F1 mice were administered 1, 3-dichloropropene (1,3-D) via their diets for up to 2 years, at dose levels of 0, 2.5, 12.5, or 25 mg 1,3-D/kg body wt/day for rats and 0, 2.5, 25, or 50 mg 1,3-D/kg body wt/day for mice. The test material was stabilized in the feed by microencapsulation in a starch/sucrose matrix (80/20%). Rats given 12.5 or 25 mg/kg/day, and mice given 25 or 50 mg/kg/day, had decreased body weights and body weight gains. There were no effects on survival or clinical pathology parameters for rats or mice. Histopathologic effects attributed to treatment in rats consisted of basal cell hyperplasia of the nonglandular mucosa of the stomach in males and females given 12.5 or 25 mg/kg/day for 12 and 24 months and an increased number of hepatocellular adenomas in males given 12.5 or 25 mg/kg/day and females given 25 mg/kg/day for 24 months. The increase in hepatocellular adenomas was statistically identified by pairwise comparison only in males given 25 mg/kg/day. An increased incidence of eosinophilic foci of altered cells in the liver was also noted in all treated groups of rats at 24 months. The latter observation, however, was considered of equivocal toxicological significance because of the common spontaneous occurrence of liver foci in aged Fischer 344 rats. The only histologic change attributed to treatment in mice was decreased size of hepatocytes in males given 50 mg/kg/day for 12 months. The decreased size of hepatocytes was consistent with decreased cytoplasmic glycogen content and corresponded to decreased liver weights. This effect was not present at 24 months. There was no oncogenic response observed in mice. The low-dose level of 2.5 mg/kg/day was interpreted as the no-observed-adverse-effect level (NOAEL) for systemic chronic toxicity of 1,3-D in the Fischer 344 rat. The no-observed-effect level (NOEL) for chronic systemic toxicity was 2.5 mg/kg/day in the B6C3F1 mouse.

Hypothermic circulatory arrest in octogenarians: risk of stroke and mortality.

BACKGROUND: The proportion of patients in their ninth decade of life undergoing complex cardiovascular procedures has increased over the past decade. The purpose of this study is to quantify the potential for stroke and mortality associated with deep hypothermic circulatory arrest (DHCA) in this age group. METHODS: At our institution, 251 adult patients had cardiovascular procedures that required DHCA since 1989. This included 20 patients 80 years of age or older (group I) and 231 patients less than 80 years (group II). Additionally, we analyzed 632 patients 80 years of age or older who underwent a variety of cardiovascular procedures since 1989 that required cardiopulmonary bypass but not DHCA (group III). Neurologic outcomes have been maintained in our database prospectively since 1991. RESULTS: The 30-day mortality in group I was 5%, in group II 15.2%, and in group III 8.2%. The stroke rate was 20% in group I, 8.8% in group II, and 6.5% in group III. CONCLUSIONS: DHCA can be performed with acceptable early mortality in patients in their ninth decade of life, but they are at an increased risk of stroke. Follow-up shows satisfactory late survival.

Operative management of Marfan syndrome: The Johns Hopkins experience.

BACKGROUND: Doctor Antoine Marfan described the first case of Marfan syndrome in 1896. It was over 50 years later that the development of aortic aneurysms and subsequent rupture was appreciated as the most life-threatening component of the syndrome. METHODS: Doctor Vincent Gott, at our institution, performed the first Bentall procedure for an aneurysm of the ascending aorta in 1976. Since that time, the aortic root has been replaced in 231 Marfan patients. Of this group, 218 patients had a composite graft repair, 11 had an aortic root replacement with a homograft, and 2 patients had valve sparing procedures. There were 168 males and 63 females. Of the total 231 patients, 150 were operated on by Dr Gott. The remaining 81 patients were operated on by 10 other Hopkins surgeons. The average diameter of the ascending aorta was 6.8 cm, with a range from 4.5 to 10. The average aortic diameter of 43 patients who had an ascending aortic dissection was 7.3 cm. Fourteen of these patients had dissection with an aortic diameter of 6.5 cm or less. RESULTS: Among the 198 patients who underwent elective repair, there was no 30-day mortality. Thirty-three patients underwent urgent repair with 2 deaths, yielding a 30-day mortality of 6.1%. The mortality for the entire group of patients was 0.9%. Complications associated with this series of patients included 8 with endocarditis, 7 with thromboembolism, and 4 late coronary dehiscences. Actuarial survival was 88% at 5 years, 81% at 10 years, and 75% at 20 years. Multivariate analysis revealed New York Heart Association classification, male gender and urgent surgery as independent risk factors for mortality. CONCLUSION: Marfan patients with aortic aneurysms can undergo elective surgery with a low operative risk and excellent long-term survival with low morbidity. We feel that elective resection of an aneurysm in a Marfan patient should occur when it approaches a diameter of 5.5 cm. It is essential that a timely diagnosis be made in this group of young patients.

