Influence of Standard Laboratory Procedures on Measures of Erythrocyte Damage.

The ability to characterize the mechanical properties of erythrocytes is important in clinical and research contexts: to diagnose and monitor hematologic disorders, as well as to optimize the design of cardiovascular implants and blood circulating devices with respect to blood damage. However, investigation of red blood cell (RBC) properties generally involves preparatory and processing steps. Even though these impose mechanical stresses on cells, little is known about their impact on the final measurement results. In this study, we investigated the effect of centrifuging, vortexing, pipetting, and high pressures on several markers of mechanical blood damage and RBC membrane properties. Using human venous blood, we analyzed erythrocyte damage by measuring free hemoglobin, phosphatidylserine exposure by flow cytometry, RBC deformability by ektacytometry and the parameters of a complete blood count. We observed increased levels of free hemoglobin for all tested procedures. The release of hemoglobin into plasma depended significantly on the level of stress. Elevated pressures and centrifuging also altered mean cell volume (MCV) and mean corpuscular hemoglobin (MCH), suggesting changes in erythrocyte population, and membrane properties. Our results show that the effects of blood handling can significantly influence erythrocyte damage metrics. Careful quantification of this influence as well as other unwanted secondary effects should thus be included in experimental protocols and accounted for in clinical laboratories.

Barrier dysfunction or drainage reduction: differentiating causes of CSF protein increase.

BACKGROUND: Cerebrospinal fluid (CSF) protein analysis is an important element in the diagnostic chain for various central nervous system (CNS) pathologies. Among multiple existing approaches to interpreting measured protein levels, the Reiber diagram is particularly robust with respect to physiologic inter-individual variability, as it uses multiple subject-specific anchoring values. Beyond reliable identification of abnormal protein levels, the Reiber diagram has the potential to elucidate their pathophysiologic origin. In particular, both reduction of CSF drainage from the cranio-spinal space as well as blood-CNS barrier dysfunction have been suggested ρas possible causes of increased concentration of blood-derived proteins. However, there is disagreement on which of the two is the true cause. METHODS: We designed two computational models to investigate the mechanisms governing protein distribution in the spinal CSF. With a one-dimensional model, we evaluated the distribution of albumin and immunoglobulin G (IgG), accounting for protein transport rates across blood-CNS barriers, CSF dynamics (including both dispersion induced by CSF pulsations and advection by mean CSF flow) and CSF drainage. Dispersion coefficients were determined a priori by computing the axisymmetric three-dimensional CSF dynamics and solute transport in a representative segment of the spinal canal. RESULTS: Our models reproduce the empirically determined hyperbolic relation between albumin and IgG quotients. They indicate that variation in CSF drainage would yield a linear rather than the expected hyperbolic profile. In contrast, modelled barrier dysfunction reproduces the experimentally observed relation. CONCLUSIONS: High levels of albumin identified in the Reiber diagram are more likely to originate from a barrier dysfunction than from a reduction in CSF drainage. Our in silico experiments further support the hypothesis of decreasing spinal CSF drainage in rostro-caudal direction and emphasize the physiological importance of pulsation-driven dispersion for the transport of large molecules in the CSF.

Patient-Specific Surgical Planning, Where Do We Stand? The Example of the Fontan Procedure.

The Fontan surgery for single ventricle heart defects is a typical example of a clinical intervention in which patient-specific computational modeling can improve patient outcome: with the functional heterogeneity of the presenting patients, which precludes generic solutions, and the clear influence of the surgically-created Fontan connection on hemodynamics, it is acknowledged that individualized computational optimization of the post-operative hemodynamics can be of clinical value. A large body of literature has thus emerged seeking to provide clinically relevant answers and innovative solutions, with an increasing emphasis on patient-specific approaches. In this review we discuss the benefits and challenges of patient-specific simulations for the Fontan surgery, reviewing state of the art solutions and avenues for future development. We first discuss the clinical impact of patient-specific simulations, notably how they have contributed to our understanding of the link between Fontan hemodynamics and patient outcome. This is followed by a survey of methodologies for capturing patient-specific hemodynamics, with an emphasis on the challenges of defining patient-specific boundary conditions and their extension for prediction of post-operative outcome. We conclude with insights into potential future directions, noting that one of the most pressing issues might be the validation of the predictive capabilities of the developed framework.

