Perinatal systemic inflammatory responses of growth-restricted preterm newborns.

AIM: To compare the early post-natal pattern of systemic inflammation in growth-restricted infants born before the 28th week of gestation to that of appropriately grown peers. METHODS: We measured the concentrations of 25 inflammation-related proteins in blood spots collected from 939 newborns during the first 2 post-natal weeks. We calculated the odds ratios (99% confidence intervals) that concentrations would be in the highest quartile. RESULTS: Severely growth-restricted infants (birth weight Z-score <-2) were not at increased risk of systemic inflammation shortly after birth. On post-natal day 14, however, they were significantly more likely than their peers to have a CRP, IL-1ß, IL-6, TNF-α, IL-8, MCP-4, ICAM-1, ICAM-3, E-SEL, MMP-9, VEGF-R2 and/or IGFBP-1 concentration in the highest quartile. These increased risks could not be attributed to delivery indication, bacteremia or duration of ventilation. CONCLUSION: Growth-restricted preterm newborns appear to be at increased risk of elevated concentrations of inflammation-associated proteins by post-natal day 14.

Pregnancy disorders that lead to delivery before the 28th week of gestation: an epidemiologic approach to classification.

Epidemiologists have grouped the multiple disorders that lead to preterm delivery before the 28th week of gestation in a variety of ways. The authors sought to identify characteristics that would help guide how to classify disorders that lead to such preterm delivery. They enrolled 1,006 women who delivered a liveborn singleton infant of less than 28 weeks' gestation at 14 centers in the United States between 2002 and 2004. Each delivery was classified by presentation: preterm labor (40%), prelabor premature rupture of membranes (23%), preeclampsia (18%), placental abruption (11%), cervical incompetence (5%), and fetal indication/intrauterine growth restriction (3%). Using factor analysis (eigenvalue = 1.73) to compare characteristics identified by standardized interview, chart review, placental histology, and placental microbiology among the presentation groups, the authors found 2 broad patterns. One pattern, characterized by histologic chorioamnionitis and placental microbe recovery, was associated with preterm labor, prelabor premature rupture of membranes, placental abruption, and cervical insufficiency. The other, characterized by a paucity of organisms and inflammation but the presence of histologic features of dysfunctional placentation, was associated with preeclampsia and fetal indication/intrauterine growth restriction. Disorders leading to preterm delivery may be separated into two groups: those associated with intrauterine inflammation and those associated with aberrations of placentation.

Reference weights for placentas delivered before the 28th week of gestation.

CONTEXT: Very few studies have measured the weight of large numbers of placentas delivered before the 28th post-menstrual week. METHODS: We measured the weight of 930 singleton placentas delivered before the 28th post-menstrual week, and examined the distributions of weights in selected groups (week of gestation, reason for preterm birth, birth weight Z-score categories, placenta histology). We excluded 90 singleton placentas based on growth restriction as indicated by birth weight Z-score, resulting in a normative sample of 840 placentas. Weights for unfused twin placentas are also presented. RESULTS: Standard weights derived from our data set differ from those previously published, partly due to a larger sample size. Placenta weight varied with birth weight. Placentas from pregnancies ending due to preeclampsia, fetal indications or those showing evidence of poor perfusion on histology were among the smallest and their weights correlated with the smallest birth weights for gestational age. CONCLUSIONS: Placenta weights appear to be influenced by multiple maternal and fetal processes. We present a standard weight table for singleton placentas among live infants born between 23 and 27 completed weeks.

Early postnatal illness severity scores predict neurodevelopmental impairments at 10 years of age in children born extremely preterm.

