Society of cardiovascular anesthesiologists: the effect of blood pressure regulation during aortic coarctation repair on brain, kidney, and muscle oxygen saturation measured by near-infrared spectroscopy: a randomized, clinical trial.

BACKGROUND: In this study, we compared the effects of 3 frequently used arterial blood pressure-regulating agents on brain (rScO2), renal (SrO2), and muscle (SmO2) oxygen saturation, during aortic coarctation repair in children. Based on the reported adverse effect of sodium nitroprusside (SNP) on left-sided rScO2 during aortic coarctation repair, we tested the hypothesis that the alterations in left rScO2 occurring with SNP would not be present with sevoflurane and nitroglycerin (NTG). Additionally, we explored the effects of blood pressure regulation with SNP, NTG, or sevoflurane on right-sided rScO2, SrO2, and SmO2. METHODS: Children with isolated aortic coarctation undergoing surgical repair through a left thoracotomy without the use of cardiopulmonary bypass were considered eligible for the study. During aortic cross-clamping, control of mean arterial blood pressure (MAP) was conducted according to randomization by the use of SNP, NTG, or sevoflurane to obtain a mean target right brachial blood pressure of 120% to 150% of the MAP value before cross-clamping. Bilateral rScO2, SrO2, and SmO2 were recorded continuously with near-infrared spectroscopy. As a primary end point, the maximal relative change in left-sided rScO2 in response to aortic cross-clamping was compared among treatment groups. RESULTS: Ten patients per group were included. No significant difference among treatment groups was observed in maximal relative change in left-sided rScO2 (SNP versus sevoflurane: mean difference -0.7%, 99% confidence interval [CI] -31% to 29%, P = 1.0; SNP versus NTG: mean difference -1.8%, 99% CI -32% to 28%, P = 1.0; sevoflurane versus NTG: mean difference -1.1%, 99% CI -31% to 29%, P = 1.0). Additional analyses also detected no difference between groups in right rScO2 (P = 0.4). Compared with NTG, treatment with SNP resulted in a significantly larger (-64% ± 17% vs -34% ± 25%, P = 0.01) and faster (-9 ± 4 %·min(-1) vs -4 ± 3 %·min(-1), P = 0.004) decrease in SmO2. Right-sided rScO2 and MAP showed a poor correlation for NTG (r = -0.2, P = 0.93), whereas borderline for sevoflurane (r = 0.44, P = 0.09) and SNP (r = 0.56, P = 0.04). CONCLUSIONS: The mean differences in left-sided rScO2 among the patients treated with SNP, NTG, or sevoflurane for proximal hypertension during aortic cross-clamping were no more than 32%. Additional analysis demonstrated a low MAP-rScO2 dependence with the use of NTG. Because NTG also resulted in a smaller and slower decrease of oxygen saturation in peripheral tissues, our data suggest that its use might be preferable for proximal blood pressure control during surgical procedures involving aortic cross-clamping.

Improving mitral valve coaptation with adjustable rings: outcomes from a European multicentre feasibility study with a new-generation adjustable annuloplasty ring system.

