Assessment of Availability and Human Health Risk Posed by Arsenic Contaminated Well Waters from Timis-Bega Area, Romania.

Mobilization of As from geological materials into ground and drinking water sources may represent an important threat to human health. The objective of this study was to assess the As concentration and availability in underground water used as drinking water sources. Water samples were collected from public and private wells in Timis-Bega area of Pannonian Basin, West Romania. Total-dissolved As measured after "classical" filtration of water samples was in the range of 0.10-168 µg L-1, thus exceeding the guideline value in majority of the samples. The aim of this study was also to assess the "truly dissolved" concentrations of As considered as available concentrations, in well waters, after passive sampling by Diffusive Gradients in Thin-films (DGT). The results showed that over 70% of total-dissolved As is in available forms. The obtained data were used to evaluate the risks of using the wells as drinking water source. Hazard quotients for ingestion and dermal pathways and hazard index (HI) for exposure to As were calculated. The HI values > 1 found that majority of samples indicated a health risk for local residents.

Clinical indicators of paraplegia underplay universal spinal cord neuronal injury from transient aortic occlusion.

Paraplegia following complex aortic intervention relies on crude evaluation of lower extremity strength such as whether the patient can lift their legs or flex the ankle. Little attention has been given to the possible long-term neurologic sequelae following these procedures in patients appearing functionally normal. We hypothesize that mice subjected to minimal ischemic time will have functional and histological changes despite the gross appearance of normal function. Male mice underwent 3 min of aortic occlusion (n=14) or sham surgery (n=4) via a median sternotomy. Neurologic function was graded by Basso Motor Score (BMS) preoperatively and at 24h intervals after reperfusion. Mice appearing functionally normal and sham mice were placed on a walking beam and recorded on high-definition, for single-frame motion analysis. After 96 hrs, spinal cords were removed for histological analysis. Following 3 min of ischemia, functional outcomes were split evenly with either mice displaying almost normal function n=7 or near complete paraplegia n=7. Additionally, single-frame motion analysis revealed significant changes in gait. Histologically, there was a significant stepwise reduction of neuronal viability, with even the normal function ischemic group demonstrating significant loss of neurons. Despite the appearance of normal function, temporary ischemia induced marked cyto-architectural changes and neuronal degeneration. Furthermore high-definition gait analysis revealed significant changes in gait and activity following thoracic aortic occlusion. These data suggest that all patients undergoing procedures, even with short ischemic times, may have spinal cord injury that is not evident clinically.

Spinal Cord Ischemia-Reperfusion Injury Induces Erythropoietin Receptor Expression.

BACKGROUND: Paraplegia remains a devastating complication of aortic surgery, occurring in up to 20% of complex thoracoabdominal repairs. Erythropoietin (EPO) attenuates this injury in models of spinal cord ischemia. Upregulation of the beta-common receptor (ßcR) subunit of the EPO receptor is associated with reduced damage in murine models of neural injury. This receptor activates anti-apoptotic pathways including signaling transducer and activator of transcription 3 (STAT3). We hypothesized that spinal cord ischemia-reperfusion injury upregulates the ßcR subunit with a subsequent increase in activated STAT3. METHODS: Adult male C57/BL6 mice received an intraperitoneal injection of 0.5 mL of EPO (10 U/kg) or 0.9% saline after induction of anesthesia. Spinal cord ischemia was induced through sternotomy and 4-minute thoracic aortic cross-clamp. Sham mice underwent sternotomy without cross-clamp placement. Four groups were studied: ischemic and sham groups, each with and without EPO treatment. After 4 hours of reperfusion, spinal cords were harvested and homogenized. The ßcR subunit expression and STAT3 activation were evaluated by immunoblot. RESULTS: Ischemia reperfusion increased ßcR subunit expression in spinal cords of ischemia + saline and ischemia + EPO mice compared with shams (3.4 ± 1.39 vs 1.31 ± 0.3, p = 0.01 and 3.80 ± 0.58 vs 1.56 ± 0.32, p = 0.01). Additionally, both ischemic groups demonstrated increased STAT3 activation compared with shams (1.35 ± 0.14 vs 1.09 ± 0.07, p = 0.01 and 1.66 ± 0.35 vs 1.08 ± 0.17, p = 0.02). CONCLUSIONS: Ischemia-reperfusion injury induces EPO receptor ßcR subunit expression and early downstream anti-apoptotic signaling through STAT3 activation. Further investigation into the role of the ßcR subunit is warranted to determine tissue protective functions of EPO. Elucidation of mechanisms involved in spinal cord protection is essential for reducing delayed paraplegia.

