Rethink analgo-sedation in digestive endoscopy: the role of scientific societies in tracing training path.

OBJECTIVE: The Italian Society of Anesthesia, Analgesia, Reanimation and Intensive Care Medicine (SIAARTI) and the Italian Society of Digestive Endoscopy (SIED) worked together to produce a joint Good Clinical Practice (GCP) on analgo-sedation in digestive endoscopy and launched a survey to support the document. The aim was to identify and describe the actual clinical practice of sedation in Italian digestive endoscopy units and offer material for a wider and more widespread discussion among anesthetists and endoscopists. SUBJECTS AND METHODS: A national survey was planned, in order to support the statements of the GCP. Twelve thousand and five hundred questionnaires were sent to the members of SIAARTI and SIED in June 2020. RESULTS: A total of 662 forms (5.3%) returned completed. Highly complex procedures are performed according to 70% of respondents; daily anesthesiologist's assistance is guaranteed in 26%, for scheduled sessions in 14.5% and as needed in 8%. 69% of respondents declared not to have a dedicated team of anesthesiologists, while just 5% reported an anesthesiologist in charge. A complete monitoring system was assured by 70% of respondents. Dedicated pathways for COVID-19-positive patients were confirmed in <40% of the answers. With regard to moderate/deep sedation, 90% of respondents stated that an anesthetist decides timing and doses. Propofol was exclusively administered by anesthetists according to 94% of answers, and for 6% of respondents the endoscopist is allowed to administer propofol in presence of a dedicated nurse, but with a readily available anesthetist. Only 32.8% of respondents reported institutional training courses on procedural analgo-sedation. CONCLUSIONS: The need to provide patients scheduled for endoscopy procedures with an adequate analgo-sedation is becoming an increasing concern, well-known in almost all countries, but many factors compromise the quality of patient care. Results of a national survey would give strength to the need for a shared GCP in gastrointestinal endoscopy. Training and certification of non-anesthetist professionals should be one of the main ways to center the objective.

Effect Of α2-Adrenergic Agonists And Antagonists On Cytokine Release From Human Lung Macrophages Cultured In Vitro.

The most trusted hypothesis to explain how α2-adrenergic agonists may preserve pulmonary functions in critically ill patients is that they directly act on macrophages by interfering with an autocrine/paracrine adrenergic system that controls cytokine release through locally synthetized noradrenaline and α1- and α2-adrenoreceptors. We tested this hypothesis in primary cultures of resident macrophages from human lung (HLMs). HLMs were isolated by centrifugation on percoll gradients from macroscopically healthy human lung tissue obtained from four different patients at the time of lung resection for cancer. HLMs from these patients showed a significant expression of α2A, α2B and α2C adrenoreceptors both at the mRNA and at the protein level. To evaluate whether α2 adrenoreceptors controlled cytokine release from HMLs, we measured IL-6, IL-8 and TNF-α concentrations in the culture medium in basal conditions and after preincubation with several α2-adrenergic agonists or antagonists. Neither the pretreatment with the α2-adrenergic agonists clonidine, medetomidine or dexdemetomidine or with the α2-adrenergic antagonist yohimbine caused significant changes in the response of any of these cytokines to LPS. These results show that, different from what reported in rodents, clonidine and dexdemetomidine do not directly suppress cytokine release from human pulmonary macrophages. This suggests that alternative mechanisms such as effects on immune cells activation or the modulation of autonomic neurotransmission could be responsible for the beneficial effects of these drugs on lung function in critical patients.

Navigator® and SmartPilot® View are helpful in guiding anesthesia and reducing anesthetic drug dosing.

