Postoperative complications associated with perioperative sirolimus prior to pediatric cardiac retransplantation.

OBJECTIVES: Sirolimus has been used in pediatric cardiac transplantation for the past decade for chronic renal dysfunction, recurrent rejection, and/or coronary allograft vasculopathy. There has been concern regarding the effect of sirolimus on wound healing and other postoperative complications. To date, the pediatric literature on its use is limited and has not specifically addressed its use in the perioperative period following repeat cardiac transplantation. METHODS: We compared the patients in our institution who received sirolimus before repeat cardiac transplantation to those in the same era who did not receive sirolimus. RESULTS: Of the 5 patients in the study group, 5 (100%) developed pleural effusions vs 1 (17%) in the control group (p=0.013). There was no increase in mortality in the sirolimus group, and there were no significant differences in renal dysfunction, serious bacterial infection, rejection, or postoperative length of stay. CONCLUSIONS: In this small data set, there was a statistically significant increase in pleural effusions in patients on sirolimus. Further study is needed to develop an appropriate strategy to avoid postoperative complications in this patient population.

Cerebral and somatic oxygen saturations after repair of tetralogy of Fallot: effects of extubation on regional blood flow.

BACKGROUND: After repair of tetralogy of Fallot, some patients experience a low cardiac output state owing to right ventricular diastolic failure. Negative-pressure ventilation has been shown to improve cardiac output in these patients. What has not been evaluated is the effect of extubation and loading of the respiratory muscles on the distribution of cardiac output after repair of tetralogy of Fallot. METHODS: In 23 consecutive patients undergoing repair of tetralogy of Fallot, standard hemodynamic variables, central venous oxygen saturations, and near infrared spectroscopy of the brain, mesenteric, and renal circulations were monitored for 30 minutes before and after extubation. RESULTS: With extubation, the systolic blood pressure increased significantly from 96 ± 11 to 106 ± 15 mm Hg (p = 0.002) while the heart rate remained unchanged. With extubation, the central venous oxygen saturation increased significantly from 65% ± 7% to 70% ± 10% (p = 0.003). Cerebral oxygen saturations increased significantly from 67% ± 10% to 72% ± 9% (p = 0.0001), whereas mesenteric oxygenation fell significantly from 74% ± 15% to 72% ± 15% (p = 0.04). Renal oxygenation was unaffected by extubation. CONCLUSIONS: Cardiac output and cerebral oxygenation increased significantly during spontaneous respiration, the latter suggesting that the brain was in or approaching an oxygen supply-dependent state before extubation. Despite the increase in cardiac output, the presumed increase in respiratory pump perfusion, as well as the concurrent increase in cerebral perfusion, came at the expense of mesenteric perfusion. Renal oxygenation remained unchanged with extubation.

Outcomes of heart failure-related hospitalization in adults with congenital heart disease in the United States.

BACKGROUND: Heart failure (HF) accounts for >3 million hospital admissions annually in adults with acquired cardiovascular disease, but there are limited data on HF admissions in adults with congenital heart disease (ACHD). The purpose of this study was to test the hypotheses that HF admissions are common in ACHD and associated with significant morbidity and mortality. METHODS: The 2007 Nationwide Inpatient Sample was used to assess national prevalence, morbidities, and risk factors for mortality during hospitalizations among ACHD with HF. RESULTS: Of the 84,308 (95% CI 71,345-97,272) ACHD admissions in the United States in 2007, 17,193 (95% CI 14,157-20,229) had a diagnosis of HF (20%). ACHD with HF was associated with an increased risk of death compared to ACHD without HF (OR 3.3, 95% CI 2.6-4.1). On multivariable analysis independent risk factors for mortality included nonoperative intubation (OR 6.1, 95% CI 3.3-11.4), sepsis (OR 4.3, 95% CI 2.4-7.4), and acute myocardial infarction (OR 3.2, 95% CI 1.8-5.7). Cardiac defects associated with an increased risk of mortality included ventricular septal defects (VSDs) (OR 1.8, 95% CI 1.0-3.4). CONCLUSIONS: In this large population-based study, HF-related hospitalizations were common in ACHD and associated with an increased risk of death compared to non-HF admissions. The risk of mortality is increased with the diagnoses of VSDs and the presence of specific comorbidities such as respiratory failure and sepsis.

Positive end-expiratory pressure oscillation facilitates brain vascular reactivity monitoring.