Alpha-2 agonist attenuates ischemic injury in spinal cord neurons.

BACKGROUND: Paraplegia secondary to spinal cord ischemia-reperfusion injury remains a devastating complication of thoracoabdominal aortic intervention. The complex interactions between injured neurons and activated leukocytes have limited the understanding of neuron-specific injury. We hypothesize that spinal cord neuron cell cultures subjected to oxygen-glucose deprivation (OGD) would simulate ischemia-reperfusion injury, which could be attenuated by specific alpha-2a agonism in an Akt-dependent fashion. MATERIALS AND METHODS: Spinal cords from perinatal mice were harvested, and neurons cultured in vitro for 7-10 d. Cells were pretreated with 1 µM dexmedetomidine (Dex) and subjected to OGD in an anoxic chamber. Viability was determined by MTT assay. Deoxyuridine-triphosphate nick-end labeling staining and lactate dehydrogenase (LDH) assay were used for apoptosis and necrosis identification, respectively. Western blot was used for protein analysis. RESULTS: Vehicle control cells were only 59% viable after 1 h of OGD. Pretreatment with Dex significantly preserves neuronal viability with 88% viable (P < 0.05). Dex significantly decreased apoptotic cells compared with that of vehicle control cells by 50% (P < 0.05). Necrosis was not significantly different between treatment groups. Mechanistically, Dex treatment significantly increased phosphorylated Akt (P < 0.05), but protective effects of Dex were eliminated by an alpha-2a antagonist or Akt inhibitor (P < 0.05). CONCLUSIONS: Using a novel spinal cord neuron cell culture, OGD mimics neuronal metabolic derangement responsible for paraplegia after aortic surgery. Dex preserves neuronal viability and decreases apoptosis in an Akt-dependent fashion. Dex demonstrates clinical promise for reducing the risk of paraplegia after high-risk aortic surgery.

On the role of 4-hydroxynonenal in health and disease.

Polyunsaturated fatty acids are susceptible to peroxidation and they yield various degradation products, including the main α,ß-unsaturated hydroxyalkenal, 4-hydroxy-2,3-trans-nonenal (HNE) in oxidative stress. Due to its high reactivity, HNE interacts with various macromolecules of the cell, and this general toxicity clearly contributes to a wide variety of pathological conditions. In addition, growing evidence suggests a more specific function of HNE in electrophilic signaling as a second messenger of oxidative/electrophilic stress. It can induce antioxidant defense mechanisms to restrain its own production and to enhance the cellular protection against oxidative stress. Moreover, HNE-mediated signaling can largely influence the fate of the cell through modulating major cellular processes, such as autophagy, proliferation and apoptosis. This review focuses on the molecular mechanisms underlying the signaling and regulatory functions of HNE. The role of HNE in the pathophysiology of cancer, cardiovascular and neurodegenerative diseases is also discussed.

Spinal cord protection via alpha-2 agonist-mediated increase in glial cell-line-derived neurotrophic factor.

OBJECTIVES: Delayed paraplegia secondary to ischemia-reperfusion injury is a devastating complication of thoracoabdominal aortic surgery. Alpha-2 agonists have been shown to attenuate ischemia-reperfusion injury, but the mechanism for protection has yet to be elucidated. A growing body of evidence suggests that astrocytes play a critical role in neuroprotection by release of neurotrophins. We hypothesize that alpha-2 agonism with dexmedetomidine increases glial cell-line-derived neurotrophic factor in spinal cord astrocytes to provide spinal cord protection. METHODS: Spinal cords were isolated en bloc from C57BL/6 mice, and primary spinal cord astrocytes and neurons were selected for and grown separately in culture. Astrocytes were treated with dexmedetomidine, and glial cell-line-derived neurotrophic factor was tested for by enzyme-linked immunosorbent assay. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to assess neuronal viability. RESULTS: Spinal cord primary astrocytes treated with dexmedetomidine at 1 µmol/L and 10 µmol/L had significantly increased glial cell-line-derived neurotrophic factor production compared with control (P < .05). Neurons subjected to oxygen glucose deprivation had significant preservation (P < .05) of viability with use of dexmedetomidine-treated astrocyte media. Glial cell-line-derived neurotrophic factor neutralizing antibody eliminated the protective effects of the dexmedetomidine-treated astrocyte media (P < .05). CONCLUSIONS: Astrocytes have been shown to preserve neuronal viability via release of neurotrophic factors. Dexmedetomidine increases glial cell-derived neurotrophic factor from spinal cord astrocytes via the alpha-2 receptor. Treatment with alpha-2 agonist dexmedetomidine may be a clinical tool for use in spinal cord protection in aortic surgery.

