Perfusion techniques for an 800 g premature neonate undergoing Arterial Switch Procedure for Transposition of the Great Arteries☠.

Early cardiac surgery in neonates and infants with congenital heart disease has been performed since the middle to late years of the twentieth century. To date, there are very few reports of successful congenital heart surgery using cardiopulmonary bypass (CPB) in premature babies less than 1000 g with serious congenital heart disease. Limited information is available in the literature describing perfusion techniques for this extremely fragile patient population. Miniaturization of the CPB circuit contributes to multiple factors that affect this population significantly. These factors include the reduction of patient-to-circuit ratios, volume of distribution of pharmacological agents, management of pressure gradients within the CPB system, and increased tactile control by the attending perfusionist. Careful management of the physiological environment of the patient is of utmost importance and can mitigate risks during CPB, including volume shifts into the interstitial space, electrolyte, and acid-base imbalance, and intracranial hemorrhage. We report perfusion techniques successfully utilized during the surgical repair of transposition of the great arteries for an 800 g, 28-week-old neonate. CPB techniques for the smallest and youngest patients may be executed safely when proper physical, chemical, and perfusion process adjustments are made and managed meticulously.

Increased cerebral mitochondrial dysfunction and reactive oxygen species with cardiopulmonary bypass.

OBJECTIVES: Neurodevelopmental injury after cardiac surgery using cardiopulmonary bypass (CPB) for congenital heart defects is common, but the mechanism behind this injury is unclear. This study examines the impact of CPB on cerebral mitochondrial reactive oxygen species (ROS) generation and mitochondrial bioenergetics. METHODS: Twenty-three piglets (mean weight 4.2 ± 0.5 kg) were placed on CPB for either 1, 2, 3 or 4 h (n = 5 per group) or underwent anaesthesia without CPB (sham, n = 3). Microdialysis was used to measure metabolic markers of ischaemia. At the conclusion of CPB or 4 h of sham, brain tissue was harvested. Utilizing high-resolution respirometry, with simultaneous fluorometric analysis, mitochondrial respiration and ROS were measured. RESULTS: There were no significant differences in markers of ischaemia between sham and experimental groups. Sham animals had significantly higher mitochondrial respiration than experimental animals, including maximal oxidative phosphorylation capacity of complex I (OXPHOSCI) (3.25 ± 0.18 vs 4-h CPB: 1.68 ± 0.10, P < 0.001) and maximal phosphorylating respiration capacity via convergent input through complexes I and II (OXPHOSCI+CII) (7.40 ± 0.24 vs 4-h CPB: 3.91 ± 0.20, P < 0.0001). At 4-h, experimental animals had significantly higher ROS related to non-phosphorylating respiration through complexes I and II (ETSCI+CII) than shams (1.08 ± 0.13 vs 0.64 ± 0.04, P = 0.026). CONCLUSIONS: Even in the absence of local markers of ischaemia, CPB is associated with decreased mitochondrial respiration relative to shams irrespective of duration. Exposure to 4 h of CPB resulted in a significant increase in cerebral mitochondrial ROS formation compared to shorter durations. Further study is needed to improve the understanding of cerebral mitochondrial health and its effects on the pathophysiology of neurological injury following exposure to CPB.

Comparison of three autotransfusion devices for utilization in the pediatric population.

INTRODUCTION: A device that may help attenuate the amount of homologous blood product given to pediatric cardiac surgical patients is the autotransfusion device. Three separate autotransfusion devices were selected for evaluation. The Sorin Xtra, Fresenius Continuous Autotransfusion System Plus (CATS*plus), and the Fresenius Continuous Autotransfusion System Smart (CATSmart) were evaluated based on the mechanical processes of each device, hematocrit value of the salvaged packed red cell product, time of processing, and the advantageous accessories with each device. METHODS: Each of the autotransfusion devices were used to collect salvageable blood from the surgical field as well as to process residual blood from the cardiopulmonary bypass circuit after decannulation. The cell salvage process was performed in accordance with the manufacturer's instructions for use and the recommended settings for processing and washing. The Sorin Xtra device had the 55 mL bowl set up for all cases, while the Fresenius continuous autotransfusion systems utilized the standard disposable for each device. RESULTS: Each cell salvage device was employed during 30 pediatric cardiac surgery procedures, and data for each device, was broken down into four groups based on patient weight (0-10, 10-20, 20-40, and >40 kg). For all patient sizes, the Sorin Xtra tended to produce the greatest volume of cell saver product (55-825 mL) as compared to the CATS*plus and CATSmart devices (7-550 mL and 0-860 mL, respectively). The Continuous Autotransfusion System Smart tended to produce the highest hematocrit product, ranging from 44 to 81%. DISCUSSION: Through this evaluation, it was determined the continuous autotransfusion systems provided the highest hematocrit with the lowest recovered packed red cell volume, while the Sorin Xtra packed red cell product showed to have a lower hematocrit with a larger packed red cell volume. Each device proved effective within our pediatric population.