The pressure reactivity index (PRx) identifies optimal cerebral perfusion pressure after traumatic brain injury. We describe a method to improve PRx precision by induced variations in arterial blood pressure (ABP) using positive end-expiratory pressure (PEEP) modulation (iPRx). Neonatal swine (n = 10) were ventilated with static PEEP and then with PEEP oscillated between 5 and 10 cmH(2)O at a frequency of 1/min. PRx was recorded as a moving correlation coefficient between ABP and intracranial pressure (ICP) from spontaneous ABP activity (0.05-0.003 Hz) during static PEEP. iPRx was similarly recorded with PEEP oscillation-induced ABP waves. The lower limit of autoregulation (LLA) was delineated with continuous cortical laser Doppler flux monitoring. PEEP oscillation increased autoregulation-monitoring precision. The ratios of median absolute deviations to range of possible values for the PRx and iPRx were 9.5% (8.3-13.7%) and 6.2% (4.2-8.7%), respectively (P = 0.006; median, interquartile range). The phase-angle difference between ABP and ICP above LLA was 161° (150°-166°) and below LLA, -31° (-42° to 12°, P < 0.0001). iPRx above LLA was -0.42 (-0.67 to -0.29) and below LLA, 0.32 (0.22-0.43, P = 0.0004). A positive iPRx was 97% specific and 91% sensitive for perfusion pressure below LLA. PEEP oscillation caused stable, low-frequency ABP oscillations that reduced noise in the PRx. Safe translation of these findings to clinical settings is expected to yield more accurate and rapid delineation of individualized optimal perfusion-pressure goals for patients.

Identifying arrhythmias in adults with congenital heart disease by 24-h ambulatory electrocardiography.

Adults with congenital heart disease (CHD) are at risk for the development of arrhythmias. This study aimed to assess the incidence of unsuspected arrhythmias among adults with CHD identified on electrocardiograms (ECGs) and 24-h ambulatory electrocardiographic monitoring (Holter monitoring). A review of the cardiology database at the authors' institution from July 2004 through December 2007 identified all clinic patients 18 years old or older who had a recent ECG and Holter monitoring. Data collection included diagnosis, ECG and Holter monitoring results, arrhythmias, and the presence or absence of symptoms. The review identified 140 patients. Analysis of the ECGs showed that 15% of the patients had an arrhythmia. These arrhythmias consisted of ectopy (6%), supraventricular tachycardia (SVT) (3%), pacemaker issues (2%), and previously unrecognized atrioventricular block (AVB) (1%). The majority of the patients with arrhythmias were asymptomatic (76%). Analysis of the Holter monitoring results showed that 31% of the patients had arrhythmias consisting of ectopy (17%), SVT (12%), ventricular tachycardia (7%), high-grade AVB (5%), and pacemaker issues (3%). Of the patients with arrhythmias, 80% were asymptomatic. Among the patients without arrhythmias on ECG, 26% had arrhythmias noted on Holter monitoring. Of the patients with multiple Holter monitorings performed, 34% had a new arrhythmia noted on repeat monitoring. In conclusion, arrhythmias were present in a significant number of adults with CHD, but the majority were asymptomatic. Among adults with CHD, even those with normal ECGs, arrhythmias were frequently detected on Holter monitoring. In addition, repeat Holter monitoring may identify significant arrhythmias over time.

Effect of financial incentives on improvement in medical quality indicators for primary care.

PURPOSE: The efficacy of rewarding physicians financially for preventive services is unproven. The objective of this study was to evaluate the effect of a physician pay-for-performance program similar to the Medicare Physician Quality Reporting Initiative program on quality of preventive care in a network of community health centers. METHODS: A retrospective review of administrative data was done to evaluate a natural quasi-experiment in a network of publicly funded primary care clinics. Physicians in 6 of 11 clinics were given a financial incentive twice the size of the current Centers for Medicare and Medicaid Services' incentive for achieving group targets in preventive care that included cervical cancer screening, mammography, and pediatric immunization. They also received productivity incentives. Six years of performance indicators were compared between incentivized and nonincentivized clinics. We also surveyed the incentivized clinicians about their perception of the incentive program. RESULTS: Although some performance indicators improved for all measures and all clinics, there were no clinically significant differences between clinics that had incentives and those that did not. A linear trend test approached conventional significance levels for Papanicolaou smears (P = .08) but was of very modest magnitude compared with observed nonlinear variations; there was no suggestion of a linear trend for mammography or pediatric immunizations. The survey revealed that most physicians felt the incentives were not very effective in improving quality of care. CONCLUSION: We found no evidence for a clinically significant effect of financial incentives on performance of preventive care in these community health centers. Based on our findings and others, we believe there is great need for more research with strong research designs to determine the effects, both positive and negative, of financial incentives on clinical quality indicators in primary care.