BACKGROUND: The recently introduced Navigator® (GE Healthcare, Helsinki, Finland) and SmartPilot® View (Dräger Medical, Lübeck, Germany) show the concentrations and predicted effects of combined anesthetic drugs, and should facilitate more precisely their titration. Our aim was to evaluate if Navigator® or SmartPilot® View guided anesthesia was associated with a good quality of analgesia, depth of hypnosis and may reduce anesthetic requirements. METHODS: We performed a prospective non-randomized study. Sixty ASA I-II patients undergoing balanced general anesthesia for abdominal and plastic surgery were enrolled. Patients were divided in 4 groups. Group 1 (N. 15) and group 3 (N. 15) were cases in whom anesthesia was performed with standard monitoring plus the aid of Navigator® (Nav) or SmartPilot® View (SPV) display. Group 2 (N. 15) and group 4 (N. 15) were controls in whom anesthesia was performed with standard monitoring (heart rate, NIBP, SpO2, end-tidal CO2, end-expired sevoflurane concentration, train of four, Bispectral Index [Aspect Medical Systems, Natick, MA, USA] or Entropy [GE Healthcare]). Patients' vital parameters and end-expired sevoflurane concentration were recorded during anesthesia. RESULTS: All patients recovered uneventfully and showed hemodynamic stability. End-tidal sevoflurane concentrations values [median (min-max)], during maintenance of anesthesia, were significantly (P<0.05) lower in SPV [1.1% (0.8-1.5)] and Nav [1%(0.8-1.8)] groups compared to SPV-control group [1.5%(1-2.5)] and Nav-control group [1.5%(0.8-2)]. BIS and entropy values were respectively higher in the SPV group [53 (46-57)] compared to the control group [43 (37-51)] (P<0.05) and Nav group [53 (43-60)] compared to the control group [41 (35-51)] (P<0.05). No significant differences in Remifentanil dosing were observed in the four groups. CONCLUSION: Navigator® and SmartPilot® View may be of clinical use in monitoring adequacy of anesthesia. Both displays can optimize the administration and monitoring of anesthetic drugs during general anesthesia and may reduce the consumption of volatile anesthetic agents.

S100B induces the release of pro-inflammatory cytokines in alveolar type I-like cells.

S100B, a 21kDa cytosolic calcium-binding protein of the EF-hand type, present in high abundance in the brain, stimulates inflammatory responses in different cellular types inside and outside the central nervous system. Most of extracellular S100B effects are mediated by Receptor for Advanced Glycation End-products (RAGE). RAGE is highly expressed in lung by Alveolar Type-I (AT-I) cells and its activation contributes to ALI/ARDS pathogenesis. In this in-vitro study, we tested the hypothesis that S100B stimulates an ATI-derived cell line (R3/1) to secrete inflammatory mediators involved in lung inflammation. Our main result is that S100B stimulates R3/1 cells to secrete TNF-alpha and IL-6 (well-known pro-inflammatory cytokines in lung inflammation and neurogenic pulmonary edema), but not sICAM-1, CINC-1 or CINC-3. Soluble RAGE (sRAGE) reduced S100B-dependent secretion of TNF-alpha but did not decrease S100B-dependent secretion of IL-6. Moreover, in absence of S100B, sRAGE enhanced IL-6 release. This study demonstrates that in vitro S100B dose-dependently stimulated R3/1 cells, to enhance the secretion of TNF-alpha and IL-6; S100B pro-inflammatory activity might be mediated at least in part by RAGE. Besides acting as decoy receptor, sRAGE could have pro-inflammatory properties.

The RNA-binding protein bicaudal C regulates polycystin 2 in the kidney by antagonizing miR-17 activity.

The RNA-binding protein Bicaudal C is an important regulator of embryonic development in C. elegans, Drosophila and Xenopus. In mouse, bicaudal C (Bicc1) mutants are characterized by the formation of fluid-filled cysts in the kidney and by expansion of epithelial ducts in liver and pancreas. This phenotype is reminiscent of human forms of polycystic kidney disease (PKD). Here, we now provide data that Bicc1 functions by modulating the expression of polycystin 2 (Pkd2), a member of the transient receptor potential (TRP) superfamily. Molecular analyses demonstrate that Bicc1 acts as a post-transcriptional regulator upstream of Pkd2. It regulates the stability of Pkd2 mRNA and its translation efficiency. Bicc1 antagonized the repressive activity of the miR-17 microRNA family on the 3'UTR of Pkd2 mRNA. This was substantiated in Xenopus, in which the pronephric defects of bicc1 knockdowns were rescued by reducing miR-17 activity. At the cellular level, Bicc1 protein is localized to cytoplasmic foci that are positive for the P-body markers GW182 and HEDLs. Based on these data, we propose that the kidney phenotype in Bicc1(-/-) mutant mice is caused by dysregulation of a microRNA-based translational control mechanism.