Comparison of three infant venous reservoirs with vacuum-assisted venous drainage during varying levels of cardiotomy suction.

BACKGROUND: Vacuum-assisted venous drainage has gained widespread use within the pediatric perfusion community for use during cardiopulmonary bypass. It is questioned whether its efficiency may be compromised with application of excessive cardiotomy suction to the infant hard-shell venous reservoir. An in vitro simulation circuit was used to research this phenomenon. A comparison of three different infant hard-shell venous reservoirs also took place to determine if one reservoir type was more advantageous when handling cardiotomy suction. The reservoirs tested were the Maquet VHK 11000, Medtronic Affinity Pixie, and Terumo Capiox FX05. METHODS: The in vitro simulation circuit consisted of a 1 L reservoir bag that was cannulated at one access point with an Edwards Lifesciences 10Fr aortic cannula and the other access area with an Edwards Lifesciences 10Fr right angle venous cannula and 12Fr right angle venous cannula that were joined together. Key points of measurement and response variables were the pressures on the connection of the venous cannulas, inlet of the venous reservoir, and flow through the venous line. Vacuum was applied and manipulated with a Maquet VAVD Controller to settings of -20 mmHg, -30 mmHg, -40 mmHg, -50 mmHg, and -60 mmHg. Cardiotomy suction was added at settings of 1 LPM, 2 LPM, 3 LPM, and 4 LPM. Values from each response variable were monitored and recorded. These data were utilized to compare the reservoirs with a random coefficient model for each response variable. CONCLUSIONS: There is an adverse effect of excessive cardiotomy suction on the efficacy of vacuum-assisted venous drainage in infant hard-shell venous reservoirs. There is no significant difference between the VHK 11000, Pixie, and FX05 regarding their ability to handle this occurrence. An important discovery was that the FX05 showed a greater transfer of vacuum to the venous cannulas and reservoir inlet.

Implementation of a Pharmacist-Directed Antimicrobial Stewardship Protocol Utilizing Rapid Diagnostic Testing.

Background: Rapid identification of gram-positive bacteria and resistance determinants from blood cultures can reduce the time to optimal antibiotic therapy. Objective: This study evaluates the use of technology to rapidly identify gram-positive bacteria in combination with a pharmacist-directed antimicrobial stewardship protocol in a tertiary-care facility. Methods: Rapid diagnostic testing was performed on gram-positive blood cultures. Pharmacists were instructed to notify prescribers of results and recommend appropriate antimicrobial therapy based on targeted treatment chart. The primary outcomes were mean time to optimal antibiotic therapy, mean time antibiotics were avoided before traditional culture results, and percent of patients with time to optimal antibiotic therapy reached in less than or equal to 2 hours. Results: Inclusion criteria were met for 297 patients. Mean time to identify bacteria was 26.8 hours with nucleic acid assay versus 75.3 hours with traditional culture (difference = 48.5 hours, p < .0001). The rapid identification of gram-positive bacteria combined with accepted pharmacist intervention improved time to optimal antibiotic therapy (8.4 vs 15.4 hours, p = .0095). When contaminants were identified, antibiotics were avoided for 39.5 hours before traditional culture with pharmacist intervention versus 37.2 hours (p > .05). Antibiotic change occurred in less than or equal to 2 hours in more patients in the pharmacist intervention group (28% vs 10.5%, p = .0002). Conclusions: Rapid identification combined with pharmacist intervention significantly improved time to optimal antibiotic therapy and significantly increased the number of patients receiving optimal antibiotic therapy in less than or equal to 2 hours over rapid identification alone. A pharmacist-directed protocol combined with rapid identification enhanced antimicrobial stewardship.

Implementing RTI in a high school: a case study.

This case study chronicles the efforts of a small high school over a 2-year period as it designed an implemented a response to intervention (RTI) program for students at the school. Their efforts were largely successful, with improved achievement, attendance, and grade point averages and a decrease in special education referrals. Major themes include the need to focus on quality core instruction as a means for preventing school failure, adopting a schoolwide approach, and developing curriculum-based assessments that make intervention meaningful.