Assessing the impact of cerebral injury after cardiac surgery: will determining the mechanism reduce this injury?

BACKGROUND: Central nervous system dysfunction continues to produce significant morbidity and associated mortality in patients undergoing cardiac surgery. Using a closed-chest canine cardiopulmonary bypass model, dogs underwent 2 h of hypothermic circulatory arrest (HCA) at 18 degrees C, followed by resuscitation and recovery for 3 days. Animals were assessed functionally by a species-specific behavioral scale, histologically for patterns of selective neuronal necrosis, biochemically by analysis of microdialysis effluent, and by receptor autoradiography for N-methyl-D-aspartate (NMDA) glutamate receptor subtype expression. RESULTS: Using a selective NMDA (glutamate) receptor antagonist (MK801) and an AMPA antagonist (NBQX), glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. A microdialysis technique was employed to evaluate the role of nitric oxide (NO) in neuronal cell death. Arginine plus oxygen is converted to NO plus citrulline (CIT) by the action of NO synthase (nNOS). CIT recovery in the cerebrospinal fluid and from canine cortical homogenates increased during HCA and reperfusion. These studies demonstrated that neurotoxicity after HCA involves a significant and early induction of nNOS expression, and neuronal processes leading to widespread augmentation of NO production in the brain. To further investigate the production of excitatory amino acids in the brain, we hypothesized the following scenario: HCA--> increased glutamate, increased aspartate, increased glycine--> increased intracellular Ca2+--> increased NO + CIT. Using the same animal preparation, we demonstrated that HCA caused increased intracerebral glutamate and aspartate that persists up to 20 h post-HCA. HCA also resulted in CIT (NO) production, causing a continued and delayed neurologic injury. Confirmatory evidence of the role of NO was demonstrated by a further experiment using a specific nNOS inhibitor, 7-nitroindazole. Animals underwent 2 h of HCA, and then were evaluated both physiologically and for NO production. 7-Nitroindazole reduced CIT (NO) production by 58.4 +/- 28.3%. In addition, dogs treated with this drug had superior neurologic function compared with untreated HCA controls. CONCLUSIONS: These experiments have documented the role of glutamate excitotoxicity in neurologic injury and have implicated NO as a significant neurotoxin causing necrosis and apoptosis. Continued research into the pathophysiologic mechanisms involved in cerebral injury will eventually yield a safe and reliable neuroprotectant strategy. Specific interventional agents will include glutamate receptor antagonists and specific neuronal NO synthase inhibitors.

Clinical markers in CSF for determining neurologic deficits after thoracoabdominal aortic aneurysm repairs.

BACKGROUND: Spinal cord ischemia is a major cause of morbidity and mortality after thoracoabdominal aortic aneurysm operations. The incidence of paraplegia is high even in experienced institutions. METHODS: We investigated whether neurotransmitter excitotoxicity is associated with neurologic deficits after thoracoabdominal aortic aneurysm operations. We hypothesized that patients with spinal cord injury would manifest elevated levels of excitatory amino acids in their cerebrospinal fluid. Sixteen patients undergoing thoracoabdominal aortic aneurysm operations had cerebrospinal fluid drawn through lumbar spinal drains preoperatively, intraoperatively, and postoperatively. Excitatory amino acid levels (glutamate, aspartate, glycine) were measured using high-performance liquid chromatography. Excitatory amino acid levels were compared in patients who exhibited no neurologic deficits postoperatively (group I; n = 12) with patients who had clinically evident lower extremity and cerebral neurologic deficits (group II; n = 4). RESULTS: Significant elevations in glutamate and aspartate levels from baseline (p < 0.05) were limited to group II. Excitatory amino acid levels in group II were significantly elevated (p < 0.05) compared with those observed in group I. Glutamate levels were especially increased during aortic cross-clamping and late reperfusion, whereas aspartate levels were increased only during late reperfusion. CONCLUSIONS: These data suggest that neurotransmitter excitotoxicity plays a significant role in central nervous system injury.