Mad is required for wingless signaling in wing development and segment patterning in Drosophila.

A key question in developmental biology is how growth factor signals are integrated to generate pattern. In this study we investigated the integration of the Drosophila BMP and Wingless/GSK3 signaling pathways via phosphorylations of the transcription factor Mad. Wingless was found to regulate the phosphorylation of Mad by GSK3 in vivo. In epistatic experiments, the effects of Wingless on wing disc molecular markers (senseless, distalless and vestigial) were suppressed by depletion of Mad with RNAi. Wingless overexpression phenotypes, such as formation of ectopic wing margins, were induced by Mad GSK3 phosphorylation-resistant mutant protein. Unexpectedly, we found that Mad phosphorylation by GSK3 and MAPK occurred in segmental patterns. Mad depletion or overexpression produced Wingless-like embryonic segmentation phenotypes. In Xenopus embryos, segmental border formation was disrupted by Smad8 depletion. The results show that Mad is required for Wingless signaling and for the integration of gradients of positional information.

Do you think my ICU will benefit from an electronic medical record system?

In many Hospitals, Intensive Care Units (ICUs) are the most technologically advanced areas since the Intensive Care physicians deal with a massive quantity of data and information, because of the critical status of their patients each day. An electronic medical record (EMR) is a computer-base patient record optimized to support ambulatory settings and ward activities. An EMR may provide the physician with all the necessary information clearly gathered and stored and satisfy the need for more direct integration of the different information. Even if the installation of an EMR is a positive signal of modernity, it may represent a useless investment with minor effects on the clinical staff improvement and on the risk reduction, because of mayor failures in the installation planning, integration in the hospital system, personnel education. Definitions, advantages and limitation, implementation strategies and objectives of an ICU EMR system are reviewed.

Conscious analgosedation for radiofrequency ablation of lung neoplasm.

AIM: Radiofrequency ablation (RFA) is a minimally invasive therapy for pulmonary malignant cancers in patients with medical co-morbidities or refusal of surgery. The aim of this study was to evaluate a conscious analgosedation protocol for RFA of lung neoplasm. METHODS: Ten RFAs were performed. Following analgesic premedication patients underwent local anesthesia (lidocaine 2%) and propofol infusion. RESULTS: The procedures were always uneventful. Postoperative severe pain was not reported; a deep sedation was required to allow the quick and safe management of RFA. CONCLUSIONS: Spontaneous breathing sedation is safe in monitored and well-oxygenated patients and may limit the incidence of tension pneumothorax. Postoperative period needs a proper pain control for the first 24 h. Data on the long-term efficacy of lung tumor RFA are not yet available.

[Rhabdomyolysis associated with respiratory infection in chronic psychiatric patients during neuroleptic treatment]. / Rabdomiolisi associata a infezione polmonare in pazienti schizofrenici in trattamento con neurolettici.

Rhabdomyolysis is a disorder characterized by skeletal muscle injury and fatal complications at times. The causes of rhabdomyolysis are usually traumatic and non-traumatic, such as neuroleptic malignant syndrome and rhabdomyolysis associated to septicemia. The cases of 2 schizophrenic patients with rhabdomyolisis during pneumonia infection and neuroleptic therapy are reported. At admission, both patients had important respiratory distress and hyperthermia; the clinical conditions required endotracheal intubation. Blood and urine cultures were always negative, while the bronchial sputum culture was positive. The diagnosis of rhabdomyolysis was confirmed by myoglobinemia dosage and ortholuidine test. Pneumonia infection was treated with antibiotic specific therapy whereas renal failure was treated with adequate hydratation and strained diuresis. The absence of muscle rigidity, the improvement of X-r images and the reduction of corporeal temperature, during antibiotic treatment, excluded neuroleptic malignant syndrome. The impro-vement allowed extubation and discharge of the patients from intensive care unit. In both cases neuroleptic malignant syndrome was excluded, therefore rhabdomyolysis was the consequence of pneumonia infection or of a combination of factors capable to cause an important damage of skeletal muscles.

The pro-BMP activity of Twisted gastrulation is independent of BMP binding.

