Efficacy of Dexmedetomidine as a Sole Sedative Agent in Small Diagnostic and Therapeutic Procedures: A Systematic Review.

Dexmedetomidine is an upcoming agent with sedative, anxiolytic, and analgesic properties. This review summarizes empirical evidence for the efficacy of dexmedetomidine as a sole sedative agent, and its effectiveness for small diagnostic and therapeutic procedure, in comparison with other frequently used sedatives. All randomized controlled trials on the effect of dexmedetomidine were reviewed. Pain level, patient satisfaction, operator satisfaction, procedure duration, recovery time, and hemodynamic and respiratory characteristics were examined. A total of 1993 patients (1,621 adults; 372 children) from 35 studies were included. In the adult studies, dexmedetomidine yielded significantly lower pain levels compared to the other sedatives (in 31.25% of the included studies) and significantly more patient satisfaction (68.2%). In studies on children, more favorable results concerning respiratory safety and the level of adequate sedation were found compared to the control sedatives. Implications for future studies are discussed.

Dexmedetomidine as a Sedative in the Awake Implantation of a Neuromodulative System.

OBJECTIVE: During implantation of a neuromodulative system, high patient satisfaction is closely associated with the equilibrium between an effective analgesia and sedation regimen, and the possibility for the patient to be awake and cooperative during procedure. This study assessed the efficacy of the sedative dexmedetomidine to achieve this balance, with patient satisfaction as the primary outcome. METHODS: Ten patients undergoing implantation of a dorsal column and dorsal root ganglion stimulator received dexmedetomidine (1 mcg/kg over 10 minutes, followed by 0.6 mcg/kg/hour) in combination with remifentanil at a set dose (3 mcg/kg/hour). Sedation was titrated to a Ramsay Sedation Score of 3. Recorded were as follows: patient satisfaction score, patient comfort score, operator comfort score, pain score, rescue medication and number of adjustments of dexmedetomidine intra-operatively, as well as sedation level, hemodynamic (blood pressure and heart rate), and respiratory characteristics (SpO2 ). RESULTS: Scores were high on patient satisfaction (median 8.5; IQR 2.0), patient comfort (3.0; IQR 1.25), and operator comfort (4.0; IQR 1.0). In all patients, intra-operative heart rate and mean arterial pressure were lower compared with baseline values. No respiratory depression or other complications related to anesthesia were reported. Moments of incident pain were effectively treated in 6 patients requiring an extra bolus of remifentanil. CONCLUSION: In this study group, dexmedetomidine combined with remifentanil provided a high level of patient satisfaction and comfort, as well as operator comfort, without any clinically relevant adverse events. All patients were highly cooperative and instructable; incident pain needs to be closely monitored.

Impact of dedicated neuro-anesthesia management on clinical outcomes in glioblastoma patients: A single-institution cohort study.

BACKGROUND: Glioblastomas are mostly resected under general anesthesia under the supervision of a general anesthesiologist. Currently, it is largely unkown if clinical outcomes of GBM patients can be improved by appointing a neuro-anesthesiologist for their cases. We aimed to evaluate whether the assignment of dedicated neuro-anesthesiologists improves the outcomes of these patients. We also investigated the value of dedicated neuro-oncological surgical teams as an independent variable in both groups. METHODS: A cohort consisting of 401 GBM patients who had undergone resection was retrospectively investigated. Primary outcomes were postoperative neurological complications, fluid balance, length-of-stay and overall survival. Secondary outcomes were blood loss, anesthesia modality, extent of resection, total admission costs, and duration of surgery. RESULTS: 320 versus 81 patients were operated under the anesthesiological supervision of a general anesthesiologist and a dedicated neuro-anesthesiologist, respectively. Dedicated neuro-anesthesiologists yielded significant superior outcomes in 1) postoperative neurological complications (early: p = 0.002, OR = 2.54; late: p = 0.003, OR = 2.24); 2) fluid balance (p<0.0001); 3) length-of-stay (p = 0.0006) and 4) total admission costs (p = 0.0006). In a subanalysis of the GBM resections performed by an oncological neurosurgeon (n = 231), the assignment of a dedicated neuro-anesthesiologist independently improved postoperative neurological complications (early minor: p = 0.0162; early major: p = 0.00780; late minor: p = 0.00250; late major: p = 0.0364). The assignment of a dedicated neuro-oncological team improved extent of resection additionally (p = 0.0416). CONCLUSION: GBM resections with anesthesiological supervision of a dedicated neuro-anesthesiologists are associated with improved patient outcomes. Prospective evidence is needed to further investigate the usefulness of the dedicated neuro-anesthesiologist in different settings.

