Search

Introduction: Although the maxillary nerve block (MNB) provides adequate pain relief in cleft palate surgery, it is not routinely used globally, and reported techniques are heterogeneous. This study aims to describe relevant anatomy and to present the preferred technique of MNB administration based on the current literature and the expert opinion of the authors., Method and Materials: First, a survey was sent to 432 registrants of the International Cleft Palate Master Course Amsterdam 2023. Second, MEDLINE (PubMed interface) was searched for relevant literature on maxillary artery (MA) anatomy and MNB administration in pediatric patients., Results: Survey response rate was 18% (n=78). Thirty-five respondents (44.9%) used MNB for cleft palate surgery before the course. A suprazygomatic approach with needle reorientation towards the ipsilateral commissure before incision was most frequently reported, mostly without the use of ultrasound. Ten and 20 articles were included on, respectively, MA anatomy and MNB administration. A 47.5% to 69.4% of the MA's run superficial to the lateral pterygoid muscle and 32% to 52.5% medially. The most frequently described technique for MNB administration is the suprazygomatic approach. Reorientation of the needle towards the anterior aspect of the contralateral tragus appears optimal. Needle reorientation angles do not have to be adjusted for age, unlike needle depth. The preferred anesthetics are either ropivacaine or (levo)bupivacaine, with dexmedetomidine as an adjuvant., Conclusion: Described MNB techniques are heterogeneous throughout the literature and among survey respondents and not routinely used. Further research is required comparing different techniques regarding efficacy and safety., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Mutaz B. Habal, MD.)

In patients born with anorectal malformations (ARM), additional congenital heart defects (CHD) can occur. We aimed to provide an overview on disease and treatment details of CHD identified in patients born with ARM, from a unique large cohort of a very rare disease. We performed a retrospective single-center cohort study between January 2000 and July 2023. All consecutive patients with ARM were included. Outcomes were the number of patients with CHD, and screening percentage and percentage of patients diagnosed with CHD over 3 time periods (2000-2006, 2007-2014, 2015-2023). We used uni- and multi-variable logistic regression analyses to search for associations between CHD present and baseline characteristics. In total, 281 patients were included. Some 241 (85.8%) underwent echocardiography, of whom 80 (33.2%) had CHD. Screening percentage with echocardiography increased (74.1% vs. 85.7% vs. 95.9%, p < 0.001) and percentage of patients diagnosed with CHD remained similar over time (30.2% vs. 34.5% vs. 34.0%, p = 0.836). Atrial and ventricular septal defects (n = 36, n = 29), and persistent left superior vena cava (n = 17) were most identified. The presence of VACTERL-association or a genetic syndrome was independently associated with the presence of CHD. CHD were present in 33% of patients with ARM that underwent echocardiography. Over time, the number of CHD identified through screening remained similar. Patients with the presence of VACTERL-association or a genetic syndrome had a higher risk of having CHD. Therefore, acknowledging the potential presence of CHD in patients with ARM remains important., (© 2024. The Author(s).)

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes ( CREBBP , EP300 ) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP ; RTS2: EP300 ), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background:  Nuss procedure for pectus excavatum is a minimally invasive, but painful procedure. Recently, intercostal nerve cryoablation has been introduced as a pain management technique., Materials and Methods:  In this cohort study, we compared the efficacy of multimodal pain management strategies in children undergoing a Nuss procedure. The effectiveness of intercostal nerve cryoablation combined with patient-controlled systemic opioid analgesia (PCA) was compared with continuous epidural analgesia (CEA) combined with PCA. The study was conducted between January 2019 and July 2022. Primary outcome was length of stay (LOS), and secondary outcomes were operation room time, postoperative pain, opioid consumption, and gabapentin use., Results:  Sixty-six consecutive patients were included, 33 patients in each group. The cryoablation group exhibited lower Numeric Rating Scale (NRS) pain scores on postoperative day 1 and 2 ( p  = 0.002, p  = 0.001) and a shorter LOS (3 vs. 6 days ( p  < 0.001). Cryoablation resulted in less patients requiring opioids at discharge (30.3 vs. 97.0%; p  < 0.001) and 1 week after surgery (6.1 vs. 45.4%; p  < 0.001)). In the CEA group, gabapentin use was more prevalent (78.8 vs. 18.2%; p  < 0.001) and the operation room time was shorter (119.4 vs. 135.0 minutes; p  < .010). No neuropathic pain was reported., Conclusions:  Intercostal nerve cryoablation is a superior analgesic method compared with CEA, with reduced LOS, opioid use, and NRS pain scores. The prophylactic use of gabapentin is redundant., Competing Interests: S.A.B. works as a proctor for cryotherapy in pectus patients contracted by the company Atricure., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Functional constipation in the pediatric population is a prevalent issue that is usually well managed. However, in rare cases, conservative treatment fails, and surgical intervention is necessary. This retrospective cohort study aimed to describe and compare different perioperative analgesic techniques in children undergoing major abdominal surgery for intractable constipation. Conducted between 2011 and 2021, this study enrolled patients under 18 years old who underwent initial major abdominal surgery for intractable constipation (i.e., creation of ostomy or subtotal colectomy). Patients were categorized according to the perioperative analgesic technique (i.e., systemic, neuraxial, or truncal block). Of 65 patients, 46 (70.8%) were female, and the median age was 13.5 [8.8-16.1] years during initial major abdominal surgery. Systemic analgesia was used in 43 (66.2%), neuraxial in 17 (26.2%), and truncal blocks in 5 (7.7%) of the surgeries. Patients with neuraxial analgesia reported less postoperative pain (median [interquartile range] numeric rating scale (NRS) 2.0 [0-4.0]), compared to systemic analgesia (5.0 [2.0-7.0], p < 0.001) and to truncal blocks (5.0 [3.0-6.5], p < 0.001). In this preliminary investigation, neuraxial analgesia appears to be the most effective approach to reducing acute postoperative pain in pediatric patients undergoing major abdominal surgery for intractable functional constipation. However, well-designed studies are warranted.