The determination of the vertebrate dorsoventral body axis is regulated in the extracellular space by a system of interacting secreted molecules consisting of BMP, Chordin, Tolloid and Twisted Gastrulation (Tsg). Tsg is a BMP-binding protein that forms ternary complexes with BMP and Chordin. We investigated the function of Tsg in embryonic patterning by generating point mutations in its two conserved cysteine-rich domains. Surprisingly, Tsg proteins with mutations in the N-terminal domain were unable to bind BMP, yet ventralized the embryo very effectively, indicating strong pro-BMP activity. This hyperventralizing Tsg activity required an intact C-terminal domain and could block the anti-BMP activity of isolated BMP-binding modules of Chordin (CRs) in embryonic assays. This activity was specific for CR-containing proteins as it did not affect the dorsalizing effects of Noggin or dominant-negative BMP receptor. The ventralizing effects of the xTsg mutants were stronger than the effect of Chordin loss-of-function in Xenopus or zebrafish. The results suggest that xTsg interacts with additional CR-containing proteins that regulate dorsoventral development in embryos.

Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta.

Connective-tissue growth factor (CTGF) is a secreted protein implicated in multiple cellular events including angiogenesis, skeletogenesis and wound healing. It is a member of the CCN family of secreted proteins, named after CTGF, cysteine-rich 61 (CYR61), and nephroblastoma overexpressed (NOV) proteins. The molecular mechanism by which CTGF or other CCN proteins regulate cell signalling is not known. CTGF contains a cysteine-rich domain (CR) similar to those found in chordin and other secreted proteins, which in some cases have been reported to function as bone morphogenetic protein (BMP) and TGF-beta binding domains. Here we show that CTGF directly binds BMP4 and TGF-beta 1 through its CR domain. CTGF can antagonize BMP4 activity by preventing its binding to BMP receptors and has the opposite effect, enhancement of receptor binding, on TGF-beta 1. These results show that CTGF inhibits BMP and activates TGF-beta signals by direct binding in the extracellular space.

Luxatio cordis due to right pericardium tear, a difficult diagnosis: report of a case.

BACKGROUND: Dislocation of the heart is a rare complication of thoracic blunt trauma. A high index of suspicion of pericardium rupture is necessary to formulate an early diagnosis to reduce morbidity and mortality. PATIENTS: A 23-year-old man suffered a blunt thoracoabdominal trauma and was admitted 3 days later to a university hospital ICU for right heart luxation due to right pericardial tear. Mechanical ventilation delayed radiological findings. METHODS AND RESULTS: Surgery by repositioning the heart and repairing the pericardial tear allowed restoration of hemodynamic equilibrium.

Chordin-like CR domains and the regulation of evolutionarily conserved extracellular signaling systems.

In fruit flies as well as in humans the Short gastrulation (Sog)/Chordin protein functions as an antagonist of the signaling of decapentaplegic (Dpp)/bone morphogenetic protein (BMP) in the extracellular space. Such antagonism inhibits Dpp/BMP signaling by blocking its binding to the receptor. Modulation of Dpp/BMP signaling is phylogenetically conserved and is a key step for the establishment of the dorso-ventral axis in vertebrates and invertebrates. Molecular studies have shown that the inhibitory activity of Chordin on BMP resides in specific cysteine-rich (CR) domains. Interestingly, Chordin-like CR domains are present in a growing number of extracellular proteins, several of which appear to be involved in BMP signaling regulation. We review here the conservation of the Chordin and Sog proteins, and in particular their functional domain, the CR domain. We discuss how the study of CR domains may provide a general mechanism for the regulation of growth factor signaling in the extracellular space.

Mouse Crossveinless-2 is the vertebrate homolog of a Drosophila extracellular regulator of BMP signaling.

The Dpp/BMP signaling pathway is highly conserved between vertebrates and invertebrates. The recent molecular characterization of the Drosophila crossveinless-2 (cv-2) mutation by Conley and colleagues introduced a novel regulatory step in the Dpp/BMP pathway (Development 127 (2000) 3945). The CV-2 protein is secreted and contains five cysteine-rich (CR) domains similar to those observed in the BMP antagonist Short gastrulation (Sog) of Drosophila and Chordin (Chd) of vertebrates. The mutant phenotype in Drosophila suggests that CV-2 is required for the differentiation of crossvein structures in the wing which require high Dpp levels. Here we present the mouse and human homologs of the Drosophila cv-2 protein. The mouse gene is located on chromosome 9A3 while the human locus maps on chromosome 7p14. CV-2 is expressed dynamically during mouse development, in particular in regions of high BMP signaling such as the posterior primitive streak, ventral tail bud and prevertebral cartilages. We conclude that CV-2 is an evolutionarily conserved extracellular regulator of the Dpp/BMP signaling pathway.