Cardiac operations in children with Marfan's syndrome: indications and results.

BACKGROUND: The development of new screening techniques for the early detection of Marfan's syndrome has prompted evaluation of the results of cardiac operations in children with this syndrome. The purpose of this study was to determine the surgical indications, operative results, and need for reoperation in children with Marfan's syndrome. METHODS: From 1980 to 1996, 245 patients underwent cardiac operations for complications of Marfan's syndrome; 26 (11%) were less than 18 years of age. The mean age at the time of operation was 10.3 +/- 1 years (range, 8 months to 17 years); 18 of the patients were male. Indications for operation were aortic root dilatation (15 patients), mitral regurgitation (4 patients), aortic root dilatation and mitral regurgitation (6 patients), and aortic arch aneurysm (1 patient). Operations included aortic root replacement (15 patients), aortic root replacement and mitral repair (5 patients), aortic root replacement and mitral replacement (1 patient), mitral repair (3 patients), mitral replacement (1 patient), and arch aneurysm repair (1 patient). The mean aortic root diameter in patients undergoing aortic root replacement was 6.2 +/- 0.2 cm. Only 1 patient underwent ascending aortic dissection. RESULTS. There were no operative deaths. At a mean follow-up of 67.1 +/- 10.2 months, 8 patients required a second cardiac procedure (41% +/- 17% 10-year freedom from reoperation). Indications for further operations were distal aortic pathology (3 patients), aortic root dilatation after initial mitral operation (3 patients), failed mitral repair (1 patient), and homograft degeneration (1 patient). Risk factors for a second cardiac procedure were age less than 10 years at the time of the first operation (p < 0.003) and mitral regurgitation (p < 0.04). Overall, 25 (96%) of 26 patients have undergone aortic root replacement and 11 (42%) patients have undergone a mitral procedure. There have been 4 late deaths, all of presumed cardiac origin. The 10-year survival rate is 79% +/- 10%. All surviving patients are in New York Heart Association functional class I or II. CONCLUSIONS: We conclude that (1) aortic root dilatation is the most common surgical indication in children with Marfan's syndrome, (2) mitral regurgitation is the second most common indication, (3) aortic dissection is unusual in children with Marfan's syndrome, and (4) careful follow-up is necessary, particularly in younger children, because more than half of all children with Marfan's syndrome require repeated cardiac operations within 10 years.

Intermediate results of the extracardiac Fontan procedure.

BACKGROUND: Fourteen children (ages 2 to 14 years) and 1 adult (32 years) have undergone a modification of the Fontan procedure in which an extracardiac lateral tunnel or conduit is used in combination with staged or simultaneous bidirectional Glenn shunt(s). METHODS: Extracardiac lateral tunnels (n = 9) were constructed using a polytetrafluoroethylene patch (n = 7), pericardial patch (n = 1), or in situ pericardial flap (n = 1). Extracardiac lateral conduits (n = 6) were constructed using nonvalved homografts (n = 2) or polytetrafluoroethylene tube grafts (n = 4). Fenestrations were created in 4 patients (2 each in extracardiac lateral tunnel and extracardiac lateral conduit patients). Aortic cross-clamping was completely avoided in 12/15 patients (aortic cross-clamping in 2 patients for atrial septal defect enlargement and 1 for Damus-Kaye-Stansel procedure). RESULTS: There have been no operative deaths. Prolonged postoperative chest tube drainage (> 2 weeks) has been rare (n = 1). At follow-up (range, 6 to 54 months; mean, 27.5 months), all patients are in New York Heart Association class I or II and remain in normal sinus rhythm. Late protein-losing enteropathy was seen in 1 patient and was successfully treated by percutaneous creation of a stented fenestration from the extracardiac tunnel to the systemic atrium. Late catheterizations reveal unobstructed extracardiac lateral tunnel function and low pulmonary pressures (range, 11 to 13 mm Hg). Advantages of the extracardiac Fontan include (1) avoidance of aortic cross-clamping in most patients, (2) the hemodynamic benefits of total cavopulmonary connection, (3) avoidance of atriotomy and intraatrial suture lines, (4) preservation of sinus rhythm and no arrhythmias at 2 year follow-up, (5) drainage of the coronary sinus to low pressure atrium, (6) allowance for early/late fenestrations, (7) prevention of baffle leaks and intraatrial obstruction, and (8) allowance for growth (tunnel procedures only). CONCLUSIONS: We recommend this extracardiac procedure for all suitable patients undergoing surgical conversion to the Fontan circulation.