Background:  Normalization of metabolic alkalosis is an important pillar in the treatment of infantile hypertrophic pyloric stenosis (IHPS) because uncorrected metabolic alkalosis may lead to perioperative respiratory events. However, the evidence on the incidence of respiratory events is limited. We aimed to study the incidence of peroperative hypoxemia and postoperative respiratory events in infants undergoing pyloromyotomy and the potential role of metabolic alkalosis., Materials and Methods:  We retrospectively reviewed all patients undergoing pyloromyotomy between 2007 and 2017. All infants received intravenous fluids preoperatively to correct metabolic abnormalities close to normal. We assessed the incidence of perioperative hypoxemia (defined as oxygen saturation [SpO 2 ] < 90% for > 1min) and postoperative respiratory events. Additionally, the incidence of difficult intubations was evaluated. We performed a multivariate logistic regression analysis to evaluate the association between admission or preoperative serum pH values, bicarbonate or chloride, and peri- and postoperative hypoxemia or respiratory events., Results:  Of 406 included infants, 208 (51%) developed 1 or more episodes of hypoxemia during the perioperative period, of whom 130 (32%) experienced it during induction, 43 (11%) intraoperatively, and 112 (28%) during emergence. About 7.5% of the infants had a difficult intubation and 17 required more than 3 attempts by a pediatric anesthesiologist. Three patients developed respiratory insufficiency and 95 postoperative respiratory events were noticed. We did not find a clinically meaningful association between laboratory values reflecting metabolic alkalosis and respiratory events., Conclusions:  IHPS frequently leads to peri- and postoperative hypoxemia or respiratory events and high incidence of difficult tracheal intubations. Preoperative pH, bicarbonate, and chloride were bad predictors of respiratory events., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Respiratory motion presents a challenge in radiotherapy of thoracic and upper abdominal tumors. Techniques to account for respiratory motion include tracking. Using magnetic resonance imaging (MRI) guided radiotherapy systems, tumors can be tracked continuously. Using conventional linear accelerators, tracking of lung tumors is possible by determining tumor motion on kilo voltage (kV) imaging. But tracking of abdominal tumors with kV imaging is hampered by limited contrast. Therefore, surrogates for the tumor are used. One of the possible surrogates is the diaphragm. However, there is no universal method for establishing the error when using a surrogate and there are particular challenges in establishing such errors during free breathing (FB). Prolonged breath-holding might address these challenges., Purpose: The aim of this study was to quantify the error when using the right hemidiaphragm top (RHT) as surrogate for abdominal organ motion during prolonged breath-holds (PBH) for possible application in radiation treatments., Methods: Fifteen healthy volunteers were trained to perform PBHs in two subsequent MRI sessions (PBH-MRI1 and PBH-MRI2). From each MRI acquisition, we selected seven images (dynamics) to determine organ displacement during PBH by using deformable image registration (DIR). On the first dynamic, the RHT, right and left hemidiaphragm, liver, spleen and right and left kidney were segmented. We used the deformation vector fields (DVF), generated by DIR, to determine