Blood Pressure During Endovascular Treatment Under Conscious Sedation or Local Anesthesia.

OBJECTIVE: To evaluate the role of blood pressure (BP) as mediator of the effect of conscious sedation (CS) compared to local anesthesia (LA) on functional outcome after endovascular treatment (EVT). METHODS: Patients treated in the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry centers with CS or LA as preferred anesthetic approach during EVT for ischemic stroke were analyzed. First, we evaluated the effect of CS on area under the threshold (AUT), relative difference between baseline and lowest procedural mean arterial pressure (∆LMAP), and procedural BP trend, compared to LA. Second, we assessed the association between BP and functional outcome (modified Rankin Scale [mRS]) with multivariable regression. Lastly, we evaluated whether BP explained the effect of CS on mRS. RESULTS: In 440 patients with available BP data, patients treated under CS (n = 262) had larger AUTs (median 228 vs 23 mm Hg*min), larger ∆LMAP (median 16% vs 6%), and a more negative BP trend (-0.22 vs -0.08 mm Hg/min) compared to LA (n = 178). Larger ∆LMAP and AUTs were associated with worse mRS (adjusted common odds ratio [acOR] per 10% drop 0.87, 95% confidence interval [CI] 0.78-0.97, and acOR per 300 mm Hg*min 0.89, 95% CI 0.82-0.97). Patients treated under CS had worse mRS compared to LA (acOR 0.59, 95% CI 0.40-0.87) and this association remained when adjusting for ∆LMAP and AUT (acOR 0.62, 95% CI 0.42-0.92). CONCLUSIONS: Large BP drops are associated with worse functional outcome. However, BP drops do not explain the worse outcomes in the CS group.

Periostin expression by epicardium-derived cells is involved in the development of the atrioventricular valves and fibrous heart skeleton.

The epicardium is embryologically formed by outgrowth of proepicardial cells over the naked heart tube. Epicardium-derived cells (EPDCs) migrate into the myocardium, contributing to myocardial architecture, valve development, and the coronary vasculature. Defective EPDC formation causes valve malformations, myocardial thinning, and coronary defects. In the atrioventricular (AV) valves and the fibrous heart skeleton isolating atrial from ventricular myocardium, EPDCs colocalize with periostin, a matrix molecule involved in remodeling. We investigated whether proepicardial outgrowth inhibition affected periostin expression and how this related to development of the AV valves and fibrous heart skeleton. Periostin expression by epicardium and EPDCs was confirmed in vitro in primary cultures of human and quail EPDCs. Disturbing EPDC formation in quail embryos reduced periostin expression in the endocardial cushions and AV junction. Disturbed fibrous tissue development resulted in AV myocardial connections reflected by preexcitation electrocardiographic patterns. We conclude that EPDCs are local producers of periostin. Disturbance of EPDC formation results in decreased cardiac periostin levels and hampers the development of fibrous tissue in AV junction and the developing AV valves. The resulting cardiac anomalies might link to Wolff-Parkinson White syndrome with persistent AV myocardial connections.

Conscious sedation or local anesthesia during endovascular treatment for acute ischemic stroke.