New kinase regulation mechanism found in HipBA: a bacterial persistence switch.

Bacterial persistence is the ability of individual cells to randomly enter a period of dormancy during which the cells are protected against antibiotics. In Escherichia coli, persistence is regulated by the activity of a protein kinase HipA and its DNA-binding partner HipB, which is a strong inhibitor of both HipA activity and hip operon transcription. The crystal structure of the HipBA complex was solved by application of the SAD technique to a mercury derivative. In this article, the fortuitous and interesting effect of mercury soaks on the native HipBA crystals is discussed as well as the intriguing tryptophan-binding pocket found on the HipA surface. A HipA-regulation model is also proposed that is consistent with the available structural and biochemical data.

Ensemble stump classifiers and gene expression signatures in lung cancer.

Microarray data sets for cancer tumor tissue generally have very few samples, each sample having thousands of probes (i.e., continuous variables). The sparsity of samples makes it difficult for machine learning techniques to discover probes relevant to the classification of tumor tissue. By combining data from different platforms (i.e., data sources), data sparsity is reduced, but this typically requires normalizing data from the different platforms, which can be non-trivial. This paper proposes a variant on the idea of ensemble learners to circumvent the need for normalization. To facilitate comprehension we build ensembles of very simple classifiers known as decision stumps--decision trees of one test each. The Ensemble Stump Classifier (ESC) identifies an mRNA signature having three probes and high accuracy for distinguishing between adenocarcinoma and squamous cell carcinoma of the lung across four data sets. In terms of accuracy, ESC outperforms a decision tree classifier on all four data sets, outperforms ensemble decision trees on three data sets, and simple stump classifiers on two data sets.

A nuclear magnetic resonance-based functional assay for nicotinamide adenine dinucleotide synthetase.

Nicotinamide adenine dinucleotide synthetase (NadE) is an essential enzyme for bacterial pathogens and is thus a promising antibacterial target. It catalyzes the conversion of nicotinic acid adenine dinucleotide to nicotinamide adenine dinucleotide. Changes in chemical shifts that occur in the nicotinic acid ring as it is converted to nicotinamide can be used for monitoring the reaction. A robust nuclear magnetic resonance-based activity assay was developed using robotically controlled reaction initiation and quenching. The single-enzyme assay has less potential for false positives compared to a coupled activity assay and is especially well suited to the high concentration of compounds in fragment screens. The assay has been used to screen fragment libraries for NadE inhibitors.

Data mining for gene networks relevant to poor prognosis in lung cancer via backward-chaining rule induction.

We use Backward Chaining Rule Induction (BCRI), a novel data mining method for hypothesizing causative mechanisms, to mine lung cancer gene expression array data for mechanisms that could impact survival. Initially, a supervised learning system is used to generate a prediction model in the form of "IF THEN " style rules. Next, each antecedent (i.e. an IF condition) of a previously discovered rule becomes the outcome class for subsequent application of supervised rule induction. This step is repeated until a termination condition is satisfied. "Chains" of rules are created by working backward from an initial condition (e.g. survival status). Through this iterative process of "backward chaining," BCRI searches for rules that describe plausible gene interactions for subsequent validation. Thus, BCRI is a semi-supervised approach that constrains the search through the vast space of plausible causal mechanisms by using a top-level outcome to kick-start the process. We demonstrate the general BCRI task sequence, how to implement it, the validation process, and how BCRI-rules discovered from lung cancer microarray data can be combined with prior knowledge to generate hypotheses about functional genomics.

A new chemical tool for exploring the role of the PDE4D isozyme in leukocyte function.

Nicotinamide (2) is a potent and selective inhibitor of the PDE4D isozyme and as a chemical tool selectively blocks eosinophil mediator release and chemotaxis thus linking the role of PDE4D to eosinophil function.

Using prior knowledge and rule induction methods to discover molecular markers of prognosis in lung cancer.

An iterative computational scientific discovery approach is proposed and applied to gene expression data for resectable lung adenocarcinoma patients. We use genes learned from the C5.0 rule induction algorithm, clinical features and prior knowledge derived from a network of interacting genes as represented in a database obtained with PathwayAssist to discover markers for prognosis in the gene expression data. This is done in an iterative fashion with machine learning techniques seeding the prior knowledge. This research illustrates the utility of combining signaling networks and machine learning techniques to produce simple prognostic classifiers.

Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.

Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.