Ibuprofen for neuroprotection after cerebral ischemia

ObjectiveIbuprofen has been shown to reduce cerebral ischemic injury, such as may occur after deep hypothermic circulatory arrest. We investigated whether ibuprofen has direct protective effects against excitotoxic neuronal injury, as may be seen after cerebral ischemia, by using a cell culture model.MethodsMixed cortical cultures containing neuronal and glial cells were prepared from fetal mice at 13 to 15 days gestation, plated on a layer of confluent astrocytes from 1- to 3-day-old postnatal pups. Near-pure neuronal cultures containing less than 5% astrocytes were obtained from mice of the same gestational stage. Slowly triggered excitotoxic injury was induced at 37°C by 24-hour exposure to 12.5 μmol/L N-methyl-D-aspartate or 50 μmol/L kainate. Neuronal death was quantified by release of lactate dehydrogenase from damaged cells. Data were analyzed using 1-way analysis of variance with Tukey post hoc multiple comparisons.ResultsIn mixed cultures, ibuprofen concentrations of 25 μg/mL, 50 μg/mL, and 100 μg/mL all significantly reduced N-methyl-D-aspartate–induced neuronal cell death from 74.5% to 56.1%, 38.7%, and 12.3%, respectively, revealing a strong dose response (P < .001). In near-pure cultures, ibuprofen at a concentration of 25 μg/mL failed to protect neurons, indicating that the neuroprotective effects of ibuprofen require interaction with glial cells. Furthermore, ibuprofen at 100 μg/mL was not protective against neuronal cell death induced by kainate exitotoxicity in near-pure culture but was effective in mixed cultures.ConclusionIbuprofen provides neuroprotection through glial cells against excitotoxic neuronal injury caused by glutamatergic excitotoxicity after cerebral ischemia as demonstrated by reduced neuronal cell death in mixed cell cultures. Further studies are needed to evaluate the potential of ibuprofen to reduce neurologic injury in patients experiencing an hypoxic/ischemic insult

Evaluation of hemostatic and coagulation factor abnormalities in patients undergoing the Fontan operation

AbstractObjective: Low-velocity and nonlaminar flow patterns in the Fontan circulation, as well as abnormal liver function in some patients, may partly account for the coagulation abnormalities seen. We examined (1) coagulation factor abnormalities before and after the Fontan procedure and (2) regional coagulation factor abnormalities in the Fontan circulation. Methods: Levels of factors V, VII, VIII, X, antithrombin III, prothrombin fragment F1+2, protein C, and protein S were measured in 2 groups of patients: In 14 patients undergoing the Fontan procedure, blood was analyzed before the operation and 5 days after the operation (group 1). The median age in this group was 3.2 years. In 10 patients who had undergone the Fontan procedure, cardiac catheterization was performed and samples were taken from the femoral vein, inferior vena cava, right atrium, and pulmonary artery (group 2). The median age in this group was 6.2 years and the median follow-up from the Fontan procedure was 4.1 years. Results: In group 1 a significant increase was noted postoperatively in the concentration of factor VIII (P < .001), factor X (P < .001), and prothrombin fraction F1+2 (P < .001). A significant decrease in the levels of antithrombin III (P < .001), protein C (P < .004), and protein S (P < .02) was also found. The increase in factors VIII and X persisted at 4 years' follow-up in group 2 patients. In group 2, no significant regional differences were observed between the coagulation factors measured at different sites. Conclusions: There is an increased tendency toward coagulation after the Fontan procedure. A prothrombotic state is supported by thrombin generation associated with reduced antithrombin III concentration. This increase in coagulation may contribute to the early and late risks of thromboembolism observed after the Fontan procedure. We did not find any regional differences in coagulation abnormalities in patients late after the Fontan procedure. Therefore, the mechanisms and causes of the coagulation abnormalities remain unclear. (J Thorac Cardiovasc Surg 2000;120:778-82

Prospective longitudinal study of coagulation profiles in children with hypoplastic left heart syndrome from stage I through Fontan completion