the displacement of each organ between two dynamics in inferior-superior (IS), anterior-posterior (AP), left-right (LR) direction and we calculated the 3D vector magnitude (|d|). The displacements of the RHT, both hemidiaphragms and the abdominal organs were compared using a linear fit to determine the correlation (R 2 of the fit) and the displacement ratio (DR, slope of the fit) between displacements of the RHT and each organ. We quantified the median difference between the DRs of PBH-MRI1 and PBH-MRI2 for each organ. Additionally, we estimated organ displacement in the second PBH by applying the DR from the first PBH to the displacement of the RHT measured during the second PBH. We compared the estimated organ displacement to the measured organ displacement during the second PBH. The difference between the two values was defined as the estimation error of using the RHT as a surrogate and assuming a constant DR over MRI sessions., Results: The linear relationships were confirmed by the high R 2 values of the linear fit between the displacements of the RHT and the abdominal organs (R 2 > 0.96) in the IS and AP direction and |d|, and high to moderate correlations in the LR direction (0.93 > R 2 > 0.64). The median DR difference between PBH-MRI1 and PBH-MRI2 varied between 0.13 and 0.31 for all organs. The median estimation error of the RHT as a surrogate varied between 0.4 and 0.8 mm/min for all organs., Conclusion: The RHT could serve as an accurate surrogate for abdominal organ motion during radiation treatments, for example, in tracking, provided the error of the RHT as motion surrogate is taken into account in the margins., Trial Registration: The study was registered in the Netherlands Trial Register (NL7603)., (© 2023 Amsterdam UMC - location AMC. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: The advantages of PCEA over CEA have been demonstrated in obstetric patients. Whether a similar benefit applies to surgical patients is unclear., Methods: Embase, PubMed, and Cochrane Library were searched, enabling a systematic review of studies comparing PCEA and CEA in adult surgical patients (PROSPERO: CRD42018106644). The study quality was assessed using the Cochrane risk-of-bias tool (RoB2). The primary outcome was pain scores on postoperative day one (POD1). Secondary outcomes were 24 or 48 h epidural or intravenous total analgesic dose, systemic analgesics, manual top-ups, side effects, and patient satisfaction., Results: Six randomized controlled trials with high heterogeneity of study characteristics were identified with a moderate risk of bias. Two studies showed significantly reduced resting pain scores on POD1 in PCEA compared with CEA patients (36-44%, p < 0.05). Four studies found comparable pain scores between these groups. PCEA use reduced epidural medication (28% to 40% reduction, p < 0.01) in four studies. One study found a 23% reduction ( p < 0.001) of top-ups in PCEA; intravenous morphine use by PCEA patients was reduced (0.16 vs. 3.45 mg per patient, p < 0.05) in one study. PCEA patients were more satisfied with analgesia ( p < 0.001) in two studies. Nausea and vomiting were reduced in PCEA ( p = 0.01)., Conclusions: Regarding the reduction in pain scores, the effects of PCEA were not significant or clinically not relevant. However, regarding the amount of epidural drug use, the amount of required rescue systemic analgesics, patient satisfaction, and the number of required top-ups, PCEA had advantages over CEA in surgical patients.

