Ascending thoracic aortic aneurysm size at presentation and growth by diameter.

AIM: To investigate the hypothesis that lung cancer screening allows for earlier identification of ascending thoracic aortic aneurysms (aTAAs) and that growth rates for aTAAs are greatest at larger sizes. MATERIALS AND METHODS: This single referral centre retrospective study manually gathered computed tomography (CT) data from 732 patients presenting from July 2002 to August 2022. Five hundred and seventeen patients with aTAA >39 mm were identified to compare presenting diameter by year of presentation. Four hundred and thirty-two patients had CT examinations >3 months apart, allowing for growth analysis. Patients were separated by initial examination date (before or after 12/31/2013) for presenting size comparison. Patients were then divided into five groups based on aTAA diameter for growth rate analysis. RESULTS: At identification, patients had a median aTAA diameter of 44 mm (IQR 41-47 mm). Patients with aTAAs identified prior to December 2013 (n=129) had an average aTAA diameter 1.7 mm larger than those identified later (n=388; p=0.003). The growth analysis showed an average growth rate of 0.1 mm/year (p<0.001) across the entire cohort. Patients with an aTAA diameter of ≥55 mm (n=12) grew the fastest at 1.9 mm/year (p<0.001). In the <40 mm group (n=43), the aTAAs expanded at 0.2 mm/year, faster than the 0.1 mm/year of the slowest expanding 45-49 mm group (n=130; p=0.04). CONCLUSION: aTAA size at discovery was larger before lung cancer screening guidelines took effect in December 2013. The largest aTAAs expanded fastest, but growth rates were slowest in the medium-sized 45-49 mm diameter group.

Weight-adjusted tinzaparin for venous thromboembolism prophylaxis in bariatric surgery patients weighing 160 kg or more.

INTRODUCTION: Bariatric surgery patients experience an increased risk of venous thromboembolism (VTE), however, the optimal dose of low-molecular-weight heparin for VTE prophylaxis remains uncertain. Currently, St. Joseph's Healthcare Hamilton utilizes a weight-adjusted tinzaparin dosage (50 to 75 units/kg rounded to nearest pre-filled syringe) for postoperative VTE prophylaxis. OBJECTIVES: This study analyzed the safety of weight-adjusted tinzaparin for VTE prophylaxis in bariatric surgery patients weighing ≥160 kg. METHODS: This was a retrospective study involving patients weighing ≥160 kg that underwent bariatric surgery from September 2015 to September 2019. Patients received a single dose of weight-adjusted subcutaneous unfractionated heparin (UFH) [5000 or 7500 IU] immediately prior to surgery, subcutaneous UFH [5000 IU, 7500 IU, or unspecified] immediately postoperatively, and either 10,000 or 14,000 IU of tinzaparin, beginning on the day after surgery, for 10 days. Intra-operative sequential compression devices could be used at the attending surgeon's discretion. Occurrence of VTE and major bleeding within 30 days of surgery were assessed. RESULTS: A total of 389 patients were included for analysis, all patients received in-hospital follow-up while 349 patients had also 30-day follow-up. For the primary safety and efficacy analysis of in-hospital events, VTE and major bleeding rates were 0.26% [95% CI 0.01%-1.44%] (1/389) and 0.77% [95% CI 0.21%-2.24%] (3/389) respectively. For patients with 30-day follow-up VTE and major bleeding rates were 0.57% [95% CI 0.1%-2.07%] (2/349) and 1.43% [95% CI 0.61%-3.3%] (5/349) respectively. CONCLUSIONS: Weight-adjusted tinzaparin was associated with a low risk of bleeding and VTE events, supporting its use for VTE prophylaxis for patients weighing ≥160 kg.

Long-term retention in an employer-based, commercial weight-loss programme.

The aim of this study is to examine factors associated with long-term retention in a commercial weight-loss programme. We conducted a retrospective analysis of an employer-based, commercial programme from 2013 to 2016. Our dependent variable was 'long-term retention', defined as continuously enrolled participants who actively engaged through coach calls at 6 and 12 months. Independent variables included baseline demographics, programme engagement and weight change. We conducted multivariate logistic regression analyses assessing for differences in long-term retention by several factors, adjusted for employer clustering. Overall, 68.3% were retained at 6% and 45.9% at 12 months. Greater number of coach calls and website logins during the first 3 months significantly increased the odds of long-term retention, while having chronic conditions significantly decreased the odds. Weight-loss success (≥5% loss at 6 months) was significantly associated with increased odds of retention (12-month: odds ratio [OR] 2.80, P < 0.001), while early weight-loss failure (≥0% weight change at 1 month) significantly decreased odds of retention (12-month: OR 0.66, P = 0.008). In an employer-based, commercial weight loss programme, greater early programme engagement was associated with long-term retention. Given these programmes' popularity and potential reach, our results could be used to develop and test strategies designed to improve retention in commercial weight-loss programmes.