OBJECTIVES: To evaluate the performance and safety of an adjustable semi-rigid annuloplasty ring for mitral regurgitation (MR) in a multicentre study. METHODS: Between March 2010 and December 2011, 30 subjects underwent mitral valve (MV) repair using the Cardinal adjustable annuloplasty ring. This device is a semi-rigid ring allowing postimplantation size adjustment, under beating-heart conditions, to optimize leaflet coaptation under echocardiographic guidance. Coaptation length was determined before and after adjustment by transoesophageal echocardiography. RESULTS: The study enrolled 21 (70%) male and 9 (30%) female subjects with a mean age of 64 years. The approach was conventional midline sternotomy or mini-invasive right thoracotomy. Leaflet resection was done in 17 subjects, and chordal repair was used in 13. Concomitant procedures included coronary artery bypass grafting in 2 (7%) subjects, atrial ablation in 4 (13%) and tricuspid repair in 4 (13%). There was 1 (3%) early death unrelated to the study device. Intraoperative ring adjustment was performed in 24 of the 30 subjects. Residual MR was detected prior to adjustment in 6 subjects (4 mild and 2 moderate MR). Following adjustment, 5 subjects had no MR and 1 had trace MR. After adjustment, mean coaptation length improved from 7 ± 3 to 10 ± 3 mm (P < 0.0001). All patients who completed 1-year follow-up had less-than-mild MR, with the exception of 1 patient with ring dehiscence (and resultant 2+ MR) and 1 functional MR patient who developed recurrent 2+ MR due to persistent leaflet tethering. CONCLUSIONS: MV repair with the Cardinal adjustable annuloplasty ring is a reliable technique that enables the adjustment of the ring diameter on a beating heart under echocardiographic control. Such technology allows the optimization of leaflet coaptation, providing minimal residual MR and durable repair.

Real-time monitoring of somatostatin receptor-cAMP signaling in live pituitary.

Fluorescence resonance energy transfer using genetically encoded biosensors has proven to be a powerful technique to monitor the spatiotemporal dynamics of cAMP signals stimulated by G(s)-coupled receptors in living cells. In contrast, real-time imaging of G(i)-mediated cAMP signals under native conditions remains challenging. Here, we describe the use of transgenic mice for cAMP imaging in living pituitary slices and primary pituitary cells. This technique can be widely used to assess the contribution of various pituitary receptors, including individual G(i) protein-coupled somatostatin receptors, to the regulation of cAMP levels under physiologically relevant settings.

Psychiatric comorbidity and additional abuse of drugs in maintenance treatment with L- and D,L-methadone.

Sixty D,L- or L-methadone treated patients in maintenance therapy were interviewed for additional drug abuse and psychiatric comorbidity; 51.7% of the entire population had a comorbid Axis-I disorder, with a higher prevalence in females (P=0.05). Comorbid patients tended to have higher abuse of benzodiazepines, alcohol, cannabis, and cocaine, but not of heroin. They had received a significantly lower D,L- (P<0.05) and L-methadone dose than non-comorbid subjects. The duration of maintenance treatment showed an inverse relationship to frequency of additional heroin intake (P<0.01). Patients with additional heroin intake over the past 30 days had been treated with a significantly lower L-methadone dosage (P<0.05) than patients without. Axis-I comorbidity appears to be decreased when relatively higher dosages of D,L- (and L-methadone) are administered; comorbid individuals, however, were on significantly lower dosages. Finally, L-, but not D,L-methadone seems to be more effective in reducing additional heroin abuse.

Pasireotide and octreotide stimulate distinct patterns of sst2A somatostatin receptor phosphorylation.

Pasireotide (SOM230) is currently under clinical evaluation as a successor compound to octreotide for the treatment of acromegaly, Cushing's disease, and carcinoid tumors. Whereas octreotide acts primarily via the sst(2A) somatostatin receptor, pasireotide was designed to exhibit octreotide-like sst(2A) activity combined with enhanced binding to other somatostatin receptor subtypes. In the present study, we used phophosite-specific antibodies to examine agonist-induced phosphorylation of the rat sst(2A) receptor. We show that somatostatin and octreotide stimulate the complete phosphorylation of a cluster of four threonine residues within the cytoplasmic (353)TTETQRT(359) motif in a variety of cultured cell lines in vitro as well as in intact animals in vivo. This phosphorylation was mediated by G protein-coupled receptor kinases (GRK) 2 and 3 and followed by rapid cointernalization of the receptor and ss-arrestin into the same endocytic vesicles. In contrast, pasireotide failed to promote substantial phosphorylation and internalization of the rat sst(2A) receptor. In the presence of octreotide or SS-14, SOM230 showed partial agonist behavior, inhibiting phosphorylation, and internalization of sst(2A). Upon overexpression of GRK2 or GRK3, pasireotide stimulated selective phosphorylation of Thr356 and Thr359 but not of Thr353 or Thr354 within the (353)TTETQRT(359) motif. Pasireotide-mediated phosphorylation led to the formation of relatively unstable beta-arrestin-sst(2A) complexes that dissociated at or near the plasma membrane. Thus, octreotide and pasireotide are equally active in inducing classical G protein-dependent signaling via the sst(2A) somatostatin receptor. Yet, we find that they promote strikingly different patterns of sst(2A) receptor phosphorylation and, hence, stimulate functionally distinct pools of beta-arrestin.