Neuraxial drug administration, i.e., the injection of drugs into the epidural or intrathecal space to produce anesthesia or analgesia, is a technique developed more than 120 years ago. Today, it still is widely used in daily practice in anesthesiology and in acute and chronic pain therapy. A multitude of different drugs have been introduced for neuraxial injection, only a part of which have obtained official approval for that indication. A broad understanding of the pharmacology of those agents is essential to the clinician to utilize them in a safe and efficient manner. In the present narrative review, we summarize current knowledge on neuraxial anatomy relevant to clinical practice, including pediatric anatomy. Then, we delineate the general pharmacology of neuraxial drug administration, with particular attention to specific aspects of epidural and intrathecal pharmacokinetics and pharmacodynamics. Furthermore, we describe the most common clinical indications for neuraxial drug administration, including the perioperative setting, obstetrics, and chronic pain. Then, we discuss possible neurotoxic effects of neuraxial drugs, and moreover, we detail the specific properties of the most commonly used neuraxial drugs that are relevant to clinicians who employ epidural or intrathecal drug administration, in order to ensure adequate treatment and patient safety in these techniques. Finally, we give a brief overview on new developments in neuraxial drug therapy., (© 2022. The Author(s).)

Neonatal surgery and concomitant anesthesia coincide with a timeframe of rapid brain development. The speed and complexity of early brain development superimposed on immature regulatory mechanisms that include incomplete cerebral autoregulation, insufficient free radical scavenging and an immature immune response puts the brain at risk. Brain injury may have long-term consequences for multiple functional domains including cognition, learning skills, and behavior. Neurodevelopmental follow-up studies have noted mild-to-moderate deficits in children who underwent major neonatal surgery and related anesthesia. The present review evaluates neonatal surgery against the background of neurobiological processes that unfold at a pace unparalleled by any other period of human brain development. First, a structured summary of early brain development is provided in order to establish theoretical groundwork. Next, literature on brain injury and neurodevelopmental outcome after neonatal surgery is discussed. Special attention is given to recent findings of structural brain damage reported after neonatal surgery. Notably, high-quality imaging data acquired before surgery are currently lacking. Third, mechanisms of injury are interrogated taking the perspective of early brain development into account. We propose a novel disease model that constitutes a triad of inflammation, vascular immaturity, and neurotoxicity of prolonged exposure to anesthetic drugs. With each of these components exacerbating the other, this amalgam incites the perfect storm, resulting in brain injury. When examining the brain, it seems intuitive to distinguish between neonates (i.e., <60 postconceptional weeks) and more mature infants, multiple and/or prolonged anesthesia exposure and single, short surgery. This review culminates in an outline of anesthetic considerations and future directions that we believe will help move the field forward., (© 2022 The Authors. Pediatric Anesthesia published by John Wiley & Sons Ltd.)

Background: Due to respiratory motion, accurate radiotherapy delivery to thoracic and abdominal tumors is challenging. We aimed to quantify the ability of mechanical ventilation to reduce respiratory motion, by measuring diaphragm motion magnitudes in the same volunteers during free breathing (FB), mechanically regularized breathing (RB) at 22 breaths per minute (brpm), variation in mean diaphragm position across multiple deep inspiration breath-holds (DIBH) and diaphragm drift during single prolonged breath-holds (PBH) in two MRI sessions., Methods: In two sessions, MRIs were acquired from fifteen healthy volunteers who were trained to be mechanically ventilated non-invasively We measured diaphragm motion amplitudes during FB and RB, the inter-quartile range (IQR) of the variation in average diaphragm position from one measurement over five consecutive DIBHs, and diaphragm cranial drift velocities during single PBHs from inhalation (PIBH) and exhalation (PEBH) breath-holds., Results: RB significantly reduced the respiratory motion amplitude by 39%, from median (range) 20.9 (10.6-41.9) mm during FB to 12.8 (6.2-23.8) mm. The median IQR for variation in average diaphragm position over multiple DIBHs was 4.2 (1.0-23.6) mm. During single PIBHs with a median duration of 7.1 (2.0-11.1) minutes, the median diaphragm cranial drift velocity was 3.0 (0.4-6.5) mm/minute. For PEBH, the median duration was 5.8 (1.8-10.2) minutes with 4.4 (1.8-15.1) mm/minute diaphragm drift velocity., Conclusions: Regularized breathing at a frequency of 22 brpm resulted in significantly smaller diaphragm motion amplitudes compared to free breathing. This would enable smaller treatment volumes in radiotherapy. Furthermore, prolonged breath-holding from inhalation and exhalation with median durations of six to seven minutes are feasible., Trial Registration: Medical Ethics Committee protocol NL.64693.018.18., (© 2022. The Author(s).)

Background and Objectives: Documentation is important for quality improvement, education, and research. There is currently a lack of recommendations regarding key aspects of documentation in regional anesthesia. The aim of this study was to establish recommendations for documentation in regional anesthesia., Methods: Following the formation of the executive committee and a directed literature review, a long list of potential documentation components was created. A modified Delphi process was then employed to achieve consensus amongst a group of international experts in regional anesthesia. This consisted of 2 rounds of anonymous electronic voting and a final virtual round table discussion with live polling on items not yet excluded or accepted from previous rounds. Progression or exclusion of potential components through the rounds was based on the achievement of strong consensus. Strong consensus was defined as ≥75% agreement and weak consensus as 50%-74% agreement., Results: Seventy-seven collaborators participated in both rounds 1 and 2, while 50 collaborators took part in round 3. In total, experts voted on 83 items and achieved a strong consensus on 51 items, weak consensus on 3 and rejected 29., Conclusion: By means of a modified Delphi process, we have established expert consensus on documentation in regional anesthesia., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2022. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ.)