OBJECTIVE: A neonatal illness severity score, The Score for Neonatal Acute Physiology-II (SNAP-II), predicts neurodevelopmental impairments at two years of age among children born extremely preterm. We sought to evaluate to what extent SNAP-II is predictive of cognitive and other neurodevelopmental impairments at 10 years of age. STUDY DESIGN: In a cohort of 874 children born before 28 weeks of gestation, we prospectively collected clinical, physiologic and laboratory data to calculate SNAP-II for each infant. When the children were 10 years old, examiners who were unaware of the child's medical history assessed neurodevelopmental outcomes, including neurocognitive, gross motor, social and communication functions, diagnosis and treatment of seizures or attention deficit hyperactivity disorder (ADHD), academic achievement, and quality of life. We used logistic regression to adjust for potential confounders. RESULTS: An undesirably high SNAP-II (⩾30), present in 23% of participants, was associated with an increased risk of cognitive impairment (IQ, executive function, language ability), adverse neurological outcomes (epilepsy, impaired gross motor function), behavioral abnormalities (attention deficit disorder and hyperactivity), social dysfunction (autistic spectrum disorder) and education-related adversities (school achievement and need for educational supports. In analyses that adjusted for potential confounders, Z-scores ⩽-1 on 11 of 18 cognitive outcomes were associated with SNAP-II in the highest category, and 6 of 18 were associated with SNAP-II in the intermediate category. Odds ratios and 95% confidence intervals ranged from 1.4 (1.01, 2.1) to 2.1 (1.4, 3.1). Similarly, 2 of the 8 social dysfunctions were associated with SNAP-II in the highest category, and 3 of 8 were associated with SNAP-II in the intermediate category. Odds ratios and 95% confidence intervals were slightly higher for these assessments, ranging from 1.6 (1.1, 2.4) to 2.3 (1.2, 4.6). CONCLUSION: Among very preterm newborns, physiologic derangements present in the first 12 postnatal hours are associated with dysfunctions in several neurodevelopmental domains at 10 years of age. We are unable to make inferences about causality.

Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma.

BACKGROUND: Axillary lymph node status has been the most important prognostic factor in operable breast carcinoma, but it does not fully account for the varied disease outcome. More accurate prognostic indicators would help in selection of patients at high risk for disease recurrence and death who are candidates for systemic adjuvant therapy. Our recent findings indicated that microvessel density (count or grade) in invasive breast carcinoma (a measure of tumor angiogenesis) is associated with metastasis and thus may be a prognostic indicator. PURPOSE: This study was designed to further define the relationship of microvessel density with overall and relapse-free survival and with other reported prognostic indicators in breast carcinoma. METHODS: In a prospective, blinded study of 165 consecutive patients, the microvessels within primary invasive breast carcinoma were highlighted by immunocytochemical staining to detect factor VIII-related antigen. Using light microscopy, we counted microvessels per 200x field in the most active areas of neovascularization and graded microvessel density. These findings were correlated, by univariate and multivariate analyses, with overall and relapse-free survival, axillary node status, and other prognostic indicators (median follow-up, 51 months). RESULTS: There was a highly significant (P < or = .001) association of microvessel density with overall survival and relapse-free survival in all patients, including node-negative and node-positive subsets. All patients with breast carcinomas having more than 100 microvessels per 200x field experienced tumor recurrence within 33 months of diagnosis, compared with less than 5% of the patients with breast carcinoma having 33 or fewer microvessels per 200x field. Moreover, microvessel density was the only statistically significant predictor of overall survival among node-negative women (P < .001). Only microvessel density (P < .001) and histologic grade (P = .04) showed statistically significant correlations with relapse-free survival in the node-negative subset. CONCLUSIONS: Microvessel density in the area of the most intense neovascularization in invasive breast carcinoma is an independent and highly significant prognostic indicator for overall and relapse-free survival in patients with early-stage breast carcinoma (I or II by International Union Against Cancer criteria). IMPLICATIONS: Such an indicator would be useful in selection of those node-negative patients with breast carcinoma who are at high risk for having occult metastasis at presentation. These patients could then be given systemic adjuvant therapy.

Heterogeneity of angiogenic activity in a human liposarcoma: a proposed mechanism for "no take" of human tumors in mice.