Fontan hemodynamics from 100 patient-specific cardiac magnetic resonance studies: a computational fluid dynamics analysis.

OBJECTIVES: This study sought to quantify average hemodynamic metrics of the Fontan connection as reference for future investigations, compare connection types (intra-atrial vs extracardiac), and identify functional correlates using computational fluid dynamics in a large patient-specific cohort. Fontan hemodynamics, particularly power losses, are hypothesized to vary considerably among patients with a single ventricle and adversely affect systemic hemodynamics and ventricular function if suboptimal. METHODS: Fontan connection models were created from cardiac magnetic resonance scans for 100 patients. Phase velocity cardiac magnetic resonance in the aorta, vena cavae, and pulmonary arteries was used to prescribe patient-specific time-averaged flow boundary conditions for computational fluid dynamics with a customized, validated solver. Comparison with 4-dimensional cardiac magnetic resonance velocity data from selected patients was used to provide additional verification of simulations. Indexed Fontan power loss, connection resistance, and hepatic flow distribution were quantified and correlated with systemic patient characteristics. RESULTS: Indexed power loss varied by 2 orders of magnitude, whereas, on average, Fontan resistance was 15% to 20% of published values of pulmonary vascular resistance in single ventricles. A significant inverse relationship was observed between indexed power loss and both systemic venous flow and cardiac index. Comparison by connection type showed no differences between intra-atrial and extracardiac connections. Instead, the least efficient connections revealed adverse consequences from localized Fontan pathway stenosis. CONCLUSIONS: Fontan power loss varies from patient to patient, and elevated levels are correlated with lower systemic flow and cardiac index. Fontan connection type does not influence hemodynamic efficiency, but an undersized or stenosed Fontan pathway or pulmonary arteries can be highly dissipative.

Simulating hemodynamics of the Fontan Y-graft based on patient-specific in vivo connections.

BACKGROUND: Using a bifurcated Y-graft as the Fontan baffle is hypothesized to streamline and improve flow dynamics through the total cavopulmonary connection (TCPC). This study conducted numerical simulations to evaluate this hypothesis using postoperative data from 5 patients. METHODS: Patients were imaged with cardiac magnetic resonance or computed tomography after receiving a bifurcated aorto-iliac Y-graft as their Fontan conduit. Numerical simulations were performed using in vivo flow rates, as well as 2 levels of simulated exercise. Two TCPC models were virtually created for each patient to serve as the basis for hemodynamic comparison. Comparative metrics included connection flow resistance and inferior vena caval flow distribution. RESULTS: Results demonstrate good hemodynamic outcomes for the Y-graft options. The consistency of inferior vena caval flow distribution was improved over TCPC controls, whereas the connection resistances were generally no different from the TCPC values, except for 1 case in which there was a marked improvement under both resting and exercise conditions. Examination of the connection hemodynamics as they relate to surgical Y-graft implementation identified critical strategies and modifications that are needed to potentially realize the theoretical efficiency of such bifurcated connection designs. CONCLUSIONS: Five consecutive patients received a Y-graft connection to complete their Fontan procedure with positive hemodynamic results. Refining the surgical technique for implementation should result in further energetic improvements that may help improve long-term outcomes.

Comparing pre- and post-operative Fontan hemodynamic simulations: implications for the reliability of surgical planning.

Virtual modeling of cardiothoracic surgery is a new paradigm that allows for systematic exploration of various operative strategies and uses engineering principles to predict the optimal patient-specific plan. This study investigates the predictive accuracy of such methods for the surgical palliation of single ventricle heart defects. Computational fluid dynamics (CFD)-based surgical planning was used to model the Fontan procedure for four patients prior to surgery. The objective for each was to identify the operative strategy that best distributed hepatic blood flow to the pulmonary arteries. Post-operative magnetic resonance data were acquired to compare (via CFD) the post-operative hemodynamics with predictions. Despite variations in physiologic boundary conditions (e.g., cardiac output, venous flows) and the exact geometry of the surgical baffle, sufficient agreement was observed with respect to hepatic flow distribution (90% confidence interval-14 ± 4.3% difference). There was also good agreement of flow-normalized energetic efficiency predictions (19 ± 4.8% error). The hemodynamic outcomes of prospective patient-specific surgical planning of the Fontan procedure are described for the first time with good quantitative comparisons between preoperatively predicted and postoperative simulations. These results demonstrate that surgical planning can be a useful tool for single ventricle cardiothoracic surgery with the ability to deliver significant clinical impact.