Background: The incidence of metachronous contralateral inguinal hernia (MCIH) is high in infants with an inguinal hernia (5-30%), with the highest risk in infants aged 6 months or younger. MCIH is associated with the risk of incarceration and necessitates a second operation. This might be avoided by contralateral exploration during primary surgery. However, contralateral exploration may be unnecessary, leads to additional operating time and costs and may result in additional complications of surgery and anaesthesia. Thus, there is no consensus whether contralateral exploration should be performed routinely., Methods: The Hernia-Exploration-oR-Not-In-Infants-Analysis (HERNIIA) study is a multicentre randomised controlled trial with an economic evaluation alongside to study the (cost-)effectiveness of contralateral exploration during unilateral hernia repair. Infants aged 6 months or younger who need to undergo primary unilateral hernia repair will be randomised to contralateral exploration or no contralateral exploration (n = 378 patients). Primary endpoint is the proportion of infants that need to undergo a second operation related to inguinal hernia within 1 year after primary repair. Secondary endpoints include (a) total duration of operation(s) (including anaesthesia time) and hospital admission(s); (b) complications of anaesthesia and surgery; and (c) participants' health-related quality of life and distress and anxiety of their families, all assessed within 1 year after primary hernia repair. Statistical testing will be performed two-sided with α = .05 and according to the intention-to-treat principle. Logistic regression analysis will be performed adjusted for centre and possible confounders. The economic evaluation will be performed from a societal perspective and all relevant costs will be measured, valued and analysed., Discussion: This study evaluates the effectiveness and cost-effectiveness of contralateral surgical exploration during unilateral inguinal hernia repair in children younger than 6 months with a unilateral inguinal hernia., Trial Registration: ClinicalTrials.gov NCT03623893 . Registered on August 9, 2018 Netherlands Trial Register NL7194. Registered on July 24, 2018 Central Committee on Research Involving Human Subjects (CCMO) NL59817.029.18. Registered on July 3, 2018., (© 2021. The Author(s).)

Objective: Uncorrected metabolic alkalosis in infantile hypertrophic pyloric stenosis (IHPS) could lead to perioperative apnea. However, the precise incidence of preoperative respiratory problems and the association with metabolic alkalosis are unknown. Therefore, we aimed to determine the incidence of preoperative respiratory problems in IHPS and to assess the association with metabolic alkalosis., Methods: We retrospectively reviewed all patients diagnosed with IHPS during 2007-2017. Respiratory problems were classified as present or absent. With multivariate logistic regression we analyzed the association between bicarbonate and respiratory problems, corrected for gestational age and birth weight., Results: We included 459 infants, of whom 23 developed preoperative respiratory problems (5.0%). Infants with preoperative respiratory problems were more often female (43.5% vs. 13.3% p = 0.001) and had significantly higher median serum levels of bicarbonate (32.0 mmol/L vs. 30.0 mmol/L), base excess (6.5 mmol/L vs. 5.3 mmol/L) and pCO2 (6.4 kPa vs. 5.9 kPa), compared to infants without respiratory problems. Multivariate analysis of serum bicarbonate and presence of respiratory problems showed an OR of 2.18 per 10 mmol/L (95% CI 1.21-4.71) (p = 0.009). The optimal bicarbonate cutoff point was 25.7 mmol/L (sensitivity 100%, specificity 13.4%)., Conclusion: IHPS with metabolic alkalosis potentially results in preoperative respiratory problems. A lower bicarbonate target before surgery might be recommended and respiratory monitoring should be considered., Level of Evidence: Level IV., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The COVID-19 pandemic poses great challenges for healthcare workers around the world, including perioperative specialists. Previously, we provided a first overview of available literature on SARS-CoV-2 and COVID-19, relevant for anaesthetists and intensivists. In the current review, we provide an update of this topic, after a literature search current through May 2020. We discuss the evidence on perioperative risk for COVID-19 patients presenting for surgery, the risk of transmission of SARS-CoV-2 in the operating room, and the current literature on laboratory diagnostics. Furthermore, cardiovascular and nervous system involvement in COVID-19 are discussed, as well as considerations in diabetic patients. Lastly, the latest evidence on pharmacological treatment is summarised.