BACKGROUND: Tumor cells are known to be heterogeneous with respect to their metastatic activity, proliferation rate, and activity of several enzymes. However, little is known about the heterogeneity of tumor angiogenic activity. We investigated whether heterogeneity of angiogenic activity could be responsible for the well-known observation of "no take" of human tumors transplanted into immunodeficient mice. METHODS: Severe combined immunodeficient (SCID) mice were xenotransplanted subcutaneously with tumor tissue (n = 55) or cell suspension of a human liposarcoma cell line (SW-872) or subclones (n = 28), with varying cell proliferation rates. Xenograft tumor growth was recorded for up to 6 months. Tumor tissues were then removed and analyzed for tumor cell apoptosis, microvessel density, and cell proliferation. All statistical tests were two-sided. RESULTS: Pieces of tumor derived from the parental cell line or its clones gave rise to three kinds of tumors: 1) highly angiogenic and fast-growing (aggressive) tumors, 2) weakly angiogenic and slow-growing tumors, and 3) nonangiogenic and stable tumors. Most tumors retained the original phenotype of their parental tumor. Tumor volume correlated positively with microvessel density (Spearman correlation coefficient [r] =.89; P< or =.0001) and inversely with tumor cell apoptosis (Spearman r = -.68; P =.002). Tumor volume was less strongly but still positively correlated with tumor cell proliferation in vivo (Spearman r =.55; P =.02). CONCLUSIONS: Human liposarcoma cells appear to be heterogeneous in their angiogenic activity. When tumor cells with little or no angiogenic activity are transplanted into SCID mice, a microscopic, dormant tumor results that may not grow further. Because such tiny tumors are neither grossly visible nor palpable, they have previously been called "no take." The finding that an angiogenic tumor can contain subpopulations of tumor cells with little or no angiogenic activity may provide a novel mechanism for dormant micrometastases, late recurrence, and changes in rate of tumor progression.

Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model.

In the first Phase I clinical trials of endostatin as an antiangiogenic therapy for cancer, the protein was administered as an i.v. bolus for approximately 20-30 min each day. This protocol was based on experimental studies in which animals were treated by s.c. bolus once a day. However, it was not clear in the previous studies whether this schedule could be maximized further. Therefore, we developed experimental models involving continuous administration of endostatin to determine the potency and efficacy of this approach. Endostatin was administered to tumor-bearing mice either s.c. or i.p. in single bolus doses. The efficacy of these regimens was compared with endostatin administered continuously via an i.p. implanted mini-osmotic pump. Our results show that endostatin remains stable and active in mini-osmotic pumps for at least 7 days. We show that endostatin injected i.p. is rapidly cleared within 2 h, whereas endostatin administered continuously via mini-osmotic pump maintains systemic concentrations of 200-300 ng/ml for the duration of administration. Furthermore, continuous i.p. administration of endostatin results in more effective tumor suppression at significantly reduced doses (5-fold), compared with bolus administration. Additional experiments using a human pancreatic cancer model in severe combined immunodeficient mice showed that there was a significant decrease in the microvessel density between the treatment groups and the control group. These data show that continuous administration of human endostatin results in sustained systemic concentrations of the protein leading to: (a) increased efficacy manifested as increased tumor regression; and (b) an 8-10-fold decrease in the dose required to achieve the same antitumor effect as the single daily bolus administration of endostatin. On the basis of this approach, an additional clinical trial has been designed and initiated and is under way in two countries.

The antecedents and correlates of necrotizing enterocolitis and spontaneous intestinal perforation among infants born before the 28th week of gestation.