Alleles of the NRAMP1 gene are risk factors for pediatric tuberculosis disease.

Relatively little is known about the human genetics of susceptibility to common diseases caused by bacterial pathogens. Tuberculosis, caused by Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. So far, genetic studies of tuberculosis susceptibility have largely been focused on adult patients despite the fact that tuberculosis is highly prevalent among children. To study the host genetic component of pediatric tuberculosis susceptibility, we enrolled 184 ethnically diverse families from the Greater Houston area with at least one child affected by pediatric tuberculosis disease. Using a family-based control design, we found allelic variants of the natural resistance-associated macrophage protein gene 1 (NRAMP1) (alias SLC11A1) significantly associated with tuberculosis disease in this pediatric patient population [P = 0.01; odds ratio = 1.75 (95% confidence interval, 1.10-2.77)]. The association of NRAMP1 with pediatric tuberculosis disease was significantly heterogeneous (P = 0.01) between simplex [P <0.0008; odds ratio = 3.13 (1.54-6.25)] and multiplex families (P = 1), suggesting an interplay between mechanisms of genetic control and exposure intensities. In striking contrast to previous studies in the adult population, we observed that the common alleles of NRAMP1 polymorphisms were risk factors for pediatric tuberculosis disease. To explain the different direction of allelic association between adult and pediatric disease, we hypothesize that NRAMP1 influences the speed of progression from infection to tuberculosis disease.

Genome-wide molecular dissection of serotype M3 group A Streptococcus strains causing two epidemics of invasive infections.

Molecular factors that contribute to the emergence of new virulent bacterial subclones and epidemics are poorly understood. We hypothesized that analysis of a population-based strain sample of serotype M3 group A Streptococcus (GAS) recovered from patients with invasive infection by using genome-wide investigative methods would provide new insight into this fundamental infectious disease problem. Serotype M3 GAS strains (n = 255) cultured from patients in Ontario, Canada, over 11 years and representing two distinct infection peaks were studied. Genetic diversity was indexed by pulsed-field gel electrophoresis, DNA-DNA microarray, whole-genome PCR scanning, prophage genotyping, targeted gene sequencing, and single-nucleotide polymorphism genotyping. All variation in gene content was attributable to acquisition or loss of prophages, a molecular process that generated unique combinations of proven or putative virulence genes. Distinct serotype M3 genotypes experienced rapid population expansion and caused infections that differed significantly in character and severity. Molecular genetic analysis, combined with immunologic studies, implicated a 4-aa duplication in the extreme N terminus of M protein as a factor contributing to an epidemic wave of serotype M3 invasive infections. This finding has implications for GAS vaccine research. Genome-wide analysis of population-based strain samples cultured from clinically well defined patients is crucial for understanding the molecular events underlying bacterial epidemics.

Left heart bypass during descending thoracic aortic aneurysm repair does not reduce the incidence of paraplegia.

BACKGROUND: The preferred technique for spinal cord protection during surgical repair of descending thoracic aortic aneurysms (DTAAs) remains controversial. The purpose of this retrospective analysis was to determine if the use of left heart bypass (LHB) reduced the incidence of paraplegia in patients who underwent DTAA repair. METHODS: Over a 15-year period 387 consecutive patients underwent surgical repair of DTAAs using either the "clamp-and-sew" technique (341 patients, 88.1%) or distal aortic perfusion via a LHB circuit (46 patients, 11.9%). Data regarding patient characteristics, operative variables, and outcomes were retrieved from a prospectively maintained database. The impact of LHB on the frequency of paraplegia was determined using univariate and propensity score analyses. RESULTS: There were 17 operative deaths (4.4%) including 11 patients (2.8%) who died within 30 days. Paraplegia occurred in 10 patients (2.6%). On univariate analysis increasing age (p = 0.03), increasing aortic clamp time (p < 0.001), increasing red blood cell transfusion requirements (p = 0.01), and acute dissection (p = 0.03) were associated with increased incidence of paraplegia. Patients who received LHB had a similar incidence of paraplegia (2/46, 4%) compared with those treated without LHB (8/341, 2.3%; p = 0.3). Both matching and stratification propensity score analyses confirmed that LHB was not associated with reduced risk of paraplegia. CONCLUSIONS: On retrospective analysis the use of LHB during DTAA repair did not reduce the incidence of spinal cord injury. The "clamp-and-sew" technique remains an appropriate approach to DTAA repair.

