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

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

Single center experience on dosing and adverse events of recombinant factor seven use for bleeding after congenital heart surgery

There are limited data on the relationship between the administered dose of recombinant factor seven (rFVIIa) and the development of adverse clinical outcomes after congenital heart surgery. This single institution case series reports on dosing, adverse events, and blood product usage after the administration of rFVIIa in the congenital heart surgery patient population. A retrospective review identified 16 consecutive pediatric patients at an academic, free-standing, children’s hospital who received rFVIIa to curtail bleeding following congenital heart surgery between April 2004 and June 2012. Patients were assessed for survival to hospital discharge versus in-hospital mortality and the presence or absence of a major neurological event during inpatient hospitalization. The median age at surgery was 6.8 months (range: 3 days–42 years). Seven patients (44%) survived to hospital discharge and nine patients (56%) died. The cause of mortality included major neurological events (44%), uncontrolled bleeding (33%), and sepsis (23%). Eight patients (50%) required extracorporeal membrane oxygenation support following congenital heart surgery. The median cumulative rFVIIa dose administered was 97 mcg/kg, and the median cumulative amount of blood products administered was 452 ml/kg. In conclusion, this case series underscores the need to prospectively evaluate the effect that rFVIIa has on patient survival and the incidence of adverse events, including thrombotic and major neurological events, in congenital heart surgery patients. Ideally, a randomized, multicenter study would provide the sufficient numbers of patients and events to test these relationships

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

Interaction of temperature with hematocrit level and pH determines safe duration of hypothermic circulatory arrest

AbstractObjectivePrevious studies have demonstrated that both hematocrit level and pH influence the protection afforded by deep hypothermic circulatory arrest. The current study examines how temperature modulates the effect of hematocrit level and pH in determining a safe duration of circulatory arrest. The study also builds on previous work investigating the utility of near-infrared spectroscopy as a real-time monitor of cerebral protection during circulatory arrest.MethodsSeventy-six piglets (9.3 ± 1.2 kg) underwent circulatory arrest under varying conditions with continuous monitoring by means of near-infrared spectroscopy (hematocrit level of 20% or 30%; pH-stat or alpha-stat strategy; temperature of 15°C or 25°C; arrest time of 60, 80, or 100 minutes). Neurologic recovery was evaluated daily by a veterinarian, and the brain was fixed in situ on postoperative day 4 to be examined on the basis of histologic score in a blinded fashion.ResultsMultivariable analysis of total histologic score revealed that higher temperature, lower hematocrit level, more alkaline pH, and longer hypothermic circulatory arrest duration were predictive of more severe damage to the brain (P < .01). Regression modeling revealed that higher temperature exacerbated the disadvantage of a lower hematocrit level and longer arrest times but not pH strategy. Normalized oxyhemoglobin nadir time, derived from near-infrared spectroscopy, was positively correlated with neurologic recovery on the fourth postoperative day and with total histologic injury score (P < .0001).ConclusionHematocrit level and pH, as well as temperature, determine the safe duration of hypothermic circulatory arrest. Near-infrared spectroscopy is a useful real-time monitor of safe duration of circulatory arrest

Karate injuries in children and adolescents

Abstract Objecti6es: To identify risk factors for injury and to establish safety guidelines for children in Uechi -Ryu karate. Design: A 1-year retrospective survey of injuries. Setting: A private karate school (Uechi -Ryu style) in Plymouth, MA. Patients: A total of 68 athletes (age 6-16 years; mean age 10 years) who participated in karate during the 1995 -1996 season. Inter6entions: None. Main outcome measures: The presence or absence of injury, with grading of injuries as major, moderate or minor. The types of injuries and body region involved were also analyzed. Results: Twenty eight percent of athletes sustained at least one injury. All injuries were minor, with no time off from training required. The injuries consisted primarily of bruises (11 of 19). Other injuries included mild sprains or strains (5 of 19) and having their &apos;wind knocked out&apos; (3 of 19). Most injuries were localized to the extremities. Logistic regression analysis identified risk factors for injury. Risk of injury increased with number of years of training (odds ratio 2.95; 95% confidence interval 1.81-4.82; P B0.0001), number of hours per week (odds ratio 2.12; CI 1.15-4.21; P =0.016) and rank, specifically brown belt versus lower belts (odds ratio 6.56; CI 2.02 -21.26; P =0.006). Conclusions: Karate is a relatively safe sport for children and adolescents when properly taught. Risk of injury increases with experience; therefore, greater supervision is required of higher ranks. Injury increases with weekly training; however, 3 h a week or less appears to be associated with a low risk of significant injury in this age group

Biological and behavioral markers of pain following nerve injury in humans

The evolution of peripheral and central changes following a peripheral nerve injury imply the onset of afferent signals that affect the brain. Changes to inflammatory processes may contribute to peripheral and central alterations such as altered psychological state and are not well characterized in humans. We focused on four elements that change peripheral and central nervous systems following ankle injury in 24 adolescent patients and 12 age-sex matched controls. Findings include (a) Changes in tibial, fibular, and sciatic nerve divisions consistent with neurodegeneration; (b) Changes within the primary motor and somatosensory areas as well as higher order brain regions implicated in pain processing; (c) Increased expression of fear of pain and pain reporting; and (d) Significant changes in cytokine profiles relating to neuroinflammatory signaling pathways. Findings address how changes resulting from peripheral nerve injury may develop into chronic neuropathic pain through changes in the peripheral and central nervous system