OBJECTIVE: To identify antecedents of "medical" necrotizing enterocolitis (mNEC), "surgical" NEC (sNEC), and spontaneous intestinal perforation (SIP) in newborns delivered before 28 weeks gestation. STUDY DESIGN: Prospective multicenter cohort study. During study period, 2002- 2004, women delivering before 28 weeks gestation at one of 14 participating institutions were enrolled. Well defined antenatal and postnatal variables were collected. Bivariate analyses were performed to identify candidates for developing multinomial multivariable time-oriented logistic regression models. RESULTS: Of the 1320 infants, 5% had mNEC, 6% had sNEC, and 4% had SIP. Antecedents of mNEC included mother's identification as Black, consumption of aspirin during the pregnancy, and vaginal bleeding after the 12th week of gestation. For sNEC the antecedents were maternal self- support, obesity and anemia during the pregnancy, birth before the 24th week, birth weight ≤750gm, and receipt of fresh frozen plasma (FFP) during the first postnatal week. An infant was at increased risk of SIP if the placenta had increased syncytial knots, birth occurred before the 24th week, and received FFP during the first week. CONCLUSIONS: Maternal and neonatal characteristics might help identify at-risk ELGANs for NEC and SIP, who then may potentially benefit from targeted preventive strategies.

Maternal metabolic control and risk of microcephaly among infants of diabetic mothers.

OBJECTIVE: To measure the incidence of microcephaly among infants of diabetic mothers (IDM) and assess its relationship to metabolic control during pregnancy. RESEARCH DESIGN AND METHODS: Head circumference data for 556 consecutive live-born singleton infants of women with insulin-requiring diabetes antedating pregnancy delivered between 28 and 40 weeks of gestation and the results of 3,242 HbA1 determinations collected during their pregnancies were examined. RESULTS: There were fewer head circumferences at or below the 3rd percentile and more at or above the 97th percentile than expected. Head circumference was not related to maternal metabolic control as documented by the HbA1 values. CONCLUSIONS: The less-than-expected incidence of microcephaly observed in this patient population probably reflects the well-known tendency of IDM toward macrosomia.

Predictive value of inducible endothelial cell adhesion molecule expression for acute rejection of human cardiac allografts.

We conducted a prospective longitudinal study to determine the clinical significance of endothelial adhesion molecule expression in endomyocardial biopsies from human cardiac allografts. Ten to 18 (mean 13) consecutive allograft biopsies were obtained from 20 serial human transplant recipients over a one-year period. A total of 267 biopsies was examined. The expression of endothelial adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, as well as the presence of CD3+ T cell infiltrates was assessed by immunocytochemical staining of frozen sections. Separate specimens taken at the same time were analyzed histologically for ischemic injury or rejection. ICAM-1--and, to a lesser extent VCAM-1--was expressed at low levels in normal biopsies. E-selectin was only expressed in 15% of histologically normal biopsy specimens. Ischemic injury noted in the immediate posttransplant period was associated with increased expression of all three adhesion molecules. VCAM-1 expression increased both with the degree of CD3+ T cell infiltrates (P < 0.001) and with the degree of rejection (P < 0.05). ICAM-1 increased over constitutive levels in association with diffuse CD3+ infiltrates (P < 0.001) and with rejection (P < 0.05). E-selectin was increased on occasional vessels in association with CD3+ infiltrates (P < 0.001), but was not associated with active rejection. Increases in E-selectin were most likely to occur in biopsies just prior to rejection episodes (odds ratio 3.3), and were least likely to occur in biopsies following rejection (odds ratio 0.3). ICAM-1, but not VCAM-1, was also elevated in prerejection specimens. VCAM-1 and ICAM-1 declined in postrejection specimens. These data suggest a dynamic pattern in the expression of endothelial cell adhesion molecules during the course of cardiac allograft rejection. This study also suggests that endothelial E-selectin expression may be a useful clinical marker of impending rejection. Finally, inducible VCAM-1 expression may be a helpful adjunct in the diagnosis of ongoing acute rejection, and decreases in its expression may be indicative of successful antirejection therapy.

Antenatal corticosteroids appear to reduce the risk of postnatal germinal matrix hemorrhage in intubated low birth weight newborns.