Introduction: Pectus excavatum repair is associated with substantial postoperative pain, despite the use of epidural analgesia and other analgesic regimens. Perioperative recorded music interventions have been shown to alleviate pain and anxiety in adults, but evidence for children and adolescents is still lacking. This study protocol describes a randomised controlled trial that evaluates the effects of recorded music interventions on postoperative pain relief in children and adolescents after pectus excavatum repair., Methods: A multicentre randomised controlled trial was set up comparing the effects of perioperative recorded music interventions in addition to standard care with those of standard care only in patients undergoing a Nuss procedure for pectus excavatum repair. One hundred and seventy subjects (12-18 years of age) will be included in three centres in the Netherlands. Patient inclusion has started in November 2018, and is ongoing. The primary outcome is self-reported perceived pain measured on the visual analogue scale. Secondary outcomes are anxiety level, analgesics consumption, vital parameters such as heart rate, blood pressure and respiratory rate, length of hospital stay, postoperative complications, quality of life and cost-effectiveness., Ethics and Dissemination: This study is being conducted in accordance with the Declaration of Helsinki. The Medical Ethics Review Board of Erasmus University Medical Centre Rotterdam, The Netherlands, has approved this protocol. Results will be disseminated via peer-reviewed scientific journals and conference presentations., Trial Registration Number: NL6863., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Infantile hypertrophic pyloric stenosis (IHPS) leads to excessive vomiting and metabolic alkalosis, which may subsequently cause apnea. Although it is generally assumed that metabolic derangements should be corrected prior to surgery to prevent apnea, the exact incidence of perioperative apneas in infants with IHPS and the association with metabolic alkalosis are unknown. We performed this systematic review to assess the incidence of apnea in infants with IHPS and to verify the possible association between apnea and metabolic alkalosis., Methods: We searched MEDLINE, Embase, and Cochrane library to identify studies regarding infants with metabolic alkalosis, respiratory problems, and hypertrophic pyloric stenosis. We conducted a descriptive synthesis of the findings of the included studies., Results: Thirteen studies were included for analysis. Six studies described preoperative apnea, three studies described postoperative apnea, and four studies described both. All studies were of low quality or had other research questions. We found an incidence of 27% of preoperative and 0.2%-16% of postoperative apnea, respectively. None of the studies examined the association between apnea and metabolic alkalosis in infants with IHPS., Conclusions: Infants with IHPS may have a risk to develop perioperative apnea. However, the incidence rates should be interpreted with caution because of the low quality and quantity of the studies. Therefore, further studies are required to determine the incidence of perioperative apnea in infants with IHPS. The precise underlying mechanism of apnea in these infants is still unknown, and the role of metabolic alkalosis should be further evaluated., (© 2020 The Authors. Pediatric Anesthesia published by John Wiley & Sons Ltd.)

When preparing for the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the coronavirus infection disease (COVID-19) questions arose regarding various aspects concerning the anaesthetist. When reviewing the literature it became obvious that keeping up-to-date with all relevant publications is almost impossible. We searched for and summarised clinically relevant topics that could help making clinical decisions. This is a subjective analysis of literature concerning specific topics raised in our daily practice (e.g., clinical features of COVID-19 patients; ventilation of the critically ill COVID-19 patient; diagnostic of infection with SARS-CoV-2; stability of the virus; Covid-19 in specific patient populations, e.g., paediatrics, immunosuppressed patients, patients with hypertension, diabetes mellitus, kidney or liver disease; co-medication with non-steroidal anti-inflammatory drugs (NSAIDs); antiviral treatment) and we believe that these answers help colleagues in clinical decision-making. With ongoing treatment of severely ill COVID-19 patients other questions will come up. While respective guidelines on these topics will serve clinicians in clinical practice, regularly updating all guidelines concerning COVID-19 will be a necessary, although challenging task in the upcoming weeks and months. All recommendations during the current extremely rapid development of knowledge must be evaluated on a daily basis, as suggestions made today may be out-dated with the new evidence available tomorrow.

Background: Epidural catheters are frequently colonized by gram-positive bacteria. Although the incidence of associated epidural infections is low, their consequences can be devastating. We investigated bacterial growth on epidural catheters by quantitative bacterial culture and scanning electron microscopy (SEM) in order to explore the patterns of epidural catheter colonization., Methods: 28 patients undergoing major abdominal surgery with thoracic epidurals (treatment ≥72 hours) were studied. Before the removal of the catheter, the skin surrounding the insertion site was swabbed. The entire catheter was divided into extracorporeal, subcutaneous, and tip segments. Skin swabs and catheter segments were quantitatively cultured, bacterial species were identified, and SEM was performed on four selected catheters., Results: 27 of 28 catheters were included. The percentages of positive cultures were: skin swab 29.6%, extracorporeal segments 11.1%, subcutaneous segments 14.8%, and tip segments 33.3%. One patient was diagnosed with a catheter-associated infection. Staphylococcus epidermidis was cultured from the skin and the catheter extracorporeal, subcutaneous, and tip segments. SEM of this catheter showed bacteria-like and intraluminal host cell-like structures. SEM of two other catheters showed intraluminal fibrin networks in their tip segments., Conclusions: We present the first SEM pictures of an epidural catheter with a bacterial infection. Bacterial growth developed from the skin to the tip of this catheter, indicating the skin as a primary source of infection. By SEM, catheters with low levels of bacterial growth demonstrated an intraluminal fibrous network which possibly plays a role in catheter obstruction., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2020. Re-use permitted under CC BY. Published by BMJ.)