Complete atrioventricular septal defects: the influence of associated cardiac anomalies on surgical management and outcome.

OBJECTIVE: Major associated cardiac anomalies are known to increase the risk of repair of complete atrioventricular septal defects (CAVSDs). The purpose of this study was to examine the effects of such anomalies on the current surgical management of CAVSDs and their influence on outcome following repair. METHODS: We performed a retrospective review of a 100 consecutive non-isomeric patients undergoing repair of CAVSD at our institution, between January 1989 and December 1994; patients with partial or intermediate defects were excluded. Complete atrioventricular septal defect patients with other major cardiac abnormalities (complex) were then compared to those with isolated CAVSDs. RESULTS: There were 15 patients (15%) with associated anomalies; 3 had tetralogy of Fallot, 1 patient had pulmonary atresia, 6 had hypoplastic left or right ventricle, 1 had tetralogy of Fallot and hyperplastic right ventricle, 2 patients had double outlet right ventricle, 1 had hypoplastic aortic arch and 1 patient had aortic coarctation. The median age at operation was similar for both groups (4.2 months), while the median weight was not significantly different for isolated CAVSDs compared to complex (4.2 months vs 3.4 months, P = 0.89), but there was a higher incidence of trisomy 21 (70/85, 82% vs 8/15, 53.3%, P = 0.01). Two of the 85 isolated CAVSD patients (2.3%) had undergone palliative pulmonary artery banding, while 5 of the 15 complex patients (33.3%) had either banding or Blalock-Taussig shunts performed. The technique of CAVSD repair was identical in each group. All complex patients had standard repair of their associated anomalies. Hospital mortality was higher in the complex group (3/15, 20% vs 2/85, 2.3%, P = 0.004); all early deaths in the complex group occurred in patients with a hypoplastic ventricle. Reoperation for left atrioventricular valve regurgitation was required in six isolated CAVSD patients (7.1%) and in one complex (6.6%). CONCLUSIONS: In the absence of significant ventricular hypoplasia, the early results of surgical repair in patients with CAVSDs and associated cardiovascular anomalies are similar to those achieved in patients with isolated CAVSD.

Neurologic injury in cardiac surgical patients with a history of stroke.

BACKGROUND: Controversy still exists as to whether patients with previous stroke are at increased risk for neurologic complications after heart operations. METHODS: We performed a prospective analysis of 1,000 consecutive patients undergoing cardiac operations requiring cardiopulmonary bypass, without hypothermic circulatory arrest. Of the 1,000 patients, 71 had previously documented stroke (study group); 2 control patients with no history of stroke were selected for each of these patients (control group, n = 142). There were no significant differences between the study and control patients with respect to established risk factors for neurologic complications. RESULTS: Compared with controls, study patients took longer to awaken (12.6 +/- 10.9 versus 3.5 +/- 2.1 hours; p < 0.0001) and longer to extubate (29.5 +/- 29.3 versus 9.1 +/- 5.2 hours; p < 0.001), and had a greater incidence of reintubation (7 of 71, 9.9% versus 2 of 142, 1.4%; p < 0.01) and postoperative confusion (26 of 71, 36.6% versus 7 of 142, 4.9%; p < 0.001). There was a higher incidence of focal neurologic deficit among study patients (31 of 71, 43.7% versus 2 of 142, 1.4%; p < 0.001). These deficits included new stroke (6 of 71, 8.5%) as well as the reappearance of previous deficits (19 of 71, 26.8%) or worsening of previous deficits (6 of 71, 8.5%), without new abnormalities on head computed tomography or magnetic resonance imaging. Study patients with neurologic deficit had longer cardiopulmonary bypass times than did study patients without deficit (146 +/- 48.5 versus 110 +/- 43.3 minutes; p < 0.001). The 30-day mortality rate was greater in study patients than in controls (5 of 71, 7% versus 1 of 142, 0.7%; p < 0.02), with four deaths among the 6 study patients with a new stroke (66.7%). CONCLUSION: This analysis identifies a group of patients at high risk for neurologic sequelae and confirms the vulnerability of the previously injured brain to cardiopulmonary bypass, as evidenced by reappearance or exacerbation of focal deficits in such patients.

AMPA glutamate receptor antagonism reduces neurologic injury after hypothermic circulatory arrest.