OBJECTIVE: To determine to what extent the reduced risk in preterm newborns of intracranial hemorrhage attributed to antenatal corticosteroids (ANCS) reflects reductions in the incidence of respiratory distress and its correlates. METHODS: In a sample of 239 very low birth weight newborns recruited for a clinical trial of phenobarbital prophylaxis of subependymal/intraventricular hemorrhage, we explored the relationship between ANCS, the occurrence of germinal matrix hemorrhage (GMH) that first became evident after the 12th postnatal hour, and putative intervening variables such as acidosis, elevated peak inspiratory pressure, pneumothorax-pulmonary interstitial emphysema, and elevated continuous positive airway pressure. RESULTS: In multivariate models adjusting for confounders, newborns exposed to ANCS were at approximately one third the risk of GMH experienced by newborns not exposed to a full course of ANCS. The additions of measures and correlates of respiratory distress severity to these models did not change the GMH risk associated with ANCS. CONCLUSION: The GMH-protective effect of ANCS does not appear to be a consequence of enhanced pulmonary maturation.

Maternal glucocorticoid therapy and reduced risk of bronchopulmonary dysplasia.

Because of substantial clinical and laboratory evidence of the efficacy of glucocorticoids in the treatment of acute pulmonary surfactant deficiency in preterm newborns, we explored the hypothesis that maternal antenatal glucocorticoid receipt is followed by reduced risk of bronchopulmonary dysplasia (BPD). A sample of 223 intubated infants weighing less than 1751 g birth weight provided 76 infants with BPD (defined by both oxygen requirement and compatible chest radiograph) and 147 who had neither BPD characteristic by day 28 of life. When compared to babies who received a complete and timely course of antenatal glucocorticoids, those whose mothers received no glucocorticoids were at prominently increased risk of BPD (odds ratio = 3.0; 95% confidence interval = 1.1, 8.2). Babies whose mothers received a partial course of glucocorticoids were not at increased risk of BPD (odds ratio = 1.3; 95% confidence interval = 0.4, 4.3). Stratification by gender and birth weight at 1 kg showed a benefit of therapy in all strata except that of extremely low birth weight male infants. These data support the hypothesis that maternal antenatal glucocorticoid therapy offers very low birth weight infants protection against BPD.

Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy.

OBJECTIVE: Prenatal causation of persistent pulmonary hypertension of the newborn (PPHB) is suggested by a specific pattern of pulmonary vascular remodeling observed immediately after birth in some infants with fatal PPHN. The goal of this study was to determine whether PPHN is associated with fetal exposure to: (1) tobacco and marijuana smoking (ie, contributors to fetal hypoxemia), (2) consumption of aspirin and other nonsteroidal antiinflammatory drugs (ie, inhibitors of prostaglandin synthesis), and (3) cocaine use (ie, a contributor to vasospasm). DESIGN: Case-control interview study. SETTING: Two Harvard-affiliated newborn intensive care units. PARTICIPANTS: Mothers of case infants who had PPHN or who met criteria for the referent group. INTERVENTIONS: During July 1985 through April 1989, we interviewed mothers of 103 infants with PPHN and 298 control infants. Because of potential selection bias that might result from recruiting only inborn control infants even though two-thirds of cases were outborn, separate analyses compared the 103 total and 35 inborn infants with PPHN with the 298 inborn control infants. Multivariate analyses were used to adjust for potential confounding factors, including maternal education and Medicaid health insurance (ie, two markers of socioeconomic status), other antenatal factors found to be associated with PPHN (ie, maternal urinary tract infection and diabetes mellitus), and the infant's sex. MAIN OUTCOME MEASURES: Self-reported use or consumption of tobacco, marijuana, cocaine, aspirin, and other nonsteroidal antiinflammatory drugs during pregnancy. RESULTS: The adjusted odds ratios (and 95% confidence intervals) for maternal pregnancy exposures to the factors of principal interest among the total study population were: aspirin, 4.9 (1.6-15.3); and nonsteroidal antiinflammatory drugs, 6.2 (1.8-21.8); for the inborn group they were aspirin, 9.6 (2.4-39.0); and nonsteroidal antiinflammatory drugs, 17.5 (4.3-71.6). Although the association between tobacco smoking during pregnancy and PPHN was elevated in univariate analyses, with odds ratios (and 95% confidence intervals) of 2.0 (1.2-3.4) and 1.3 (0.6-3.3) for total and inborn populations, respectively, the relationship was not significant after adjustment for all other factors in the final logistic regression model. Acknowledged illicit drug use was too infrequent (3.2%) to evaluate. CONCLUSION: Maternal consumption of nonsteroidal antiinflammatory drugs and aspirin during pregnancy or the reasons these drugs were ingested seem to contribute to an increased risk of PPHN.