Reassessment of sst2 somatostatin receptor expression in human normal and neoplastic tissues using the novel rabbit monoclonal antibody UMB-1.

OBJECTIVE: The overexpression of somatostatin receptor 2 (sst2) in neuroendocrine tumors is the molecular basis for diagnostic and therapeutic application of the stable somatostatin analog octreotide. Recent evidence has shown that the immunocytochemical evaluation of sst2A status is of value for predicting response to octreotide therapy and disease prognosis. However, due to the lack of monoclonal and limited availability of specific polyclonal anti-sst2A antibodies, only very few patients can currently benefit from in vitro sst2 evaluation. METHODS: In the present study, we extensively characterized the novel rabbit monoclonal anti-sst2A antibody (clone UMB-1) using tissues from sst2-deficient mice and their wild-type littermates. UMB-1 was then subjected to a comparative study of immunohistochemistry on a series of histological specimens from formalin-fixed, paraffin-embedded human tumors and adjacent normal tissues. RESULTS: Immunoprecipitation experiments unequivocally demonstrated that UMB-1 selectively detected its cognate sst2A and did not cross-react with other proteins present in crude tissue homogenates. The UMB-1 monoclonal antibody, when compared with currently available polyclonal antisera, yielded several times more effective immunohistochemical staining of fixed-embedded tissues with a predominance of plasma membrane staining and very low cytoplasmic signal even without heat-based antigen retrieval. In addition, dual immunofluorescence revealed for the first time that the sst2A is present on not only gastrin-containing but also ghrelin-containing cells in human gastric mucosa. CONCLUSION: Thus, the rabbit monoclonal antibody UMB-1 may prove of great value in the assessment of sst2A status in human neuroendocrine tumors during routine histopathological examination.

Regional and cellular localization of the CXCl12/SDF-1 chemokine receptor CXCR7 in the developing and adult rat brain.

The chemokine stromal cell-derived factor-1 (SDF-1) regulates neuronal development via the chemokine receptor CXCR4. In the adult brain the SDF-1/CXCR4 system was implicated in neurogenesis, neuromodulation, brain inflammation, tumor growth, and HIV encephalopathy. Until the recent identification of RDC1/CXCR7 as the second SDF-1 receptor, CXCR4 was considered to be the only receptor for SDF-1. Here we provide the first map of CXCR7 mRNA expression in the embryonic and adult rat brain. At embryonic stages, CXCR7 and CXCR4 were codistributed in the germinative zone of the ganglionic eminences, caudate putamen, and along the routes of GABAergic precursors migrating toward the cortex. In the cortex, CXCR7 was identified in GABAergic precursors and in some reelin-expressing Cajal-Retzius cells. Unlike CXCR4, CXCR7 was abundant in neurons forming the cortical plate and sparse in the developing dentate gyrus and cerebellar external germinal layer. In the adult brain, CXCR7 was expressed by blood vessels, pyramidal cells in CA3, and mature dentate gyrus granule cells, which is reminiscent of the SDF-1 pattern. CXCR7 and CXCR4 overlapped in the wall of the four ventricles. Further neuronal structures expressing CXCR7 comprised the olfactory bulb, accumbens shell, supraoptic and ventromedial hypothalamic nuclei, medial thalamus, and brain stem motor nuclei. Also, GLAST-expressing astrocytes showed signals for CXCR7. Thus, CXCR4 and CXCR7 may cooperate or act independently in SDF-1-dependent neuronal development. In mature neurons and blood vessels CXCR7 appears to be the preponderant SDF-1-receptor.