Pharmacologic inhibition of the N-methyl-D-aspartate (NMDA) glutamate receptor can reduce the neurologic injury associated with hypothermic circulatory arrest; however, other receptor subtypes, such as the alpha-amino-3-hydroxy-5-methylisoazole-4-propionic acid/kainate or AMPA/kainate subtype, may predominate in the adult brain. In this experiment, a selective AMPA antagonist, NBQX, was used in a canine survival model of hypothermic circulatory arrest. Twelve male dogs (20 to 25 kg) were placed on closed-chest cardiopulmonary bypass, subjected to 2 hours of hypothermic circulatory arrest at 18 degrees C, and rewarmed on cardiopulmonary bypass. All were mechanically ventilated and monitored for 20 hours before extubation and survived for 3 days. Six dogs received NBQX beginning 2 hours after arrest (3 mg/kg for 3 hours then 1.5 mg/kg for 2 hours). Control dogs received vehicle only. Neurologic recovery was assessed every 12 hours using a species-specific behavior scale that yielded a neurodeficit score ranging from 0 (normal) to 500 (brain dead). After sacrifice at 72 hours, brains were examined by receptor autoradiography and histologically for patterns of selective neuronal necrosis and scored blindly from 0 (normal) to 100 (severe injury). Dogs given NBQX had better neurologic function compared with controls (neurodeficit score, 58.6 +/- 15 versus 204 +/- 30; p < 0.004) and had less neuronal injury (18.2 +/- 3 versus 52.5 +/- 6; p < 0.004). Densitometric receptor autoradiography revealed preservation of neuronal NMDA receptor expression only in dogs given NBQX. These results suggest that antagonism of the non-NMDA glutamate receptor AMPA may be neuroprotective in adults after hypothermic circulatory arrest.

Platelet activating factor inhibition reduces lung injury after cardiopulmonary bypass.

Because cardiopulmonary bypass (CPB) produces a diffuse inflammatory reaction that may injure multiple organs and complicate cardiac surgical procedures, we examined the use of a competitive inhibitor of platelet activating factor (SDZ HUL-412) in a porcine model of CPB as a means to ameliorate pulmonary injury after CPB. Thirteen pigs (35 to 40 kg) underwent CPB at 28 degrees C for 2 hours, followed by 2 hours of observation. Group I (n = 6) received SDZ HUL-412 (a quinolinium compound) intravenously (3 mg/kg loading dose and 2 mg.kg-1.h-1 continuous infusion) starting before sternotomy. Group II (n = 7) received a saline vehicle. Peak airway pressure, pulmonary arterial pressure, left atrial pressure, and arterial blood gases were measured and flow cytometry evaluated surface expression of adhesion molecule subunit CD18 on circulating neutrophils. Pulmonary function was significantly improved in group I. Fifteen minutes after CPB, dynamic lung compliance in group I was 91% +/- 12% of baseline versus 49% +/- 5.2% in group II (p = 0.06 by analysis of variance). After CPB, the arterial oxygen pressure was also significantly better in group I than in group II (425 +/- 61 versus 234 +/- 76 mm Hg) (p < 0.05). The rise in pulmonary vascular resistance after CPB was less in group I (p < 0.05) (323 +/- 55 to 553 +/- 106 dynes.s.cm-5) than in group II (531 +/- 177 to 884 +/- 419 dynes.s.cm-5) at the end of the observation period. CD18 up-regulation increased similarly in the two groups during CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Repair of coarctation of the aorta in neonates and infants: a thirty-year experience.

Between January 1962 and December 1991, 179 children less than 1 year of age underwent repair of coarctation of the aorta. Group I (1962 to 1971) consisted of 19 patients, group II (1972 to 1981) of 57 patients, group III (1982 to 1991) of 103 patients. Neonates (< 30 days old) made up 60% of group I, 57% of group II, and 70% of group III. The proportion of infants with associated complex cardiac abnormalities was 7% in group I, 25% in group II, and 39% in group III. Techniques of repair included resection with end-to-end anastomosis (n = 65), subclavian flap repair (n = 85), patch aortoplasty (n = 18), and other procedures (n = 11). The early mortality (< 30 days) was lowest in group III (group I, 21%; group II, 21%; and group III, 7%; p < 0.05), but the late mortality was similar in all groups (group I, 11%; group II, 13%; and group III, 15%). The overall actuarial survival was 57.7% +/- 0.15% at 27.1 years in group I, 65.7% +/- 0.07% at 19.7 years in group II, and 77.5% +/- 0.04% at 9.3 years in group III (p = not significant). Twenty-five restenoses requiring intervention occurred in 23 patients, for an overall restenosis rate of 16.4%. The incidence of restenosis was 23% for the patients who underwent end-to-end anastomosis, 11% for those who underwent subclavian flap repair (p < 0.1), and 27% for those who underwent patch aortoplasty (p < 0.01). Balloon angioplasty was successful in relieving 11 of the 12 restenoses in groups II and III.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged pulmonary vascular hyperreactivity in conscious dogs after cardiopulmonary bypass.