Relating the size of molecularly defined clusters of tuberculosis to the duration of symptoms.

Molecular profiling of Mycobacterium tuberculosis isolates has improved recognition of tuberculosis case clusters, but the determinants of cluster size are unknown. We hypothesized that longer duration of symptoms prior to initiation of tuberculosis therapy would be associated with increased cluster size. All patients with tuberculosis in Harris County, Texas, identified between 10/1/95 and 12/31/97 through a prospective population-based project were interviewed, had their medical records reviewed, and had M. tuberculosis isolates molecularly characterized. There were 506 symptomatic, evaluable patients in 74 clusters, ranging in size from 2 patients (32 clusters) to 61 patients (1 cluster). The median duration of symptoms was 46 days (range, 1-471 days). There was no association between the log-transformed duration of symptoms and cluster size in univariate or multivariate analysis. In multivariate analysis, age and HIV coinfection were inversely related to cluster size, but only weakly. The size of molecularly defined clusters of tuberculosis was not related to the duration of symptoms of most patients who belonged to clusters.

Molecular genetic analysis of 675 group A streptococcus isolates collected in a carrier study at Lackland Air Force Base, San Antonio, Texas.

Contemporary molecular genetic analysis methods have not been used to study large samples of carriage isolates of group A Streptococcus. To determine the emm types causing asymptomatic carriage and pharyngitis in a closed population, we analyzed 675 isolates recovered from a population-based surveillance study of 10,634 recruits at Lackland Air Force Base, Texas, during 4 months in 1993-1994. Strains with emm1 and emm6 alleles accounted for only 22% of the isolates recovered from asymptomatic recruits at entrance to training. However, these 2 emm types caused 69% of the pharyngitis cases identified during training and represented 51% of the isolates recovered from the throat on exit from training. Sequence analysis of the hypervariable sic gene documented that distinct emm1 subclones disseminated in specific training groups called flights. The preferential increase in the prevalence of emm1 and emm6 isolates during the 6-week training period indicates an enhanced ability of these strains to disseminate and cause disease in this population.

Individuation, peers, and adolescent alcohol use: a latent growth analysis.

The study used latent growth modeling to investigate longitudinal relationships between individuation, peer alcohol use, and adolescent alcohol use among African American, Mexican American, and non-Hispanic White adolescents (N = 6,048) from 7th, 8th, and 9th grades over a 3-year period. Initial levels of peer alcohol use were significantly related to changes in adolescents' alcohol use, whereas initial adolescent alcohol use also significantly related to changes in peers' alcohol use, suggesting a bidirectional relationship. Higher levels of intergenerational individuation were related to smaller increases in adolescent alcohol use and higher levels of separation were related to larger increases in youth drinking. The findings were similar across ethnic groups. Implications for development of prevention and intervention programs are discussed.

Virulence control in group A Streptococcus by a two-component gene regulatory system: global expression profiling and in vivo infection modeling.

Two-component gene regulatory systems composed of a membrane-bound sensor and cytoplasmic response regulator are important mechanisms used by bacteria to sense and respond to environmental stimuli. Group A Streptococcus, the causative agent of mild infections and life-threatening invasive diseases, produces many virulence factors that promote survival in humans. A two-component regulatory system, designated covRS (cov, control of virulence; csrRS), negatively controls expression of five proven or putative virulence factors (capsule, cysteine protease, streptokinase, streptolysin S, and streptodornase). Inactivation of covRS results in enhanced virulence in mouse models of invasive disease. Using DNA microarrays and quantitative RT-PCR, we found that CovR influences transcription of 15% (n = 271) of all chromosomal genes, including many that encode surface and secreted proteins mediating host-pathogen interactions. CovR also plays a central role in gene regulatory networks by influencing expression of genes encoding transcriptional regulators, including other two-component systems. Differential transcription of genes influenced by covR also was identified in mouse soft-tissue infection. This analysis provides a genome-scale overview of a virulence gene network in an important human pathogen and adds insight into the molecular mechanisms used by group A Streptococcus to interact with the host, promote survival, and cause disease.