Factors associated with early dropout in an employer-based commercial weight-loss program.

OBJECTIVE: Minimizing program dropout is essential for weight-loss success, but factors that influence dropout among commercial programs are unclear. This study's objective was to determine factors associated with early dropout in a commercial weight-loss program. METHODS: A retrospective analysis of a remotely delivered, employer-based commercial program from 2013 to 2016 was conducted. The dependent variable was 'early dropout', defined as enrollees who disengaged from telephone coaching by month 2's end. Independent variables included demographics, program website engagement and early weight change. Multivariate logistic regression analyses were used to assess for differences in early dropout by several factors, adjusted for employer clustering. RESULTS: Of the 5,274 participants, 26.8% dropped out early. Having ≥1 chronic condition (odds ratio [OR] 1.41, p < 0.001) and 'weight-loss failure' defined as ≥0% weight change at month 1's end (OR 1.86, p < 0.001) had significantly increased odds of early dropout. Increasing age by 10-year intervals (OR 0.90, p = 0.002) and 'meeting the website login goal' defined as ≥90 logins in 3 months (OR 0.13, p < 0.001) significantly decreased the odds of early dropout. CONCLUSIONS: Presence of comorbidities, less online engagement and weight-loss failure were associated with early dropout in a commercial program. Strategies to prevent dropout among high-risk participants, such as increased support or program tailoring, should be developed and tested.

Weight-adjusted tinzaparin for the prevention of venous thromboembolism after bariatric surgery.

Essentials The optimal dose and duration of thromboprophylaxis after bariatric surgery are unclear. We evaluated the safety of weight-adjusted tinzaparin prophylaxis in 1212 patients. In-hospital rates of venous thromboembolism and major bleeding were 0.2% and 1.8% respectively. In a sub-set of patients, trough anti-Xa levels did not show excessive anticoagulant activity. SUMMARY: Background Patients undergoing bariatric surgery are at moderate to high risk of venous thromboembolism (VTE). The optimal dose and duration of anticoagulant prophylaxis is uncertain. Objective To evaluate the safety of extended-duration weight-adjusted tinzaparin after bariatric surgery. Patients/methods We conducted a single-center retrospective cohort study of consecutive patients undergoing bariatric surgery who received weight-adjusted tinzaparin 4500-14 000 IU daily (75 IU kg-1 rounded to the nearest prefilled syringe) for 10 days after surgery (7-9 days post-hospital discharge). Primary safety outcomes were the frequency of VTE and major bleeding within 30 days of surgery in patients receiving at least one dose of tinzaparin. Results A total of 1279 patients undergoing bariatric surgery between July 2009 and December 2012 were reviewed, of whom 1212 received weight-adjusted tinzaparin. Safety outcomes were collected for 819 patients at 30 days, and for 1212 patients in-hospital only. The median age was 45.0 years, median weight was 130.0 kg and 98.8% of patients underwent gastric bypass or sleeve gastrectomy. In patients completing 30 days of follow-up, VTE occurred in 4/819 (0.5%) and major bleeding occurred in 13/819 patients (1.6%). In-hospital rates of VTE and major bleeding during surgical admission were 3/1212 (0.2%) and 22/1212 (1.8%), respectively. Conclusions Extended thromboprophylaxis with weight-adjusted tinzaparin appears to be a safe strategy after bariatric surgery, with low rates of postoperative VTE and major bleeding.

An order set and checklist improve physician transfusion ordering practices to mitigate the risk of transfusion-associated circulatory overload.