Periventricular-intraventricular hemorrhage, sonographic localization, phenobarbital, and motor abnormalities in low birth weight infants.

A total of 228 low birth weight (less than 1750 g), mechanically ventilated infants with and without periventricular-intraventricular hemorrhage were examined at 18 months corrected age to assess the relationship between cranial ultrasonographic findings and specific motor abnormalities. All infants were previously enrolled in a double-blind, randomized, prospective clinical trial of phenobarbital prophylaxis against periventricular-intraventricular hemorrhage. Ultrasonographic abnormalities on the scans performed between 7 and 13 days of life were categorized as germinal matrix hemorrhage, lateral ventricular hemorrhage, parenchymal hemorrhage, ventriculomegaly, and any hemorrhage. Regardless of anatomical location, periventricular-intraventricular hemorrhage was associated with an increased risk for developing motor abnormalities. Hypertonia and hyperreflexia/ankle clonus were most common. No abnormal motor findings distinguished unilateral from bilateral germinal matrix hemorrhage and lateral ventricular hemorrhage or between phenobarbital and placebo treatment. None of the 5 infants with parenchymal hemorrhage had spastic cerebral palsy. Ventriculomegaly was associated with a fivefold increase in risk for spastic cerebral palsy and delayed walking and a threefold increase for hypertonia and hyperreflexia/clonus. The results suggest that ventriculomegaly, observed even as early as the first week of life, might be a significant antecedent of later motor abnormalities among the survivors of periventricular-intraventricular hemorrhage.

Long-term results of open mitral valve reconstruction for mitral stenosis.

Open mitral reconstruction for rheumatic mitral stenosis (MS) was performed in 120 patients, 101 women and 19 men, aged 22 to 75 years (mean 49). Nine patients were functional class II, 106 class III, 5 class IV; 13 only underwent noninvasive studies, including echocardiography, before surgery, while 107 had preoperative cardiac catheterization studies. The latter showed a mean valve area of 1.09 cm2 and a pulmonary artery wedge to left ventricular mean diastolic gradient of 14 mm Hg. Cardiopulmonary bypass was used in all patients for open reconstruction under direct vision. Superior commissurotomy was done in 115 patients, inferior in 114, papillary muscles were incised and chordae lengthened in 39 and calcium was excised from valve leaflets in 23. Suture or ring anuloplasty was not required in any patient. The series was begun January 1972 and terminated in January 1984. Personal follow up was conducted in July 1984. There were no operative deaths in the 120 patients. There were 5 late deaths, all from noncardiac causes. The mean follow-up time was 53 months. The actuarial probability of survival at 10 years was 95 +/- 2%. Thromboemboli occurred in 9 patients; the probability of freedom from thromboemboli at 10 years was 91 +/- 3% and the linearized rate was 1.8%/patient-year of follow-up. Reoperation was required in 9 patients, an absolute incidence of 7.5% and an annual incidence of 1.7%/patient year. At 10 years the probability of freedom from reoperation was 84 +/- 5%.

Fetal vasculitis in preterm newborns: interrelationships, modifiers, and antecedents.

Histologic expressions of the fetal inflammatory response predict preterm delivery and neonatal disorders. We examined 1146 placentas in the Developmental Epidemiology Network data set for histologic evidence of membrane inflammation (subchorionitis, chorionitis, and chorioamnionitis) and fetal vasculitis (acute umbilical vasculitis or chorionic vasculitis). Our main findings are that (1) in the presence of membrane inflammation, fetal vasculitis is common, (2) duration of membrane rupture and gestational age appear to modify the risk of fetal vasculitis, (3) this risk modification differs for the different components of fetal vasculitis, i.e. umbilical and chorionic vasculitis, and (4) antecedents can be identified that appear to increase or decrease the risk of fetal vasculitis among births with membrane inflammation. We conclude that fetal vasculitis, the morphologic component of the fetal inflammatory response, might not be a homogeneous entity and deserves further study.