Mice with targeted Slc4a10 gene disruption have small brain ventricles and show reduced neuronal excitability.

Members of the SLC4 bicarbonate transporter family are involved in solute transport and pH homeostasis. Here we report that disrupting the Slc4a10 gene, which encodes the Na(+)-coupled Cl(-)-HCO(3)(-) exchanger Slc4a10 (NCBE), drastically reduces brain ventricle volume and protects against fatal epileptic seizures in mice. In choroid plexus epithelial cells, Slc4a10 localizes to the basolateral membrane. These cells displayed a diminished recovery from an acid load in KO mice. Slc4a10 also was expressed in neurons. Within the hippocampus, the Slc4a10 protein was abundant in CA3 pyramidal cells. In the CA3 area, propionate-induced intracellular acidification and attenuation of 4-aminopyridine-induced network activity were prolonged in KO mice. Our data indicate that Slc4a10 is involved in the control of neuronal pH and excitability and may contribute to the secretion of cerebrospinal fluid. Hence, Slc4a10 is a promising pharmacological target for the therapy of epilepsy or elevated intracranial pressure.

Reassessment of CXCR4 chemokine receptor expression in human normal and neoplastic tissues using the novel rabbit monoclonal antibody UMB-2.

BACKGROUND: The CXCR4 chemokine receptor regulates migration and homing of cancer cells to specific metastatic sites. Determination of the CXCR4 receptor status will provide predictive information for disease prognosis and possible therapeutic intervention. However, previous attempts to localize CXCR4 using poorly characterized mouse monoclonal or rabbit polyclonal antibodies have produced predominant nuclear and occasional cytoplasmic staining but did not result in the identification of bona fide cell surface receptors. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we extensively characterized the novel rabbit monoclonal anti-CXCR4 antibody (clone UMB-2) using transfected cells and tissues from CXCR4-deficient mice. Specificity of UMB-2 was demonstrated by cell surface staining of CXCR4-transfected cells; translocation of CXCR4 immunostaining after agonist exposure; detection of a broad band migrating at M(r) 38,000-43,000 in Western blots of homogenates from CXCR4-expressing cells; selective detection of the receptor in tissues from CXCR4+/+ but not from CXCR4-/- mice; and abolition of tissue immunostaining by preadsorption of UMB-2 with its immunizing peptide. In formalin-fixed, paraffin-embedded human tumor tissues, UMB-2 yielded highly effective plasma membrane staining of a subpopulation of tumor cells, which were often heterogeneously distributed throughout the tumor. A comparative analysis of the mouse monoclonal antibody 12G5 and other frequently used commercially available antibodies revealed that none of these was able to detect CXCR4 under otherwise identical conditions. CONCLUSIONS/SIGNIFICANCE: Thus, the rabbit monoclonal antibody UMB-2 may prove of great value in the assessment of the CXCR4 receptor status in a variety of human tumors during routine histopathological examination.

Intracellular trafficking of somatostatin receptors.

The somatostatin receptor subtypes 1-5 (sst(1)-sst(5)) exhibit different intracellular trafficking and endosomal sorting after agonist exposure. The internalization of the somatostatin receptor subtypes sst(2), sst(3) and sst(5) occurs to a much higher extent after somatostatin exposure than of sst(1) or sst(4). After endocytosis, sst(2) and sst(5) recycle to the plasma membrane, whereas sst(3) is predominantly down-regulated. This review will focus on the molecular mechanisms of the differential intracellular trafficking of sst(2), sst(3) and sst(5), and discusses our current knowledge on somatostatin receptor interacting proteins.