OBJECTIVE: To investigate the effect of conscious sedation (CS) on functional outcome and complication rates after intra-arterial treatment (IAT) for acute ischemic stroke (AIS) compared to the use of local anesthesia (LA) at the puncture site only. METHODS: Patients undergoing IAT for AIS with CS or LA in the Erasmus University Medical Center from March 2014 to June 2016 were included for analysis. The primary outcome was the score on the ordinal modified Rankin Scale (mRS). We compared CS to LA by ordinal logistic regression with covariate adjustment using propensity scoring. RESULTS: In 146 AIS patients treated with IAT, use of CS was associated with a shift towards worse mRS scores (odds ratio [OR] 0.4 [95% confidence interval (CI) 0.2-0.7]) compared to LA. Mortality after 90 days was higher in the CS group compared to the LA group (OR 2.3 [95% CI 1.0-5.2]). No differences between groups were noted with regard to procedure duration (8 minutes, ß = 6.3 [95% CI -7.4 to 20.0]) or occurrence of procedure-related complications (OR 1.3 [95% CI 0.6-2.7]). CONCLUSION: CS was associated with poor functional outcome and increased mortality rates compared to LA. Furthermore, CS did not reduce duration of intervention or interventional complications. CS during IAT for AIS is of no benefit if LA is considered safe. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence, because of nonrandom allocation, that for patients with AIS undergoing IAT, LA rather than CS improves functional outcome.

Coronary artery and orifice development is associated with proper timing of epicardial outgrowth and correlated Fas-ligand-associated apoptosis patterns.

The proepicardial organ provides differentiated cell types to the myocardial wall and facilitates coronary development. Ingrowth of the coronary arteries into the aorta has recently been linked to apoptosis. This study was set up to examine the effect of an inhibition of epicardial outgrowth on apoptotic patterning and coronary development. Epicardial outgrowth was blocked at HH15-17 in quail embryos, which survived until HH25-35 (n=33). Embryos with complete inhibition of outgrowth did not survive after HH29. These embryos presented with thin compact myocardium, devoid of vessels. In embryos with delayed epicardial outgrowth the phenotype was less severe, and surviving embryos were studied up to HH35. In these embryos, myocardial vascularization was poor and apoptosis in the peritruncal region at HH30 was diminished. Embryos at HH35 displayed an abnormal coronary network and absent coronary orifices. In a further set of experiments (n=10), outgrowth was inhibited in chicken embryos at HH15, followed by transplantation of a quail proepicardial organ into the pericardial cavity to rescue cardiac phenotype. These chimeras were studied at HH29 and HH35. Myocardial development was restored; however, in 3 of 4 embryos (HH35), the coronary orifices were absent. Examination of double stainings of quail-chicken chimeras revealed that EPDCs produce Fas ligand as an apoptotic inductor at sites of coronary ingrowth. In the absence of proper timing of epicardial outgrowth, myocardial development and vascularization are disturbed. Also apoptosis in the peritruncal region is diminished. During later development, this leads to defective or absent connections of the coronary system to the systemic circulation.

Epicardium-derived cells are important for correct development of the Purkinje fibers in the avian heart.

During embryonic development, the proepicardial organ (PEO) grows out over the heart surface to form the epicardium. Following epithelial-mesenchymal transformation, epicardium-derived cells (EPDCs) migrate into the heart and contribute to the developing coronary arteries, to the valves, and to the myocardium. The peripheral Purkinje fiber network develops from differentiating cardiomyocytes in the ventricular myocardium. Intrigued by the close spatial relationship between the final destinations of migrating EPDCs and Purkinje fiber differentiation in the avian heart, that is, surrounding the coronary arteries and at subendocardial sites, we investigated whether inhibition of epicardial outgrowth would disturb cardiomyocyte differentiation into Purkinje fibers. To this end, epicardial development was inhibited mechanically with a membrane, or genetically, by suppressing epicardial epithelial-to-mesenchymal transformation with antisense retroviral vectors affecting Ets transcription factor levels (n=4, HH39-41). In both epicardial inhibition models, we evaluated Purkinje fiber development by EAP-300 immunohistochemistry and found that restraints on EPDC development resulted in morphologically aberrant differentiation of Purkinje fibers. Purkinje fiber hypoplasia was observed both periarterially and at subendocardial positions. Furthermore, the cells were morphologically abnormal and not aligned in orderly Purkinje fibers. We conclude that EPDCs are instrumental in Purkinje fiber differentiation, and we hypothesize that they cooperate directly with endothelial and endocardial cells in the development of the peripheral conduction system.

Treatment of infected nonunion of the juxta-articular region of the distal tibia.