Although cardiopulmonary bypass (CPB) is required in all surgical procedures involving open-heart surgery, the extent to which CPB alters pulmonary vascular regulation has not been systematically investigated. Our objectives were to investigate the acute, subacute, and chronic effects of CPB on the left pulmonary vascular pressure-flow (LP-Q) relationship in conscious dogs. Continuous LP-Q plots were generated in chronically instrumented conscious dogs 2-4 days pre-CPB and again 4 h and 1, 2, 7, and 14 days after 2.5 h of closed-chest hypothermic CPB. In addition, pulmonary vascular reactivity was assessed by examining the dose-response relationship to the thromboxane analogue U-46619 pre- and post-CPB. CPB resulted in an acute (4 h post-CPB) shift in the baseline LP-Q relationship, indicating an increase in pulmonary vascular resistance (P < 0.01). The baseline LP-Q relationship returned to pre-CPB values by 1 day post-CPB. Despite this return of the baseline LP-Q relationship to pre-CPB values, the pulmonary vasoconstrictor response to U-46619 was markedly potentiated 2 days post-CPB compared with the pre-CPB response (P < 0.01). This enhanced pulmonary vasoconstrictor response to U-46619 was still apparent 7 days post-CPB (P < 0.01) but was not evident 14 days post-CPB. These results indicate that CPB results in a pronounced, but transient, increase in pulmonary vascular resistance. Moreover, CPB causes a protracted increase in pulmonary vascular reactivity even when the baseline LP-Q relationship has returned to pre-CPB values.(ABSTRACT TRUNCATED AT 250 WORDS)

Glutamate excitotoxicity: a mechanism of neurologic injury associated with hypothermic circulatory arrest.

Glutamate, the major central nervous system neurotransmitter, may have potent neurotoxic activity under conditions of metabolic stress. By receptor autoradiography, we have demonstrated that brain regions most vulnerable to injury during prolonged hypothermic circulatory arrest have the highest density of glutamate receptors. To test the hypothesis that such injury could be mediated by glutamate excitotoxicity, we used dizocilpine (MK-801), a selective N-methyl-D-aspartate-glutamate receptor antagonist in a canine survival model of hypothermic circulatory arrest. Eighteen male dogs (20 to 25 kg) were supported by closed-chest cardiopulmonary bypass, subjected to 2 hours of hypothermic circulatory arrest at 18 degrees C, and rewarmed on cardiopulmonary bypass. All were mechanically ventilated and monitored for 20 hours before extubation and survived for 3 days. Group A dogs (n = 9) received a prearrest intravenous bolus of dizocilpine (0.75 mg/kg) followed by continuous infusion (75 micrograms/kg per hour), resulting in electroencephalographic silence. Dizocilpine was weaned before extubation. Group B dogs received vehicle only. According to a species-specific behavior scale that yielded a neurologic deficit score ranging from 0 (normal) to 500 (brain dead), all animals were neurologically assessed every 12 hours. After the dogs were killed at 72 hours, brains were examined by receptor autoradiography and histologically for patterns of selective neuronal necrosis; they were scored blindly from 0 (normal) to 100 (severe injury). Group A dogs had better neurologic function than group B (neurologic deficit score 21 +/- 15 versus 192 +/- 40, p < 0.001) and had less neuronal injury (7.3 +/- 3 versus 48.3 +/- 9, p < 0.0001). Densitometric receptor autoradiography revealed preservation of neuronal N-methyl-D-aspartate-glutamate receptor expression in group A only. These results represent the first direct evidence of a role for glutamate excitotoxicity in the development of hypothermic circulatory arrest-induced brain injury and suggest that selective glutamate receptor antagonists may have a neuroprotective capacity in prolonged periods of hypothermic circulatory arrest.