Postoperative results after desflurane or sevoflurane combined with remifentanil in morbidly obese patients.

BACKGROUND: This randomized prospective study with blinded postanesthesia care unit (PACU) observers compared the recovery profiles in morbidly obese patients who received sevoflurane or desflurane for maintenance of anesthesia in combination with a remifentanil target controlled infusion (TCI). METHODS: 50 morbidly obese patients scheduled for laparoscopic gastric banding were included to receive BIS-guided sevoflurane or desflurane anesthesia with BIS-triggered inhalation boli in combination with remifentanil TCI. In the PACU, the following recovery scores were investigated: Modified Aldrete score, a modified Observers' Assessment of Alertness/Sedation Scale (OAA/S), pain numerical rating scale (NRS), oxygen saturation (SpO(2)) and postoperative nausea and vomiting (PONV). RESULTS: OAA/S and NRS pain scores showed a similar evolution in both groups from the moment of PACU admission up to 120 minutes after admission. In both groups, patients showed no serious hypoxemia during PACU stay. Incidence of PONV was shorter lasting in the sevoflurane group compared to the desflurane group. CONCLUSIONS: No clinically relevant difference was found in recovery in the PACU between morbidly obese patients anesthetized with desflurane or sevoflurane. Both agents resulted in satisfactory recovery in morbidly obese patients.

Cardio navigation: planning, simulation, and augmented reality in robotic assisted endoscopic bypass grafting.

BACKGROUND: The aim of this study is to optimize the set-up and port placement in robotic surgery and enhance intraoperative orientation by video overlay of the angiographic coronary tree. METHODS: In three mongrel dogs and two sheep an electrocardiogram-triggered computed tomographic scan and coronary angiography were performed after placing cutaneous fiducials. The regions of interest (ie, heart, ribs, coronaries, internal thoracic artery) were segmented semiautomatically to create a virtual model of the animal. In this model the target regions of the total endoscopic bypass procedure along the internal thoracic artery and anastomotic area were defined. Algorithms for weighing visibility, dexterity, and collision avoidance were calculated after defining nonadmissible areas using a virtual model of the manipulator. Intraoperatively, registration of the animal and the telemanipulator was performed using encoder data of the telemanipulator by pointing to the fiducials. After pericardiotomy, the reconstructed coronary tree was projected into the videoscopic image using a semiautomatic alignment procedure. In dogs, the total endoscopic bypass procedure was completed on the beating heart. The first human case applying preoperative planning, intraoperative registration, and augmented reality was subsequently performed. RESULTS: The rigid transformation linked the patient's preoperative frame and the robot coordinate frame with a root mean square error of 9 to 15 mm. The predicted port placement derived from the model initially varied from the one chosen due to an incomplete formulation of the weighing procedure. After only a few iterations, the algorithm became robust and predicted a collision free triangle. Video overlay of the angiographic coronary tree into the videoscopic image was feasible. CONCLUSIONS: Surgical planning and augmented reality are likely to enhance robotic surgery in the future. A more complete understanding of the surgical decision process is required to better formalize the planning algorithms.

A novel adhesion barrier facilitates reoperations in complex congenital cardiac surgery.

OBJECTIVE: Reoperations are associated with an increased surgical risk due to adhesions. We prospectively evaluated a bioresorbable membrane after surgery for congenital heart defects over a 3.5-year period. METHODS: The surgical membrane (CV Seprafilm, Genzyme, Cambridge, Mass) was applied in 350 of 1024 patients; 30 of them underwent reoperation and were evaluated in comparison to 10 random reoperated patients. Adhesions were evaluated using a subjective scoring system [1 (lowest tenacity) to 5 (highest tenacity)] and extent in percent at different regions of the heart. RESULTS: Patients were operated for atrioventricular septal defect (69), tetralogy of Fallot (65), functional single ventricle (75), valve surgery (48), ventricular septal defect (20), subaortic stenosis (17), hypoplastic left heart syndrome (17), and other diagnoses (39). Application of the surgical membrane was safe in all patients, without any infections. At reoperation patients received Glenn (14), total cavopulmonary connection (6), and others (10). Overall mortality was 2/350 (0.57%). There was a remarkable reduction in tenacity score (3.3 vs 4.3) and in the extent of adhesions (77.7% vs 86%). Duration of reoperation was significantly reduced. CONCLUSIONS: A bioresorbable surgical membrane leads to a significant reduction in the tenacity and amount of adhesions. It is recommended for general use whenever repeat operation is anticipated in congenital as well as in adult cardiac surgery.