Preliminary clinical experience with a bifurcated Y-graft Fontan procedure--a feasibility study.

OBJECTIVE: Optimizing flow and diminishing power loss in the Fontan circuit can improve hemodynamic efficiency, potentially improving the long-term outcomes. Computerized modeling has predicted improved energetics with a Y-graft Fontan. METHODS: From August to December 2010, 6 consecutive children underwent completion Fontan (n=3) or Fontan revision (n=3) using a bifurcated polytetrafluoroethylene Y-graft (18×9×9 mm in 2, 20×10×10 mm in 4) connecting the inferior vena cava to the right and left pulmonary arteries with separate graft limbs. The patents underwent magnetic resonance imaging (n=5) or computed tomography (n=1). Computational fluid dynamics assessed Fontan hemodynamics, power loss, and inferior vena cava flow splits to the branch pulmonary arteries. The clinical parameters were compared with those from 12 patients immediately preceding the present series who had undergone a lateral Fontan procedure. RESULTS: Despite longer crossclamp and bypass times (not statistically significant), the Y-graft Fontan patients had postoperative courses similar to those of the conventional Fontan patients. Other than 2 early readmissions for pleural effusions managed with diuretics, at 6 to 12 months of follow-up (mean, 8 months), all 6 patients had done well. Postoperative flow modeling demonstrated a balanced distribution of inferior vena cava flow to both pulmonary arteries with minimal flow disturbance. Improvements in hemodynamics and efficiency were noted when the Y-graft branches were anastomosed distally and aligned tangentially with the branch pulmonary arteries. CONCLUSIONS: The present preliminary surgical experience has demonstrated the clinical feasibility of the bifurcated Y-graft Fontan. Computational fluid dynamics showed acceptable hemodynamics with low calculated power losses and a balanced distribution of inferior vena cava flow to the pulmonary arteries as long as the branch grafts were anastomosed distally.

Individualized computer-based surgical planning to address pulmonary arteriovenous malformations in patients with a single ventricle with an interrupted inferior vena cava and azygous continuation.

OBJECTIVE: Pulmonary arteriovenous malformations caused by abnormal hepatic flow distribution can develop in patients with a single ventricle with an interrupted inferior vena cava. However, preoperatively determining the hepatic baffle design that optimizes hepatic flow distribution is far from trivial. The current study combines virtual surgery and numeric simulations to identify potential surgical strategies for patients with an interrupted inferior vena cava. METHODS: Five patients with an interrupted inferior vena cava and severe pulmonary arteriovenous malformations were enrolled. Their in vivo anatomies were reconstructed from magnetic resonance imaging (n = 4) and computed tomography (n = 1), and alternate virtual surgery options (intracardiac/extracardiac, Y-grafts, hepato-to-azygous shunts, and azygous-to-hepatic shunts) were generated for each. Hepatic flow distribution was assessed for all options using a fully validated computational flow solver. RESULTS: For patients with a single superior vena cava (n = 3), intracardiac/extracardiac connections proved dangerous, because even a small left or right offset led to a highly preferential hepatic flow distribution to the associated lung. The best results were obtained with either a Y-graft spanning the Kawashima to split the flow or hepato-to-azygous shunts to promote mixing. For patients with bilateral superior vena cavae (n = 2), results depended on the balance between the left and right superior inflows. When those were equal, connecting the hepatic baffle between the superior vena cavae performed well, but other options should be pursued otherwise. CONCLUSIONS: This study demonstrates how virtual surgery environments can benefit the clinical community, especially for patients with a single ventricle with an interrupted inferior vena cava. Furthermore, the sensitivity of the optimal baffle design to the superior inflows underscores the need to characterize both preoperative anatomy and flows to identify the best option.

Hemodynamic Modeling of Surgically Repaired Coarctation of the Aorta.