OBJECTIVES AND BACKGROUND: There are few studies of quality interventions to mitigate the risk of transfusion-associated circulatory overload (TACO). Our aim was to reduce TACO risk in patients admitted to internal medicine at our hospital, by addressing gaps in transfusion practice. MATERIALS AND METHODS: A 3-month baseline audit of red blood cell (RBC) transfusion orders was conducted. An intervention consisting of a transfusion order set and physician checklist was developed and implemented based on identified gaps, followed by a 3-month post-intervention audit. Compliance with appropriateness criteria for RBC transfusion was ascertained, along with documentation of transfusion rate, diuretic usage and consent. RESULTS: A total of 97 transfusion orders from 68 inpatients and 95 orders from 62 inpatients were audited in the baseline and post-intervention groups, respectively. Compliance with appropriateness criteria was similar pre- and post-intervention (87 versus 85%, P = 0·81). Specification of transfusion rate improved (84 versus 98%, P < 0·01), and diuretics were appropriately ordered more frequently for patients with TACO risk factors (37 versus 64%, P < 0·01). Timing of diuretics shifted from between or post-transfusion to pre-transfusion (35 versus 86%, P < 0·01), without increases in hypokalemia or acute kidney injury. No case of TACO was observed during the study. Documentation of specific risks discussed during consent discussion improved (4 versus 23%, P < 0·01). CONCLUSION: A checklist and order set are tools that can improve the quality of transfusion orders by increasing the judicious use of pre-transfusion diuretics and augmenting the specification of transfusion rate. These interventions could be adapted to electronic order formats to improve transfusion safety.

Monthly blood transfusions decrease after four months of azacitidine.

BACKGROUND AND OBJECTIVES: Azacitidine (AZA) improves overall survival and transfusion independence in patients with myelodysplastic syndrome (MDS). We aimed to quantify the reduction in red blood cell (RBC) transfusions and to determine when this reduction occurs, in MDS patients treated with AZA. MATERIALS AND METHODS: We performed a retrospective audit of changes in RBC transfusion burden in 51 patients with predominantly higher risk MDS (26.5% high risk, 51.0% intermediate-2) who received AZA. Transfusion requirements were audited 6 months prior to and up to 18 months after therapy initiation, and data were analysed using a generalized linear mixed model. RESULTS: At baseline, 30 patients (58.8%) were transfusion dependent (TD). Seventeen patients (56.7%) achieved transfusion independence (TI) by 18 months, and 8 of these patients (47.1%) achieved this response by 4 months on therapy. Achievement of TI was not consistently durable in these 17 patients, as 11 patients reverted to TD while on therapy. Meanwhile, 6 of 21 patients who were TI at baseline became TD on therapy. The monthly average of RBC units transfused decreased significantly beginning at 4 months, with a reduction from 2.50 units per month at baseline to 1.00 units per month at month 4. This 60% reduction was significant (P = 0.002) and sustained beyond 12 months. CONCLUSION: These results bolster the notion that AZA significantly reduces transfusion burden and resource utilization and illustrate the limitations of the current WHO erythroid response criteria which do not account for differing durability and fluctuations of response.

Acute type A aortic dissection intimal tears by 64-slice computed tomography: a role for endovascular stent-grafting?

AIM: The goal of this study was to identify physical characteristics of primary intimal tears in patients arriving to the hospital alive with acute type A aortic dissection using 64-multislice computerized tomography (MSCT) in order to determine anatomic feasibility of endovascular stent-grafting (ESG) for future treatment. METHODS: Radiology database was screened for acute type A aortic dissection since the time of acquisition of the 64-slice CT scanner and cross-referenced with surgical database. Seventeen patients met inclusion criteria. Images were reviewed for number, location, and size of intimal tears and aortic dimensions. Potential obstacles for ESG were determined. RESULTS: Ascending aorta (29%) and sinotubular junction (29%) were the most frequent regions where intimal tears originated. Location of intimal tears in nearly 75% of patients was inappropriate for ESG, and 94% of patients did not have sufficient proximal or distal landing zone required for secure fixation. Only 71% of patients underwent surgical aortic dissection repair after imaging and 86% of entry tears detected on MSCT were confirmed on intraoperative documentation. Only one patient would have met all technical criteria for ESG using currently available devices. CONCLUSION: Location of intimal tear, aortic valve insufficiency, aortic diameter>38 mm are major factors limiting use of ESG for acute type A dissection. Available stents used to treat type B aortic dissection do not address anatomic constraints present in type A aortic dissection in the majority of cases, such that development of new devices would be required.

Hemodynamic determinants of aortic dissection propagation by 2D computational modeling: implications for endovascular stent-grafting.