Augmented reality for intraoperative guidance in endoscopic coronary artery bypass grafting.

Endoscopic bypass grafting can be complicated by limited intraoperative orientation. A method to overlay the preoperative model of the coronary tree on the live endoscopic images of the heart was therefore developed. The method is three-fold: (1) the three-dimensional (3D) model of the coronary tree is reconstructed from traditional angiograms; (2) preoperative images are registered with the intraoperative position of the patient in the operating room (OR); and (3) an iterative and interactive identification of clinically relevant landmarks within the operative field on the heart surface before their registration with the preoperative model of the coronaries. This algorithm allows one to compensate deformations (breathing, intraoperative heart shift) and leads to a precise overlay of the coronary network on the heart surface. For ergonomic reasons, the 3D model can be displayed directly within the visual field of any telesurgical master console. It thus provides an effective navigational aid to the surgeon similar to a global positioning system (GPS) in vehicles. Animal trials have been performed using the Da Vinci (Intuitive Surgical, Sunnyvale, CA, USA) teleoperated system to validate the method. Qualitative and quantitative analysis demonstrate the potential value during total endoscopic coronary artery bypass grafting.

Primary repair for aortic arch obstruction associated with ventricular septal defect.

BACKGROUND: The aim of the present study was to evaluate the current outcome and reoperation rate after applying a one-stage correction strategy for interrupted aortic arch (IAA) with ventricular septal defect (VSD) and also for aortic coarctation and hypoplastic aortic arch (CoA-HyAA) with VSD beginning September 1999. METHODS: Twenty-four consecutive patients with IAA (n = 12) or CoA-HyAA (n = 12) with VSD underwent early one-stage correction. Patients' mean age was 12 days (range, 2 to 188); mean weight was 3.6 kg (range, 2.1 to 7.3), 6 patients were less than 2.5 kg. Three IAA were type A, 5 type B1, 3 type B2, and 1 type C. Associated anomalies included a large VSD in all, left ventricular outlet tract obstruction in 5, transposition of the great arteries, aortopulmonary window, persistent truncus arteriosus, and double-outlet right ventricle in 1 patient. Selective brain perfusion through innominate artery and selective coronary perfusion through aortic root during aortic arch reconstruction was used in all patients. Mean follow-up was 2.2 +/- 0.9 years. RESULTS: There was no early, no late mortality, and no postoperative neurologic complications. Mean crossclamp duration was 72 +/- 32 minutes, lowest temperature 22.8 +/- 4 degrees C and selective brain and coronary perfusion duration was 34 +/- 13 minutes. Eighteen patients required delayed sternal closure at 1.7 days postoperatively. New perioperative management reduced the overall morbidity. Four patients after IAA plus VSD repair developed aortic arch restenosis and were successfully treated by balloon dilatation. One patient with d-TGA underwent right ventricular outflow tract reconstruction of right ventricular outlet tract obstruction 7 months after the initial repair. Pressure gradients across the anastomosis at most recent follow up were less than 10 mm Hg. All patients are asymptomatic and are developing normally. CONCLUSIONS: One-stage complete correction is feasible in newborns with aortic arch obstruction with VSD. Complex cardiac anatomy presents no additional risk for the procedure. The early one-stage correction yields excellent surgical results and good functional outcome.