Introduction: In the Emergency Department, regional anesthesia is increasingly used in elderly patients with hip fractures. An example is a Fascia Iliaca Compartment Block (FICB). Traditionally, this block is administered below the inguinal ligament. There is no Emergency Department data regarding effectivity of an alternative, more cranial approach above the inguinal ligament. The objective was to determine analgesic effects of an ultrasound-guided supra-inguinal FICB in hip fracture patients in the Emergency Department., Methods: This case series included all Emergency Department hip fracture patients who were treated with a supra-inguinal FICB during a period of 10 months. All data were recorded prospectively. Primary study outcome was decrease in Numerical Rating Scale (NRS) pain scores 60 min after the FICB. Secondary outcomes included the proportion of patients achieving 1.5 NRS points decrease at 60 min; NRS differences at 30 and 120 min compared to baseline; need for additional analgesia and occurrence of adverse events., Results: A total of 22 patients were included in the study. At 60 min median NRS pain scores decreased from 6.0 to 3.0 (p < 0.001). Of all patients, a total of 59% achieved a decrease in 1.5 NRS points after 60 min. Median pain scores at 30 and 120 min were 4.0 (Interquartile Range (IQR) 2.0-5.0) and 2.5 (IQR 0.8-3.0). Seven patients (31.8%) required additional opioid analgesia after the FICB. No adverse events were recorded., Conclusion: An ultrasound-guided supra-inguinal FICB decreases NRS pain scores in hip fracture patients both clinically relevant and statistically significantly after 60 min., Clinical Trial Registration: The study was registered in the ISRCTN database (ISRCTN74920258)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Systemic administration of the local anaesthetic lidocaine is antinociceptive in both acute and chronic pain states, especially in acute postoperative and chronic neuropathic pain. These effects cannot be explained by its voltage-gated sodium channel blocking properties alone, but the responsible mechanisms are still elusive. This narrative review focuses on available experimental evidence of the molecular mechanisms by which systemic lidocaine exerts its clinically documented analgesic effects. These include effects on the peripheral nervous system and CNS, where lidocaine acts via silencing ectopic discharges, suppression of inflammatory processes, and modulation of inhibitory and excitatory neurotransmission. We highlight promising objectives for future research to further unravel these antinociceptive mechanisms, which subsequently may facilitate the development of new analgesic strategies and therapies for acute and chronic pain., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background and Objectives: Learning epidural anesthesia traditionally involves bedside teaching. Visualization aids or a simulator can help in acquiring motor skills, increasing patient safety and steepening the learning curve. We evaluated the face and construct validity of the TU-Delft Epidural Simulator and the effect of needle visualization., Methods: Sixty-eight anesthesiologists, anesthesia residents, and final-year medical students tested the epidural simulator. Participants performed six epidural simulations with and six without needle visualization. We tested face validity on a Likert scale questionnaire. We collected data with the simulator software (spinal taps, dura contacts, bone contacts, attempts, and time) and tested for correlation with the performer's experience (construct validity). A visualization aid was tested in a randomized crossover design., Results: Face validity as rated by the participants was above average, with a mean of 3.7 (2.0-4.8) on a 5-point scale. Construct validity was indicated by significantly more spinal taps (0.4 [0-4) vs 0.07 [0-2], p=0.04) and more dura contacts (0.58 [0-6] vs 0.37 [0-3], p=0.002) by the inexperienced group compared with the expert group. The visualization aid improved performance by reducing the number of bone contacts and the number of attempts, and by decreasing the procedure time. Prior visualization training reduced the total procedure time from 279 s (69-574) to 180 s (53-605) (p = 0.01) for the "blind" procedure., Conclusions: The TU-Delft Epidural Simulator is a useful tool for teaching motor skills during epidural needle placement. Prior use of a visualization tool improves performance even without visual support during consequent simulations., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2019. Re-use permitted under CC BY. Published by BMJ.)