Effects of carbon monoxide on myocardial ischemia.

The purpose of this study was to determine whether low doses of carbon monoxide (CO) exacerbate myocardial ischemia during a progressive exercise test. The effect of CO exposure was evaluated using the objective measure of time to development of electrocardiographic changes indicative of ischemia and the subjective measure of time to onset of angina. Sixty-three male subjects (41-75 years) with well-documented coronary artery disease, who had exertional angina pectoris and ischemic ST-segment changes in their electrocardiograms, were studied. Results from three randomized, double-blind test visits (room air, low and high CO) were compared. The effect of CO exposure was determined from the percent difference in the end points obtained on exercise tests performed before and after a 1-hr exposure to room air or CO. The exposures resulted in postexercise carboxyhemoglobin (COHb) levels of 0.6% +/- 0.3%, 2.0% +/- 0.1%, and 3.9% +/- 0.1%. The results obtained on the 2%-COHb day and 3.9%-COHb day were compared to those on the room air day. There were 5.1% (p = 0.01) and 12.1% (p less than or equal to 0.0001) decreases in the time to development of ischemic ST-segment changes after exposures producing 2.0 and 3.9% COHb, respectively, compared to the control day. In addition, there were 4.2% (p = 0.027) and 7.1% (p = 0.002) decreases in time to the onset of angina after exposures producing 2.0 and 3.9% COHb, respectively, compared to the control day. A significant dose-response relationship was found for the individual differences in the time to ST end point and angina for the pre- versus postexposure exercise tests at the three carboxyhemoglobin levels. These findings demonstrate that low doses of CO produce significant effects on cardiac function during exercise in subjects with coronary artery disease.

Performance of a fabricated trileaflet porcine bioprosthesis. Midterm follow-up of the Hancock modified-orifice valve.

The fabrication of the Hancock modified-orifice valve raised questions about its long-term durability. Since 1976, 315 patients (206 male, 109 female) with a mean age of 63 years underwent aortic valve replacement with 21 mm (n = 120), 23 mm (n = 153), 25 mm (n = 36), and 27 mm (n = 6) Hancock modified-orifice valves. There were five operative deaths (1.6% mortality). Two hundred sixty-two patients are alive 2 to 117 (mean 53) months postoperatively. Actuarial probability of survival at 96 months was 78% +/- 3%. Two hundred twenty-two survivors are in Functional Class I or II. Forty-three patients have had valve-related complications: thromboembolism in 25 (1.9%/pt-yr), primary valve dysfunction in eight (0.6%/pt-yr), and endocarditis in 11 (0.8%/pt-yr). Twelve patients have required reoperation (0.8%/pt-yr) for primary valve dysfunction (four patients), for endocarditis (five patients), and for perivalvular leak (three patients). At 96 months the actuarial probability of freedom from thromboembolism was 87% +/- 3%, from primary valve dysfunction 97% +/- 2%, and from endocarditis 92% +/- 3%. The probability of freedom from all valve-related complications was 78% +/- 4% and from reoperation 94% +/- 2%. The performance of this prosthesis justifies its continued use for aortic valve replacement.

Early and late risk of aortic valve replacement. A 12 year concomitant comparison of the porcine bioprosthetic and tilting disc prosthetic aortic valves.