ObjectiveThe risk for thrombosis is increased after the Fontan operation. It is unknown whether children with univentricular heart disease have an intrinsic coagulation anomaly or acquire a defect in coagulation during the course of the staged repair. This prospective, longitudinal study evaluated changes in coagulation profiles in a cohort of patients with hypoplastic left heart syndrome from stage I palliation through completion of the Fontan operation.MethodsThirty-seven patients with hypoplastic left heart syndrome were enrolled prospectively, and the concentration of factors II, V, VII, VIII, IX, X, proteins C and S, fibrinogen, antithrombin, serum albumin, and liver enzymes were measured before stage I palliation (mean age 4 ± 2 days), before bidirectional Glenn (mean age 5.9 ± 1.8 months), before the Fontan procedure (mean age 27.1 ± 6.6 months), and after the Fontan procedure (mean age 49 ± 17.6months). Healthy children were used as age-matched controls for coagulation factors. Demographic, hemodynamic variables, and elapsed time after the Fontan procedure were evaluated as possible predictors of coagulation abnormalities.ResultsSignificantly lower levels of both procoagulation and anticoagulation factors were demonstrated through to completion of the Fontan procedure. After the Fontan procedure, there was a significantly higher factor VIII level (P < .005) but no correlation with hemodynamic variables or liver function.ConclusionThis longitudinal study in patients with identical cardiac disease and staged surgical procedures confirms the increase in factor VIII level after the Fontan procedure. This is an acquired defect, and although the cause remains to be determined, monitoring factor VIII levels after the Fontan operation could indicate a subset of patients at risk for thrombosis

Prospective longitudinal study of coagulation profiles in children with hypoplastic left heart syndrome from stage I through Fontan completion

ObjectiveThe risk for thrombosis is increased after the Fontan operation. It is unknown whether children with univentricular heart disease have an intrinsic coagulation anomaly or acquire a defect in coagulation during the course of the staged repair. This prospective, longitudinal study evaluated changes in coagulation profiles in a cohort of patients with hypoplastic left heart syndrome from stage I palliation through completion of the Fontan operation.MethodsThirty-seven patients with hypoplastic left heart syndrome were enrolled prospectively, and the concentration of factors II, V, VII, VIII, IX, X, proteins C and S, fibrinogen, antithrombin, serum albumin, and liver enzymes were measured before stage I palliation (mean age 4 ± 2 days), before bidirectional Glenn (mean age 5.9 ± 1.8 months), before the Fontan procedure (mean age 27.1 ± 6.6 months), and after the Fontan procedure (mean age 49 ± 17.6months). Healthy children were used as age-matched controls for coagulation factors. Demographic, hemodynamic variables, and elapsed time after the Fontan procedure were evaluated as possible predictors of coagulation abnormalities.ResultsSignificantly lower levels of both procoagulation and anticoagulation factors were demonstrated through to completion of the Fontan procedure. After the Fontan procedure, there was a significantly higher factor VIII level (P < .005) but no correlation with hemodynamic variables or liver function.ConclusionThis longitudinal study in patients with identical cardiac disease and staged surgical procedures confirms the increase in factor VIII level after the Fontan procedure. This is an acquired defect, and although the cause remains to be determined, monitoring factor VIII levels after the Fontan operation could indicate a subset of patients at risk for thrombosis

Assessment of axial bone rigidity in rats with metabolic diseases using CT-based structural rigidity analysis

Objectives: This study aims to assess the correlation of CT-based structural rigidity analysis with mechanically determined axial rigidity in normal and metabolically diseased rat bone. Methods: A total of 30 rats were divided equally into normal, ovariectomized, and partially nephrectomized groups. Cortical and trabecular bone segments from each animal underwent micro-CT to assess their average and minimum axial rigidities using structural rigidity analysis. Following imaging, all specimens were subjected to uniaxial compression and assessment of mechanically-derived axial rigidity. Results: The average structural rigidity-based axial rigidity was well correlated with the average mechanically-derived axial rigidity results (R$^2$ = 0.74). This correlation improved significantly (p < 0.0001) when the CT-based Structural Rigidity Analysis (CTRA) minimum axial rigidity was correlated to the mechanically-derived minimum axial rigidity results (R$^2$ = 0.84). Tests of slopes in the mixed model regression analysis indicated a significantly steeper slope for the average axial rigidity compared with the minimum axial rigidity (p = 0.028) and a significant difference in the intercepts (p = 0.022). The CTRA average and minimum axial rigidities were correlated with the mechanically-derived average and minimum axial rigidities using paired t-test analysis (p = 0.37 and p = 0.18, respectively). Conclusions: In summary, the results of this study suggest that structural rigidity analysis of micro-CT data can be used to accurately and quantitatively measure the axial rigidity of bones with metabolic pathologies in an experimental rat model. It appears that minimum axial rigidity is a better model for measuring bone rigidity than average axial rigidity