Erythropoietin activates the phosporylated cAMP [adenosine 3'5' cyclic monophosphate] response element-binding protein pathway and attenuates delayed paraplegia after ischemia-reperfusion injury.

OBJECTIVE: Paraplegia remains a devastating complication of complex aortic surgery. Erythropoietin (EPO) has been shown to prevent paraplegia after ischemia reperfusion, but the protective mechanism remains poorly described in the spinal cord. We hypothesized that EPO induces the CREB (cAMP [adenosine 3'5' cyclic monophosphate] response element-binding protein) pathway and neurotrophin production in the murine spinal cord, attenuating functional and cellular injury. METHODS: Adult male mice were subjected to 4 minutes of spinal cord ischemia via an aortic and left subclavian cross-clamp. Experimental groups included EPO treatment 4 hours before incision (n = 7), ischemic control (n = 7), and shams (n = 4). Hind-limb function was assessed using the Basso motor score for 48 hours after reperfusion. Spinal cords were harvested and analyzed for neuronal viability using histology and staining with a fluorescein derivative. Expression of phosphorylated (p)AKT (a serine/threonine-specific kinase), pCREB, B-cell lymphoma 2, and brain-derived neurotrophic factor were determined using immunoblotting. RESULTS: By 36 hours of reperfusion, EPO significantly preserved hind-limb function after ischemia-reperfusion injury (P < .01). Histology demonstrated preserved cytoarchitecture in the EPO treatment group. Cords treated with EPO expressed significant increases in pAKT (P = .021) and pCREB (P = .038). Treatment with EPO induced expression of both of the neurotrophins, B-cell lymphoma 2, and brain-derived neurotrophic factor, beginning at 12 hours. CONCLUSIONS: Erythropoietin-mediated induction of the CREB pathway and production of neurotrophins is associated with improved neurologic function and increased neuronal viability following spinal cord ischemia reperfusion. Further elucidation of EPO-derived neuroprotection will allow for expansion of adjunct mechanisms for spinal cord protection in high-risk thoracoabdominal aortic intervention.

Reproducable paraplegia by thoracic aortic occlusion in a murine model of spinal cord ischemia-reperfusion.

BACKGROUND: Lower extremity paralysis continues to complicate aortic interventions. The lack of understanding of the underlying pathology has hindered advancements to decrease the occurrence this injury. The current model demonstrates reproducible lower extremity paralysis following thoracic aortic occlusion. METHODS: Adult male C57BL6 mice were anesthetized with isoflurane. Through a cervicosternal incision the aorta was exposed. The descending thoracic aorta and left subclavian arteries were identified without entrance into pleural space. Skeletonization of these arteries was followed by immediate closure (Sham) or occlusion for 4 min (moderate ischemia) or 8 min (prolonged ischemia). The sternotomy and skin were closed and the mouse was transferred to warming bed for recovery. Following recovery, functional analysis was obtained at 12 hr intervals until 48 hr. RESULTS: Mice that underwent sham surgery showed no observable hind limb deficit. Mice subjected to moderate ischemia for 4 min had minimal functional deficit at 12 hr followed by progression to complete paralysis at 48 hr. Mice subjected to prolonged ischemia had an immediate paralysis with no observable hind-limb movement at any point in the postoperative period. There was no observed intraoperative or post operative mortality. CONCLUSION: Reproducible lower extremity paralysis whether immediate or delayed can be achieved in a murine model. Additionally, by using a median sternotomy and careful dissection, high survival rates, and reproducibility can be achieved.

Dexmedetomidine, an α-2a adrenergic agonist, promotes ischemic tolerance in a murine model of spinal cord ischemia-reperfusion.