AIM: Aortic dissection is a life-threatening aortic catastrophe where layers of the aortic wall are separated allowing blood flow within the layers. Propagation of aortic dissection is strongly linked to the rate of rise of pressure (dp/dt) experienced by the aortic wall but the hemodynamics is poorly understood. The purpose of this study was to perform computational fluid dynamics (CFD) simulations to determine the relationship between dissection propagation in the distal longitudinal direction (the tearing force) and dp/dt. METHODS: Five computational models of aortic dissection in a 2D pipe were constructed. Initiation of dissection and propagation were represented in 4 single entry tear models, 3 of which investigated the role of length of dissection and antegrade propagation, 1 of which investigated retrograde propagation. The 5th model included a distal re-entry tear. Impact of pressure field distribution on tearing force was determined. RESULTS: Tearing force in the longitudinal direction for dissections with a single entry tear was approximately proportional to dp/dt and L2 where L is the length of dissection. Tearing force was much lower under steady flow than pulsatile flow conditions. Introduction of a second tear distally along the dissection away from the primary entry tear significantly reduced tearing force. CONCLUSION: The hemodynamic mechanism for dissection propagation demonstrated in these models support the use of ß-blockers in medical management. Endovascular stent-graft treatment of dissection should ideally cover both entry and re-entry tears to reduce risk of retrograde propagation of aortic dissection.

Pre-clinical properties of the alpha4beta2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence.

BACKGROUND AND PURPOSE: Smoking cessation trials with three high-affinity partial agonists of alpha4beta2 neuronal nicotinic acetylcholine receptors (nAChRs) have demonstrated differences in their clinical efficacy. This work examines the origin of the differences by taking into account brain exposure and pharmacological effects at human alpha4beta2 nAChRs. EXPERIMENTAL APPROACH: Rat plasma and brain pharmacokinetics were characterized and used to predict human steady-state plasma and brain concentrations following recommended doses of each of the three compounds. The pharmacological characterization included in vitro affinities at different nAChR subtypes, functional efficacies and potencies at the human alpha4beta2 nAChR, as well as in vivo effects on rat mesolimbic dopamine turn-over. KEY RESULTS: A comparison of predicted human brain concentrations following therapeutic doses demonstrated that varenicline and nicotine, but not dianicline and cytisine, can extensively desensitize and, to a lesser extent, activate alpha4beta2 nAChRs. The limited clinical efficacy of dianicline may be accounted for by a combination of weak functional potency at alpha4beta2 nAChRs and moderate brain penetration, while recommended doses of cytisine, despite its high in vitro potency, are predicted to result in brain concentrations that are insufficient to affect alpha4beta2 nAChRs. CONCLUSIONS AND IMPLICATIONS: The data provide a plausible explanation for the higher abstinence rate in smoking cessation trials following treatment with varenicline than with the two other alpha4beta2 nAChR partial agonists. In addition, this retrospective analysis demonstrates the usefulness of combining in vitro and in vivo parameters with estimated therapeutic human brain concentrations for translation to clinical efficacy.

Metabolism, pharmacokinetics and excretion of the GABA(A) receptor partial agonist [(14)C]CP-409,092 in rats.

The metabolism and excretion of a GABA(A) partial agonist developed for the treatment of anxiety, CP-409,092; 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide, were studied in rats following intravenous and oral administration of a single doses of [(14)C]CP-409,092. The pharmacokinetics of CP-409,092 following single intravenous and oral doses of 4 and 15 mg kg(-1), respectively, were characterized by high clearance of 169 + or - 18 ml min(-1) kg(-1), a volume of distribution of 8.99 + or - 1.46 l kg(-1), and an oral bioavailability of 2.9% + or - 3%. Following oral administration of 100 mg kg(-1) [(14)C]CP-409,092, the total recovery was 89.1% + or - 3.2% for male rats and 89.3% + or - 0.58% for female rats. Approximately 87% of the radioactivity recovered in urine and faeces were excreted in the first 48 h. A substantial portion of the radioactivity was measured in the faeces as unchanged drug, suggesting poor absorption and/or biliary excretion. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or faeces. The major metabolic pathways of CP-409,092 were hydroxylation(s) at the oxo-tetrahydro-indole moiety and oxidative deamination to form an aldehyde intermediate and subsequent oxidation to form the benzoic acid. The minor metabolic pathways included N-demethylation and subsequent N-acetylation and oxidation. The present work demonstrates that oxidative deamination at the benzylic amine of CP-409,092 and subsequent oxidation to form the acid metabolite seem to play an important role in the metabolism of the drug, and they contribute to its oral clearance and low exposure.