Aortic valve replacement was performed in 912 consecutive patients from January, 1972, to January, 1983. The 616 male and 296 female patients, whose ages ranged from 16 to 95 years (mean 60.6 years and median 63 years), received 663 bioprosthetic valves and 249 tilting disc valves. A higher incidence of Functional Class IV heart disease and ascending aortic aneurysms was noted in the group receiving the tilting disc valve. Six hundred fifty-seven patients had primarily aortic stenosis and 255 had primarily aortic regurgitation. Associated procedures were done in 308 patients (33%): 233 had coronary bypass grafting, 46 had replacement of ascending aortic aneurysms, and 29 had miscellaneous procedures. The overall operative mortality was 6.4% (59/912). The operative mortality was 4.5% (29/640) for isolated aortic valve replacement, 4.2% (21/233) for valve replacement plus coronary bypass, and 17% (8/46) for valve replacement plus replacement of an ascending aortic aneurysm. The mortality was 4.2% (20/663) for the group receiving bioprostheses and 12.4% (31/249) for those receiving tilting disc valves. The operative mortality for 1983 for all aortic valve replacement procedures was 2.1%; for isolated valve replacement, 1%; for valve replacement plus coronary bypass, 4.4%; and for valve replacement plus aortic aneurysm replacement, 0%. The long-term follow-up was analyzed as of Jan. 1, 1984, so that there was a minimum follow-up of 12 months (mean 55 months and median 51 months). The actuarial survival rate at 108 months for all patients was 67% +/- 2%; for valve replacement alone, 71% +/- 3%; for valve replacement plus coronary bypass, 58% +/- 7%; for valve replacement plus ascending aortic aneurysm replacement, 45% +/- 10%; for aortic stenosis, 70% +/- 3%; for aortic regurgitation, 61% +/- 4%; for Functional Classes I to III, 77% +/- 3%; for Class IV, 53% +/- 4%; for age less than 63 years, 75% +/- 3%; and for age greater than 63 years, 57% +/- 4%. At 108 months, the probability of freedom from thromboembolism was 85% +/- 3% after bioprosthetic valve replacement and 83% +/- 3% after replacement with a tilting disc valve (p = NS). The probability of freedom from hemorrhage at 108 months was 98.6% +/- 7% for the bioprosthetic valve group and 89% +/- 2% for the tilting disc valve group (p less than 0.001). The valve thrombosis rate was 0.34% per patient-year for the tilting disc valves and 0.07% per patient-year for the bioprostheses.(ABSTRACT TRUNCATED AT 400 WORDS)

Reoperative aortic valve replacement: partial upper hemisternotomy versus conventional full sternotomy.

OBJECTIVE: We developed techniques for partial upper hemisternotomy for reoperative aortic valve replacement and compared the results with those of reoperative aortic valve replacement by way of conventional full resternotomy. METHODS: We retrospectively analyzed data from 19 patients who underwent conventional full sternotomy and 20 patients who underwent partial hemisternotomy for isolated elective reoperative aortic valve replacements performed between November 1996 and September 1998. Univariable and multivariable analyses were used to document the differences between the groups. RESULTS: The 2 groups were similar with respect to age, sex, New York Heart Association functional class, valve pathologic characteristics, and numbers and types of previous operations. There were neither any operative deaths nor any postoperative valve-related morbidities in either group. There was 1 injury to a cardiac structure, which occurred in the conventional full sternotomy group. Univariable analysis documented that patients in the conventional full sternotomy group were significantly more likely to have at least 1000 mL blood loss during the first 24 hours after the operation (odds ratio 8.1, P =.02), were more likely to require transfusion of more than 5 units of packed red blood cell (odds ratio 3.6, P =.08), and were more likely to have a total operative duration longer than 5 hours (odds ratio 3.6, P =.08). In the multivariable analysis conventional full resternotomy remained a risk factor for greater blood loss (odds ratio 5.7, P =.06), greater transfusion requirement (odds ratio 2.4, P =.25), and longer total operative duration (odds ratio 7.7, P =.03). CONCLUSIONS: Partial upper hemisternotomy for reoperative aortic valve replacement avoids unnecessary lower mediastinal dissection, thereby reducing blood loss, transfusion needs, and total operative duration. These beneficial effects, which are accomplished without compromising the efficacy of the valve operation, make the partial upper hemisternotomy an excellent alternative to conventional full resternotomy for reoperative aortic valve replacement.