OBJECTIVE: Dexmedetomidine, an α-2a adrenergic agonist, given pre- and postoperatively was previously shown to attenuate neuronal injury in a murine model of spinal cord ischemia-reperfusion. In the brain, α-2 agonists have been shown to induce the phosphorylation of cyclic AMP response-element binding protein (CREB), a transcription factor necessary for neuron survival. We hypothesized that the α-2a adrenergic agonist given preoperatively increases CREB-mediated neuroprotective proteins, attenuating neuronal injury and cytoarchitectural decay. METHODS: Mice (ie, C57BL/6 mice) underwent 5 minutes of aortic occlusion via median sternotomy. Mice received 25 µg/kg dexmedetomidine or equivalent normal saline at 24 hours, 12 hours, and 30 minutes preoperatively. Functional outcomes were recorded at 6 to 48 hours postoperatively when spinal cords were removed for histologic analysis. Spinal cords were examined for protein kinase B, CREB, B-cell lymphoma 2, and brain-derived neurotrophic factor following treatment alone or ischemia-reperfusion surgery. RESULTS: Following aortic occlusion, mice in the treatment group had preserved neurologic function at all time points (P < .05). Histologic analysis showed preserved cytoarchitecture and decreased neuronal injury in the treatment group when compared with ischemic controls. Additionally, analysis of spinal cord homogenate following surgery and pretreatment revealed a significant (P < .05) increase in B-cell lymphoma 2 and brain-derived neurotrophic factor expression and protein kinase B and CREB phosphorylation with α-2a adrenergic agonist pretreatment. CONCLUSIONS: Pretreatment with the α-2a agonist dexmedetomidine preserved neurologic function and attenuated neuronal injury following thoracic aortic occlusion in mice. This relationship was associated with an increased phosphorylation of protein kinase B and CREB and subsequent up-regulation of antiapoptotic factor B-cell lymphoma 2 and brain-derived neurotrophic factor. Thus, α-2a receptor agonism-induced CREB phosphorylation and contributes to dexmedetomidine's protective mechanism in the spinal cord following ischemia.

Interruption of spinal cord microglial signaling by alpha-2 agonist dexmedetomidine in a murine model of delayed paraplegia.

BACKGROUND: Despite investigation into preventable pharmacologic adjuncts, paraplegia continues to complicate thoracoabdominal aortic interventions. The alpha 2a adrenergic receptor agonist, dexmedetomidine, has been shown to preserve neurologic function and neuronal viability in a murine model of spinal cord ischemia reperfusion, although the mechanism remains elusive. We hypothesize that dexmedetomidine will blunt postischemic inflammation in vivo following thoracic aortic occlusion with in vitro demonstration of microglial inhibition following lipopolysaccharide (LPS) stimulation. METHODS: Adult male C57BL/6 mice underwent 4 minutes of aortic occlusion. Mice received 25 µg/kg intraperitoneal dexmedetomidine (n = 8) or 0.9% normal saline (n = 7) at reperfusion and 12-hour intervals postoperatively until 48 hours. Additionally, sham mice (n = 3), which had aortic arch exposed with no occlusion, were included for comparison. Functional scoring was done at 6 hours following surgery and 12-hour intervals until 60 hours when spinal cords were removed and examined for neuronal viability and cytokine production. Additional analysis of microglia activation was done in 12 hours following surgery. Age- and sex-matched mice had spinal cord removed for microglial isolation culture. Cells were grown to confluence and stimulated with toll-like receptor-4 agonist LPS 100 ng/mL in presence of dexmedetomidine or vehicle control for 24 hours. Microglia and media were then removed for analysis of protein expression. RESULTS: Dexmedetomidine treatment at reperfusion significantly preserved neurologic function with mice in treatment group having a Basso Score of 6.3 in comparison to 2.3 in ischemic control group. Treatment was associated with a significant reduction in microglia activation and in interleukin-6 production. Microglial cells in isolation when stimulated with LPS had an increased production of proinflammatory cytokines and markers of activation. Treatment with dexmedetomidine significantly attenuated microglial activation and proinflammatory cytokine production in vitro with a greater than twofold reduction in tumor necrosis factor-α. CONCLUSIONS: Alpha 2a agonist, dexmedetomidine treatment at reperfusion preserved neurologic function and neuronal viability. Furthermore, dexmedetomidine treatment resulted in an attenuation of microglial activation and proinflammatory cytokine production both in vivo and in vitro following LPS stimulation. This finding lends insight into the mechanism of paralysis following thoracic aortic interventions and may guide future pharmacologic targets for attenuating spinal cord ischemia and reperfusion.

Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury.

BACKGROUND: Paraplegia continues to complicate thoracoabdominal aortic interventions. The elusive mechanism of spinal cord ischemia-reperfusion injury has delayed the development of pharmacological adjuncts. Microglia, the resident macrophages of the central nervous system, can have pathological responses after a variety of insults. This can occur through toll-like receptor 4 (TLR-4) in stroke models. We hypothesize that spinal cord ischemia-reperfusion injury after aortic occlusion results from TLR-4-mediated microglial activation in mice. METHODS AND RESULTS: TLR-4 mutant and wild-type mice underwent aortic occlusion for 5 minutes, followed by 60 hours of reperfusion when spinal cords were removed for analysis. Spinal cord cytokine production and microglial activation were assessed at 6 and 36 hours after surgery. Isolated microglia from mutant and wild-type mice were subjected to oxygen and glucose deprivation for 24 hours, after which the expression of TLR-4 and proinflammatory cytokines was analyzed. Mice without functional TLR-4 demonstrated decreased microglial activation and cytokine production and had preserved functional outcomes and neuronal viability after thoracic aortic occlusion. After oxygen and glucose deprivation, wild-type microglia had increased TLR-4 expression and production of proinflammatory cytokines. CONCLUSIONS: The absence of functional TLR-4 attenuated neuronal injury and microglial activation after thoracic aortic occlusion in mice. Furthermore, microglial upregulation of TLR-4 occurred after oxygen and glucose deprivation, and the absence of functional TLR-4 significantly attenuated the production of proinflammatory cytokines. In conclusion, TLR-4-mediated microglia activation in the spinal cord after aortic occlusion is critical in the mechanism of paraplegia after aortic cross-clamping and may provide targets for pharmacological intervention.

Intraoperative transeophageal echocardiography to diagnose an anomalous circumflex artery.

We describe a 43-year-old male presenting for hemiarch replacement and possible aortic valve replacement. Intraoperative transesophageal echocardiography (TEE) demonstrated an atypical coronary vessel, enabling proper diagnosis of an anomalous circumflex artery and appropriate operative planning.

Treatment of acute silicoproteinosis by whole-lung lavage.

Acute silicoproteinosis is a rare disease that occurs following a heavy inhalational exposure to silica dusts. Clinically, it resembles pulmonary alveolar proteinosis (PAP); silica exposure is thought to be a cause of secondary PAP. We describe a patient with biopsy-confirmed acute silicoproteinosis whose course was complicated by acute hypoxemic respiratory failure requiring mechanical ventilation. Without clinical improvement despite antibiotic and steroid treatment, the patient was scheduled for whole-lung lavage under general anesthesia. Anesthetic challenges included double-lumen tube placement and single-lung ventilation in a hypoxic patient, facilitating lung lavage, and protecting the contralateral lung from catastrophic spillage.

Preservation of motor function after spinal cord ischemia and reperfusion injury through microglial inhibition.

BACKGROUND: Paraplegia remains a devastating complication of thoracoabdominal aortic procedures resulting from spinal cord ischemia and reperfusion injury (SCIR). Pharmacologic interventions have not proven efficacious in attenuating this injury, with poor understanding of the underlying mechanisms. The resident macrophages, or microglia in the spinal cord, may play a significant role in SCIR. The macrolide antibiotic, minocycline, has been shown in stroke models to inhibit microglial activation. This study hypothesized that microglial inhibition by minocycline after SCIR will attenuate injury with preservation of motor function. METHODS: Mature male C57Bl/6 mice underwent 4 minutes of thoracic aortic occlusion with reperfusion. Mice receiving minocycline 30 minutes before ischemia and daily thereafter (90 mg/kg and 45 mg/kg, respectively) were compared with mice receiving vehicle controls. Hind-limb motor function was measured at 12-hour intervals, with spinal cord harvest for histologic and immunologic comparison at 60 hours. RESULTS: Minocycline treatment significantly preserved hind limb motor function in all mice (n = 7) compared with complete paralysis in all untreated mice (n = 8), reaching significance from 24 hours of reperfusion through 60 hours. Immunofluorescent staining for Iba-1 revealed significant inhibition of microglial activation by minocycline treatment. Vehicle control sections demonstrated a greater degree of apoptosis compared with minocycline-treated spinal cord sections. CONCLUSIONS: Minocycline limits microglial activation, paralleling functional preservation after aortic cross-clamping. These data suggest functional microglia contribute to reperfusion injury after spinal cord ischemia. The effects of minocycline demonstrate a potential pharmacological therapy as well as demonstrating a potential cellular target in preventing paraplegia after aortic intervention.