Cerebral hemodynamics changes during retrograde brain perfusion in dogs.

The objective of this study was to examine cerebral hemodynamics changes during hypothermic circulatory arrest (HCA) with and without retrograde cerebral perfusion (RCP). Thirteen colony-bred hound dogs were placed on cardiopulmonary bypass (CPB) and cooled to 18 degrees C. Five dogs underwent 2 hours of HCA without RCP and 8 with RCP. The animals were then rewarmed on CPB until normothermic and weaned. Cerebral blood flow velocity (CBFV) and Gosling Pulsatility Index (PI) in the middle cerebral artery (MCA) were studied using trans-cranial Doppler ultrasound (TCD). At baseline and during pre- and postarrest CPB, there was anterograde direction of blood flow in the MCA. During HCA with RCP, there was retrograde direction of blood flow in the MCA. There was no difference in CBFV between pre-, during, and postarrest CPB in the group with RCP; however, there was significantly increased CBFV during postarrest CPB in the group without RCP compared to the dogs with RCP. Later, at 3 hours after postarrest CPB, there was decreased CBFV in all animals accompanied by increased PI (2.4 +/- 0.4 and 2.2 +/- 0.6 for animals with RCP and without RCP, respectively) and abnormal TCD waveform changes including decreased diastolic compartment and sharp systolic peak. During hypothermic circulatory arrest, RCP provides CBFV in the MCA comparable to MCA CBFV during CPB. HCA dogs without RCP showed immediate hyperemia on reperfusion. The decreased CBFV and increased PI at 1 hour after postarrest CPB could be an indicator of progressive ischemic injury due to the increased intracranial pressure despite the implementation of RCP.

Training women surgeons and their academic advancement.

The responsibility for those of us involved in residency training programs is to foster the development of future leaders in thoracic surgery. Although the actual training of female surgeons is no different than training male surgeons, academic advancement after training can be more difficult for women due to a variety of reasons. The education and training of female surgeons has its origin in admission to medical school followed by recruitment into a residency program. Following completion of a residency program, the retainment of women and men faculty should be the goal of departments and divisions of thoracic surgery. Specific recommendations are made for retainment of faculty. In addition to academic promotion and financial reward, creating the proper environment is an important consideration to allow women the chance to succeed in medicine. This report addresses the training aspects involved in the thoracic residency program and the state of professional academic advancement at the Johns Hopkins University School of Medicine.

Prevalence of aspiration and laryngeal penetration in patients with unilateral vocal fold motion impairment.

The adverse consequences of aspiration in regard to patient health and quality of life are well documented. It is generally accepted that the probability of aspiration is increased in patients with unilateral vocal fold motion impairment, however, the incidence and proposed mechanism of aspiration vary depending on the reported series. We reviewed the cine or video pharyngoesophagographic findings in patients with documented unilateral vocal fold motion impairment, identified through the Johns Hopkins Hospital Swallowing Center database, to determine the prevalence and cause of aspiration and laryngeal penetration. Aspiration and laryngeal penetration were identified in 38% and 12% of patients, respectively. Aspiration resulted from impaired airway protection, not from esophageal obstruction with laryngeal "spill-over." The number and degree of impairments directly correlated with probability of aspiration. Obstruction potentiated the likelihood of aspiration. Video pharyngoesophagography accurately identifies patients at risk for aspiration.

Laparoscopic nephrectomy for autotransplantation.

Proximal ureteral injuries often require extensive reconstruction to repair. Management options include nephrectomy, ileal ureter interposition, extensive spiral bladder flaps, or autotransplantation. We report a patient who sustained a proximal ureteral avulsion and underwent a less invasive repair by way of a laparoscopic nephrectomy and subsequent autotransplantation.

Apoptosis detection in brain using low-magnification dark-field microscopy.

Apoptosis or programmed cell death is a feature of normal brain development and a response to brain injury. Cells undergoing apoptosis have a characteristic morphology that normally can only be appreciated at high magnification. Using dark-field transmitted light microscopy to examine Nissl-stained material, we detected groups of apoptotic cells at much lower magnifications than often were required in the two injury models we tested. This method was useful for screening entire brain sections to assess regional and global patterns of injury. We predict that this technique in which we detect the clumped chromatin associated with apoptosis can be applied to other types of tissue.