OBJECTIVE: The purpose of this study was to summarize our clinical results with distraction osteogenesis for the treatment of infected tibial nonunion around the ankle joint. METHODS: Between 1994 and 2009, 13 patients with a mean age of 50 years (range: 27-79 years) underwent tibial reconstruction for the treatment of infected nonunion of the distal tibia, with a mean bone loss of 4.8 cm (range: 1-7 cm). Lengthening over an intramedullary nail as a second procedure was used in 2 patients, bifocal compression and distraction technique in 5 cases, compression with Ilizarov external fixator in 5 cases, and Taylor Spatial Frame (TSF, Smith Nephew, Memphis, TN, USA) in 1 case. At final follow-up, functional and radiographic results were evaluated according to Paley's bone and functional healing criteria. RESULTS: Mean duration of follow-up was 36 months. Mean external fixation time was 198 days, and mean external fixation index was 29 days/cm. According to Paley's bone healing criteria, there were 10 excellent, 2 good, and 1 poor result(s); additionally, according to Paley's functional healing criteria, there were 5 excellent, 6 good, and 2 fair results. There were 11 problems, 5 obstacles, and 1 sequel according to Paley's classification of complications. There was 1 persisting nonunion, which underwent revision with a retrograde intramedullary nail. CONCLUSION: External fixator and/or combined treatment are effective and reliable methods to treat infected nonunion of the distal tibia. Every patient should be evaluated according to their infection level and bony defects for reconstruction.

Myocardial heterogeneity in permissiveness for epicardium-derived cells and endothelial precursor cells along the developing heart tube at the onset of coronary vascularization.

The coronary vasculature develops from mesothelial and endothelial precursor cells (EPCs) derived from the proepicardial organ (PEO), which migrate over the heart to form the epicardium. By epithelial-mesenchymal transition (EMT), the subepicardium and epicardium-derived cells (EPDCs) are formed. EPDCs migrate into the myocardium, where they differentiate into smooth muscle cells and fibroblasts that stabilize the developing coronary vasculature and contribute to myocardial architecture. Complete PEO ablation results in embryonic lethality due to cardiac defects, including a looping disorder with a too wide inner curvature. To investigate the behavior of early coronary contributors, we analyzed normal quail embryos and found lumenized endothelial vessels in the subepicardium already at stage HH19. Furthermore, EPCs had penetrated into the myocardium of the inner curvature. To confirm that the myocardium of the inner curvature is specifically permissive for EPCs and to study early EPDC migration in more detail, chimeric chicken embryos harboring a quail PEO were analyzed. Lateral epicardial outgrowth and EMT were observed throughout, but migration into the myocardium was restricted to the inner curvature between HH19 and 22. The permissive myocardial area expanded to the atrium, atrioventricular canal, and trabeculated ventricle at stage HH23-24. In contrast, outflow tract myocardium was never found to be permissive for EPDCs and EPCs until HH30, not even when the quail PEO was attached directly onto it. We conclude that early coronary formation starts in the inner curvature and hypothesize that the presence of PEO-derived cells is essential for the maturation of the inner curvature and subsequent looping of the heart tube.

Platelet-derived growth factors in the developing avian heart and maturating coronary vasculature.

Platelet-derived growth factors (PDGFs) are important in embryonic development. To elucidate their role in avian heart and coronary development, we investigated protein expression patterns of PDGF-A, PDGF-B, and the receptors PDGFR-alpha and PDGFR-beta using immunohistochemistry on sections of pro-epicardial quail-chicken chimeras of Hamburger and Hamilton (HH) 28-HH35. PDGF-A and PDGFR-alpha were expressed in the atrial septum, sinus venosus, and throughout the myocardium, with PDGFR-alpha retreating to the trabeculae at later stages. Additionally, PDGF-A and PDGFR-alpha were present in outflow tract cushion mesenchyme and myocardium, respectively. Small cardiac nerves and (sub)epicardial cells expressed PDGF-B and PDGFR-beta. Furthermore, endothelial cells expressed PDGF-B, while vascular smooth muscle cells and interstitial epicardium-derived cells expressed PDGFR-beta, indicating a role in coronary maturation. PDGF-B is also present in ventricular septal development, in the absence of any PDGFR. Epicardium-derived cells in the atrioventricular cushions expressed PDGFR-beta. We conclude that all four proteins are involved in myocardial development, whereas PDGF-B and PDGFR-beta are specifically important in coronary maturation.