Intermediate-Term Results of Extracorporeal Membrane Oxygenation Support Following Congenital Heart Surgery

Background: Although there are considerable data regarding in-hospital results of congenital heart surgery patients requiring post-operative extracorporeal membrane oxygenation support, there is limited information on intermediate-term outcomes. Methods: A single institution retrospective review of 25 consecutive post-operative congenital heart surgery patients who required extracorporeal membrane oxygenation and survived to hospital discharge between January 2003 and June 2008. Survival was estimated by the Kaplan-Meier method. Results: At a median follow-up of 3.3 years (interquartile range: 1.2-5.9 years), there was 1 death which occurred at 6 months post-surgery. Kaplan-Meier estimated survival at 3 years was 95% (95% confidence interval: 90-100%). Indications for extracorporeal membrane oxygenation included extracorporeal cardiopulmonary resuscitation (48%), systemic hypoxia (4%), post-operative low cardiac output syndrome (28%), and intra-operative failure to wean off of cardiopulmonary bypass (20%). Following extracorporeal membrane oxygenation support, 65% of patients had unplanned cardiac re-interventions (3 requiring operative interventions, 6 requiring percutaneous interventions, and 4 requiring both), and 47% required unplanned hospitalizations. 29% developed neurological deficits, and 12% developed chronic respiratory failure. No patients developed renal failure. Overall systemic ventricular function normalized in 83% of patients, whereas 17% had persistent mild-to-moderate systemic ventricular dysfunction. Conclusions: Intermediate-term patient survival of extracorporeal membrane oxygenation following congenital heart surgery is encouraging. However, neurological impairment and unplanned cardiac re-interventions remain significant concerns. Further delineation of risk factors to improve patient outcomes is warranted

Surgery for bilateral outflow tract obstruction in elastin arteriopathy

AbstractObjective: A number of patients with Williams syndrome or other forms of elastin arteriopathy have stenoses of pulmonary arteries in addition to supravalvular aortic stenosis. We sought to investigate the effect of the degree of pulmonary arterial stenosis on the prognosis after an operation for supravalvular aortic stenosis to help define the optimal treatment strategy for patients with severe forms of elastin arteriopathy. Methods: Between 1960 and 1999, 33 patients underwent operations for supravalvular aortic stenosis while having significant stenoses of the pulmonary arteries. We retrospectively reviewed patient charts, obtained current follow-up information, and determined risk factors for survival and reoperation. Results: Fifteen patients with moderate right-sided obstructions (confirmed by pulmonary artery Z-scores and right ventricular/descending aortic pressure ratio) underwent operations for supravalvular aortic stenosis only. Eighteen patients had more severe right-sided obstructions and underwent surgical relief of pulmonary arterial stenoses or right ventricular outflow tract obstruction in addition to operations for supravalvular aortic stenosis. Eight patients had undergone preoperative balloon dilations of stenotic pulmonary arteries. There were 6 early deaths and 1 late death in our series. Survival at 10 and 20 years was 76% (70% confidence interval, 68%-84%) and freedom from reintervention was 59% (70% confidence interval, 46%-71%) at 10 years and 49% (70% confidence interval, 35%-62%) at 20 years. Multivariate analysis revealed that patients with a right ventricular/descending aortic pressure ratio of 1.0 or more were at higher risk for reintervention but not for death. Conclusions: Surgical treatment of pulmonary artery obstructions in elastin arteriopathy is palliative but, in conjunction with balloon dilation of peripheral pulmonary arteries, offers good long-term survival to patients with the severest form of elastin arteriopathy. (J Thorac Cardiovasc Surg 2000;120:755-63

Forty-one years of surgical experience with congenital supravalvular aortic stenosis