Mouse Crossveinless-2 is the vertebrate homolog of a Drosophila extracellular regulator of BMP signaling.

The Dpp/BMP signaling pathway is highly conserved between vertebrates and invertebrates. The recent molecular characterization of the Drosophila crossveinless-2 (cv-2) mutation by Conley and colleagues introduced a novel regulatory step in the Dpp/BMP pathway (Development 127 (2000) 3945). The CV-2 protein is secreted and contains five cysteine-rich (CR) domains similar to those observed in the BMP antagonist Short gastrulation (Sog) of Drosophila and Chordin (Chd) of vertebrates. The mutant phenotype in Drosophila suggests that CV-2 is required for the differentiation of crossvein structures in the wing which require high Dpp levels. Here we present the mouse and human homologs of the Drosophila cv-2 protein. The mouse gene is located on chromosome 9A3 while the human locus maps on chromosome 7p14. CV-2 is expressed dynamically during mouse development, in particular in regions of high BMP signaling such as the posterior primitive streak, ventral tail bud and prevertebral cartilages. We conclude that CV-2 is an evolutionarily conserved extracellular regulator of the Dpp/BMP signaling pathway.

Neural and head induction by insulin-like growth factor signals.

Evidence is presented for a new pathway participating in anterior neural development. It was found that IGF binding protein 5 (IGFBP-5), as well as three IGFs expressed in early embryos, promoted anterior development by increasing the head region at the expense of the trunk in mRNA-injected Xenopus embryos. A secreted dominant-negative type I IGF receptor (DN-IGFR) had the opposite effect. IGF mRNAs led to the induction of ectopic eyes and ectopic head-like structures containing brain tissue. In ectodermal explants, IGF signals induced anterior neural markers in the absence of mesoderm formation and DN-IGFR inhibited neural induction by the BMP antagonist Chordin. Thus, active IGF signals appear to be both required and sufficient for anterior neural induction in Xenopus.

Aspiration of dead space allows isocapnic low tidal volume ventilation in acute lung injury. Relationships to gas exchange and mechanics.

OBJECTIVE: In acute lung injury (ALI) mechanical ventilation damages lungs. We hypothesised that aspiration and replacement of dead space during expiration (ASPIDS) allows normocapnic ventilation at higher end-expiratory pressure (PEEP) and reduced tidal volume (V(T)), peak and plateau pressures (Paw(peak), Paw(plat)), thus avoiding lung damage. SETTING: University Hospital. PATIENTS: Seven consecutive sedated and paralysed ALI patients were studied. INTERVENTIONS AND MEASUREMENTS: Single breath test for CO(2) and multiple elastic pressure volume (Pel/V) curves recorded from different end-expiratory pressures guided ventilatory setting at ASPIDS. ASPIDS was studied at respiratory rate (RR) of 14 min(-1) and then 20 min(-1) with minute ventilation maintaining stable CO(2) elimination. RESULTS: Alveolar and airway dead spaces were 24.3% and 31.3% of V(T), respectively. Multiple Pel/V curves showed a shift towards lower volume at decreasing PEEP, thus indicating that patients required a higher PEEP. At ASPIDS, PEEP was increased from 8.9 cmH(2)O to 12.6 cmH(2)O and VT reduced from 11 ml/kg to 8.9 ml/kg at RR 14 min(-1) and to 6.9 ml/kg at RR 20 min(-1). A significant decrease in Paw(peak) (36.7 vs 32 at RR 14 min(-1) and 28.7 at RR 20 min(-1)) and Paw(plat) (29.9 vs 27.3 at RR 14 min-1 and 24.1 at RR 20 min-1) were observed. PaCO(2) remained stable. No intrinsic PEEP developed. No side effects were noticed. CONCLUSIONS: ASPIDS allowed the use of higher PEEP at lower V(T) and inflation pressure and constant PaCO(2). Multiple Pel/V curves gave insight into the tendency of lungs to collapse.