Assessing the impact of cerebral injury after cardiac surgery: will determining the mechanism reduce this injury?

BACKGROUND: Central nervous system dysfunction continues to produce significant morbidity and associated mortality in patients undergoing cardiac surgery. Using a closed-chest canine cardiopulmonary bypass model, dogs underwent 2 h of hypothermic circulatory arrest (HCA) at 18 degrees C, followed by resuscitation and recovery for 3 days. Animals were assessed functionally by a species-specific behavioral scale, histologically for patterns of selective neuronal necrosis, biochemically by analysis of microdialysis effluent, and by receptor autoradiography for N-methyl-D-aspartate (NMDA) glutamate receptor subtype expression. RESULTS: Using a selective NMDA (glutamate) receptor antagonist (MK801) and an AMPA antagonist (NBQX), glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. A microdialysis technique was employed to evaluate the role of nitric oxide (NO) in neuronal cell death. Arginine plus oxygen is converted to NO plus citrulline (CIT) by the action of NO synthase (nNOS). CIT recovery in the cerebrospinal fluid and from canine cortical homogenates increased during HCA and reperfusion. These studies demonstrated that neurotoxicity after HCA involves a significant and early induction of nNOS expression, and neuronal processes leading to widespread augmentation of NO production in the brain. To further investigate the production of excitatory amino acids in the brain, we hypothesized the following scenario: HCA--> increased glutamate, increased aspartate, increased glycine--> increased intracellular Ca2+--> increased NO + CIT. Using the same animal preparation, we demonstrated that HCA caused increased intracerebral glutamate and aspartate that persists up to 20 h post-HCA. HCA also resulted in CIT (NO) production, causing a continued and delayed neurologic injury. Confirmatory evidence of the role of NO was demonstrated by a further experiment using a specific nNOS inhibitor, 7-nitroindazole. Animals underwent 2 h of HCA, and then were evaluated both physiologically and for NO production. 7-Nitroindazole reduced CIT (NO) production by 58.4 +/- 28.3%. In addition, dogs treated with this drug had superior neurologic function compared with untreated HCA controls. CONCLUSIONS: These experiments have documented the role of glutamate excitotoxicity in neurologic injury and have implicated NO as a significant neurotoxin causing necrosis and apoptosis. Continued research into the pathophysiologic mechanisms involved in cerebral injury will eventually yield a safe and reliable neuroprotectant strategy. Specific interventional agents will include glutamate receptor antagonists and specific neuronal NO synthase inhibitors.

Increased intracerebral excitatory amino acids and nitric oxide after hypothermic circulatory arrest.

BACKGROUND: Prolonged hypothermic circulatory arrest (HCA) results in neurologic injury, but the mechanism of this injury is unknown. This study was undertaken to measure quantitatively intracerebral excitatory amino acids and citrulline, an equal coproduct of nitric oxide, during HCA. We hypothesized that HCA resulted in higher levels of glutamate, aspartate, glycine, causing increased intracellular calcium, and therefore, nitric oxide and citrulline. METHODS: Ten dogs underwent intracerebral microdialysis and 2 hours of HCA at 18 degrees C. Effluent was analyzed by high performance liquid chromatography with electrochemical detection. Five dogs each were sacrificed at 8 and 20 hours after HCA. Neuronal apoptosis was scored from 0 (no injury) to 100 (severe injury). RESULTS: Time course of HCA was divided into six periods. Peak levels of amino acids in each period were compared with those at baseline. Glutamate, coagonist glycine, and citrulline, an equal coproduct of nitric oxide, increased significantly over baseline during HCA, cardiopulmonary bypass, and 2 to 8 hours after HCA. Aspartate increased significantly during HCA and 8 to 20 hours after HCA. Apoptosis score was 65.56 +/- 5.67 at 8 hours and 30.63 +/- 14.96 at 20 hours after HCA. CONCLUSIONS: Our results provide direct evidence that HCA causes increased intracerebral glutamate and aspartate, along with coagonist glycine. We conclude that HCA causes glutamate excitotoxicity with subsequent nitric oxide production resulting in neurologic injury, which begins during arrest and continues until 20 hours after hypothermic circulation arrest. To provide effective cerebral protection, pharmacologic strategies to reduce glutamate excitotoxicity require intervention beyond the initial ischemic insult.