AbstractObjective: Several techniques for symmetric reconstruction of the aortic root in congenital supravalvular aortic stenosis have been developed, but it remains unclear whether these prove superior to patch enlargement of the noncoronary sinus alone. We reviewed our experience with surgical treatment of supravalvular aortic stenosis and investigated the impact of the surgical technique on long-term results. Methods and results: Seventy-five patients underwent operations to treat congenital supravalvular aortic stenosis at our institution between 1957 and 1998. Surgical procedures included patch enlargement of the noncoronary sinus only (n = 34), inverted bifurcated patch plasty (n = 35), and 3-sinus reconstruction of the aortic root (n = 6). There were 7 early deaths. Among those who survived the operation, 100% were alive at 5 years, 96% were alive at 10 years, and 77% were alive at 20 years. According to time-related analysis diffuse stenosis of the ascending aorta proved a risk factor for both survival and reoperation (P < .01 for each). Patients with multiple-sinus reconstructions of the aortic root accounted for only 2 of the 14 reoperations and none of the late deaths (both P < .001). Residual gradients were lower after multiple-sinus reconstruction of the aortic root (median 10 mm Hg vs 20 mm Hg for patch enlargement of the noncoronary sinus only, P = .008), as was the prevalence of moderate aortic regurgitation at follow-up (3% vs 22%, P = .05). Conclusions: Results of operations for supravalvular aortic stenosis improved greatly after the introduction of more symmetric reconstructions of the aortic root. Multiple-sinus reconstructions (inverted bifurcated patch plasty and 3-sinus reconstruction) resulted in superior hemodynamics and were associated with reductions in both mortality rate and need for reoperation. (J Thorac Cardiovasc Surg 1999;118:874-85

Biological laterality and peripheral nerve DTI metrics

BACKGROUND AND PURPOSE: Clinical comparisons do not usually take laterality into account and thus may report erroneous or misleading data. The concept of laterality, well evaluated in brain and motor systems, may also apply at the level of peripheral nerves. Therefore, we sought to evaluate the extent to which we could observe an effect of laterality in MRI-collected white matter indices of the sciatic nerve and its two branches (tibial and fibular). MATERIALS AND METHODS: We enrolled 17 healthy persons and performed peripheral nerve diffusion weighted imaging (DWI) and magnetization transfer imaging (MTI) of the sciatic, tibial and fibular nerve. Participants were scanned bilaterally, and findings were divided into ipsilateral and contralateral nerve fibers relative to self-reporting of hand dominance. Generalized estimating equation modeling was used to evaluate nerve fiber differences between ipsilateral and contralateral legs while controlling for confounding variables. All findings controlled for age, sex and number of scans performed. RESULTS: A main effect of laterality was found in radial, axial, and mean diffusivity for the tibial nerve. Axial diffusivity was found to be lateralized in the sciatic nerve. When evaluating mean MTR, a main effect of laterality was found for each nerve division. A main effect of sex was found in the tibial and fibular nerve fiber bundles. CONCLUSION: For the evaluation of nerve measures using DWI and MTI, in either healthy or disease states, consideration of underlying biological metrics of laterality in peripheral nerve fiber characteristics need to considered for data analysis. Integrating knowledge regarding biological laterality of peripheral nerve microstructure may be applied to improve how we diagnosis pain disorders, how we track patients’ recovery and how we forecast pain chronification

DTI and MTR Measures of Nerve Fiber Integrity in Pediatric Patients With Ankle Injury

Acute peripheral nerve injury can lead to chronic neuropathic pain. Having a standardized, non-invasive method to evaluate pathological changes in a nerve following nerve injury would help with diagnostic and therapeutic assessments or interventions. The accurate evaluation of nerve fiber integrity after injury may provide insight into the extent of pathology and a patient's level of self-reported pain. The aim of this investigation was to evaluate the extent to which peripheral nerve integrity could be evaluated in an acute ankle injury cohort and how markers of nerve fiber integrity correlate with self-reported pain levels in afferent nerves. We recruited 39 pediatric participants with clinically defined neuropathic pain within 3 months of an ankle injury and 16 healthy controls. Participants underwent peripheral nerve MRI using diffusion tensor (DTI) and magnetization transfer imaging (MTI) of their injured and non-injured ankles. The imaging window was focused on the branching point of the sciatic nerve into the tibial and fibular division. Each participant completed the Pain Detection Questionnaire (PDQ). Findings demonstrated group differences in DTI and MTI in the sciatic, tibial and fibular nerve in the injured ankle relative to healthy control and contralateral non-injured nerve fibers. Only AD and RD from the injured fibular nerve correlated with PDQ scores which coincides with the inversion-dominant nature of this particular ankle injuruy cohort. Exploratory analyses highlight the potential remodeling stages of nerve injury from neuropathic pain. Future research should emphasize sub-acute time frames of injury to capture post-injury inflammation and nerve fiber recovery