PURPOSE: Late morbidity of surgically repaired coarctation of the aorta includes early cardiovascular and cerebrovascular disease, shortened life expectancy, abnormal vasomodulator response, hypertension and exercise-induced hypertension in the absence of recurrent coarctation. Observational studies have linked patterns of arch remodeling (Gothic, Crenel, and Romanesque) to late morbidity, with Gothic arches having the highest incidence. We evaluated flow in native and surgically repaired aortic arches to correlate respective hemodynamic indices with incidence of late morbidity. METHODS: Three dimensional reconstructions of each remodeled arch were created from an anatomic stack of magnetic resonance (MR) images. A structured mesh core with a boundary layer was generated. Computational fluid dynamic (CFD) analysis was performed assuming peak flow conditions with a uniform velocity profile and unsteady turbulent flow. Wall shear stress (WSS), pressure and velocity data were extracted. RESULTS: The region of maximum WSS was located in the mid-transverse arch for the Crenel, Romanesque and Native arches. Peak WSS was located in the isthmus of the Gothic model. Variations in descending aorta flow patterns were also observed among the models. CONCLUSION: The location of peak WSS is a primary difference among the models tested, and may have clinical relevance. Specifically, the Gothic arch had a unique location of peak WSS with flow disorganization in the descending aorta. Our results suggest that varied patterns and locations of WSS resulting from abnormal arch remodeling may exhibit a primary effect on clinical vascular dysfunction.

Flow study of an extracardiac connection with persistent left superior vena cava.

BACKGROUND: Numerous studies have sought to optimize the design of total cavopulmonary connections with a single superior vena cava. This study was directed to the 2% to 4.5% of the population with dual superior venae cavae, investigating the flow fields associated with such total cavopulmonary connection anatomies. Additionally, it demonstrates the potential use of computational designs and simulations as surgical planning tools. METHODS: A 3-dimensional model of a total cavopulmonary connection with bilateral superior venae cavae was reconstructed from a patient's magnetic resonance images and investigated experimentally and numerically to assess the power losses and flow structures within the connection. On the basis of these results, a virtual operation was performed in the computer to improve the original connection design. The modified anatomy was studied numerically. RESULTS: Because of a smooth connection with an extracardiac conduit and no major dimension mismatch between the baffle and the connecting vessels, the original anatomy yielded smooth flow fields, low power losses, and few disturbances. However, a large offset between the inferior vena cava and the left superior vena cava resulted in flow stasis and unbalanced hepatic flow distribution. Shifting the inferior vena cava and positioning it between the 2 superior venae cavae resulted in a 7% decrease in power losses and eliminated the associated flow stasis regions in the main pulmonary artery segment. CONCLUSIONS: This study demonstrates the potential use of computer-aided design and numeric simulations for surgical planning. It shows that locating the inferior vena cava between the superior venae cavae may lead to better-balanced lung perfusion. This may require suturing the right and left superior venae cavae closer to each other during the hemi-Fontan or Glenn stage.

In vitro flow analysis of a patient-specific intraatrial total cavopulmonary connection.

BACKGROUND: Understanding the hemodynamics of the total cavopulmonary connection may lead to further optimization of the connection design and surgical planning, which in turn may lead to improved surgical outcome. Although most experimental and numerical investigations have mainly focused on somewhat simplified geometries, investigation of the flow field of true anatomic configurations is necessary for a true understanding. METHODS: An intraatrial connection was reconstructed from patient magnetic resonance images and manufactured using transparent stereolithography. Power loss, flow visualization, and digital particle image velocimetry as well as computational fluid dynamics simulations were performed to characterize the anatomic flow structure. Given the complexity of the anatomic flow, two simplified versions of the geometry were manufactured and run through power loss and flow visualization studies. RESULTS: Experimental measurements revealed complex, unsteady, and highly three-dimensional flow structures within the anatomic model, leading to high pressure drops and power losses. The small vessel diameters were the primary cause of these losses. Numerical simulations demonstrated that most of the dissipation occurred in the pulmonary arteries. Finally, asymmetric pulmonary diameters together with the bulgy intraatrial connection favored the rise of flow unsteadiness and unbalanced lung perfusion. CONCLUSIONS: The technique developed in this study enabled a deeper understanding of the hemodynamics behind an intraatrial connection. Future endeavors would be to study variation among differing surgical techniques, comparing intraatrial and extracardiac approaches.