Anesthesia for tracheobronchial surgery.

The airway is a crucial dynamic structure that spans different anatomical zones, including the intrathoracic, extrathoracic, tracheal, bronchial, and alveolar zones. Because of its vital role as the sole oxygen-conducting pathway to the alveoli, and hence to the human body, surgery involving any portion requires careful and specific planning by both the surgeon and the anesthesiologist. The review covers essential management points for proximal and distal tracheal procedures, including a discussion of tracheal stenting and tracheoplasty.

Transesophageal echocardiography in noncardiac thoracic surgery.

In high-risk surgeries with medically complicated patients, transesophageal echocardiography (TEE) adds an additional level of monitoring with which few can disagree. This article presents multiple applications of TEE that can assist both the anesthesiologist and the surgeon through major noncardiac thoracic surgery. It highlights how TEE can be used as an adjuvant to lung resection surgery; TEE as a monitor during lung transplantation; TEE to assess patients for extracorporeal membrane oxygenation; TEE for thoracic aortic surgery; and TEE in the assessment of patients with acute pulmonary hypertension undergoing noncardiac thoracic surgery.

The evolution of chemokine release supports a bimodal mechanism of spinal cord ischemia and reperfusion injury.

BACKGROUND: Paraplegia remains a devastating complication of thoracic aortic surgery. The mechanism of the antecedent spinal cord ischemia and reperfusion injury (IR) remains poorly described. IR involves 2 injuries, an initial ischemic insult and subsequent inflammatory amplification of the injury. This mechanism is consistent with the clinical phenomenon of delayed onset paraplegia. This study sought to characterize the inflammatory response in the spinal cord after IR and hypothesized that this would support a bimodal mechanism of injury. METHODS AND RESULTS: Male C57Bl/6 mice were subjected to 5 minutes of aortic arch and left subclavian occlusion with subsequent reperfusion to generate spinal cord ischemia. Functional outcomes were scored at 12-hour intervals. Spinal cords were harvested after 0, 6, 12, 18, 24, 36, and 48 hours of reperfusion. Cytokine levels were analyzed using a mouse magnetic bead-based multiplex immunoassay. Inflammatory chemokine concentrations (interleukin [IL]-1ß, IL-6, keratinocyte-derived cytokine, macrophage inflammatory protein-1α, monocyte chemotactic protein-1, RANTES, and tumor necrosis factor-α) peaked at 6 hours and 36 to 48 hours after reperfusion. Functional scores reflected initial gain in function with subsequent decline, inversely proportional to cytokine levels. Immunofluorescent staining demonstrated microglia activation at 12 and 48 hours. CONCLUSIONS: Spinal cord ischemia and reperfusion injury occurs in 2 phases, correlating to increases in inflammatory chemokines release and microglial activation. These observations chronologically parallel the too-common clinical syndrome of delayed-onset paraplegia. Understanding the molecular pathogenesis of this injury may allow future intervention to prevent this devastating complication.

Attenuation of spinal cord ischemia-reperfusion injury by specific α-2a receptor activation with dexmedetomidine.

BACKGROUND: Despite surgical adjuncts, paralysis remains a devastating complication after thoracoabdominal aortic interventions. Dexmedetomidine, a selective α-2a agonist commonly used for sedation in the critical care setting, has been shown to have protective effects against ischemia-reperfusion injuries in multiple organ systems. We hypothesized that treatment with dexmedetomidine would attenuate spinal cord ischemia-reperfusion injury via α-2a receptor activation. METHODS: Adult C57BL/6 mice underwent sternotomy, followed by occlusion of the aortic arch for 4 minutes. Eight experimental mice received pretreatment with intraperitoneal dexmedetomidine (25 µg/kg) and at 12-hour intervals after reperfusion. Eight control mice received an equivalent amount of 0.9% normal saline. Five mice underwent the same procedure with dexmedetomidine (25 µg/kg) and atipamezole (250 µg/kg), an α-2a receptor antagonist. Functional analysis of the mice was obtained at 12-hour intervals and scored using the Basso Mouse Scale for Locomotion until 60 hours. All mice were euthanized at 60 hours. Their spinal cords were removed en bloc and were stained with hematoxylin and eosin to assess cytoarchitecture and neuronal viability. RESULTS: Mice treated with the α-2a agonist demonstrated preserved motor function compared with ischemic controls and with mice treated with the α-2a antagonist in addition to the agonist. Functional differences in the dexmedetomidine group were statistically significant from 24 hours through the remainder of the experiment (P < .05). In addition, the treated mice had preserved cytoarchitecture, decreased vacuolization, and improved neuronal viability compared with ischemic control mice and mice concurrently treated with atipamezole, the dexmedetomidine α-2a antagonist. CONCLUSIONS: Treatment of mice with the α-2a agonist dexmedetomidine preserves motor function and neuronal viability after aortic cross-clamping. In addition, mice exhibited almost complete reversal of the protective effect with the administration of the α-2a receptor antagonist atipamezole. Dexmedetomidine appears to attenuate spinal cord ischemia-reperfusion injury via α-2a receptor-mediated agonism. CLINICAL RELEVANCE: There remains a significant risk of paraplegia after thoracoabdominal aortic interventions. This complication is devastating to the patient and the health care system. Pharmacologic adjuncts to further decrease this complication have been studied; however, few viable options exist. The α-2a agonists have been shown to improve outcomes after strokes but have not been studied in spinal cord ischemia. We show that dexmedetomidine, a commonly used α-2a agonist in the operating room, can preserve neurologic function in mice after aortic cross-clamping. Although the protective mechanism of dexmedetomidine remains unknown, it might prove to be beneficial in reducing the incidence of paraplegia after aortic interventions.

Ischemic dose-response in the spinal cord: both immediate and delayed paraplegia.

BACKGROUND: Paraplegia remains a significant complication of thoracoabdominal aortic surgery. The study of this spinal cord ischemia and reperfusion injury (SCIR) has been stifled by the constraints of current models. Large animal models are costly and restricting with regard to mechanisms of both injury and protection. While few studies of a murine model of SCIR have been published, the dose-response curve of the ischemic injury has not yet been published. We hypothesized that a viable dose-response curve of the neurological injury relative to the ischemic time could be developed. MATERIALS AND METHODS: Through a cervicothoracic approach, the aortic arches of C57bl/6 mice were exposed to the origins of the left common carotid and the left subclavian arteries. The aorta was clamped between these two vessels with additional occlusion of the left subclavian artery. Ischemic times ranged from 3 to 12 min. Hindlimb motor function was observed for 48 h. Survival and motor function were evaluated. Spinal cord tissue was preserved for histologic analysis. RESULTS: Survival curves showed increasing mortality with increasing spinal cord ischemia. This model reproduced spinal cord injury ranging from immediate paraplegia to progressive paraparesis depending on the ischemic time. Spinal cord histology mirrored the extent of functional deficits. CONCLUSIONS: Reproducible spinal cord ischemic injury is possible in a murine model and is directly translatable to thoracoabdominal surgery. The dose-response curve demonstrates that different degrees of injury can be studied from dense paraplegia to delayed onset injury depending on the ischemic insult.

Total ischemia time alters the longitudinal and circumferential shortening of the right ventricle in transplanted hearts.

OBJECTIVES: Ischemia time is a risk factor for mortality and right ventricular (RV) failure after heart transplantation. The purpose of this study was to determine the effect of ischemia time on known transesophageal echocardiography (TEE) parameters of RV function and on a novel quantitative measurement of RV circumferential shortening. METHODS: Right and left ventricular (LV) function was evaluated retrospectively in 20 consecutive patients after heart transplant using known TEE parameters as well as a quantitative measurement of circumferential contraction. The control group consisted of 20 patients undergoing coronary artery bypass grafting (CABG) with no documented RV dysfunction. RESULTS: Posttransplant TEE parameters of RV function were depressed compared with post-cardiopulmonary bypass CABG patients. Significant correlation was observed between tricuspid annular planar systolic excursion, basal, mid, and global circumferential shortening and total ischemia time. CONCLUSION: Total ischemia time of the transplanted heart may play a role in deterioration of longitudinal and circumferential shortening of the RV.