Body temperature homeostasis is accurately regulated by complex feedback-driven neuronal mechanisms, which involve a multitude of thermoregulatory pathways. Thus, core temperature is constantly maintained within a narrow range. As one of the most effective regulatory systems skin temperature is dependent on skin blood flow. Skin blood flow in turn is highly dependent on sympathetic activity. Regional anaesthesia leads to blockade not only of somatosensory and motor nerve fibres but also of sympathetic fibres. As a consequence, vasoconstrictor tonic activity is abrogated and a vasodilation leads to an increase in skin blood flow and temperature. The aim of this review was to summarize the general physiology of thermoregulation and skin temperature as well as the alterations during regional anaesthesia. The main focus was the usefulness of measuring skin temperature as an indicator of regional anaesthesia success. According to the available literature, assessment of skin temperature can indeed serve to predict success of regional anaesthesia. Hence, it is important to realize that relevant and reliable temperature increase is only seen in the most distal body parts, ie fingers and toes. More proximally, temperature changes are frequently small and inconsistent, which means that assessment of block levels is not possible by temperature measurement. Furthermore, relevant skin temperature increases will only be observed in patients, which are initially vasoconstricted. In conclusion, measurement of skin temperature represents a reliable and feasible diagnostic tool to assess and predict the success or failure of regional anaesthesia procedures, especially in patients in which sensory testing is impossible., (© 2018 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: Although an emergency surgical airway is recommended in the guidelines for a paediatric cannot intubate, cannot oxygenate (CICO), there is currently no evidence regarding the best technique for this procedure., Objective: To review the available literature on the paediatric emergency surgical airway to give recommendations for establishing a best practice for this procedure., Design: Systematic review: Considering the nature of the original studies, a meta-analysis was not possible., Data Sources: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Google Scholar and LILACS databases., Eligibility Criteria: Studies addressing the paediatric emergency surgical airway and reporting the following outcomes: time to tracheal access, success rate, complications and perceived ease of use of the technique were included. Data were reported using a Strengths, Weaknesses, Opportunities and Threats analysis. Strengths and Weaknesses describe the intrinsic (dis)advantages of the techniques. The opportunities and threats describe the (dis)advantage of the techniques in the setting of a paediatric CICO scenario., Results: Five studies described four techniques: catheter over needle, wire-guided, cannula or scalpel technique. Mean time for placement of a definitive airway was 44 s for catheter over needle, 67.3 s for the cannula and 108.7 s for the scalpel technique. No time was reported for the wire-guided technique. Success rates were 43 (10/23), 100 (16/16), 56 (87/154) and 88% (51/58), respectively. Complication rates were 34 (3/10), 69 (11/16), 36 (55/151) and 38% (18/48), respectively. Analysis shows: catheter over needle, quick but with a high failure rate; wire-guided, high success rate but high complication rate; cannula, less complications but high failure rate; scalpel, high success rate but longer procedural time. The available data are limited and heterogeneous in terms of reported studies; thus, these results need to be interpreted with caution., Conclusion: The absence of best practice evidence necessitates further studies to provide a clear advice on best practice management for the paediatric emergency surgical airway in the CICO scenario.

Postoperative epidural analgesia often needs rate readjustment using top-ups. Patient-controlled epidural analgesia (PCEA) is said to reduce the requirement of epidural top-ups when compared to continuous epidural analgesia (CEA). We compared CEA and PCEA in major thoracic and abdominal surgery, in a cohort study. The primary endpoint was the required number of epidural top-ups. Secondary endpoints were pain scores, side effects and workload differences. We analysed 199 patients with CEA and 187 with PCEA. Both groups had similar pain scores. The total number of top-ups was 75 in 57 patients (CEA) versus 20 top-ups in 18 patients (PCEA). (p = 0.0001) Sedation tended to occur more frequently in patients with CEA versus PCEA, 5.5% vs 1.6% (p = 0.05). Implementation of PCEA led to a decreased number of top-ups, fewer side-effects and decreased use of the postoperative care unit.

Dexamethasone is commonly applied during arthroplasty to control post-operative nausea and vomiting (PONV). However, conflicting views of orthopaedic surgeons and anaesthesiologists regarding the use of dexamethasone raise questions about risks of impaired wound healing and surgical site infections (SSI).The aim of this systematic review is to determine the level of evidence for the safety of a peri-operative single low dose of dexamethasone in hip and knee arthroplasty.We systematically reviewed literature in PubMed, EMBASE and Cochrane databases and cited references in articles found in the initial search from 1980 to 2013 based on predefined inclusion criteria. The review was completed with a 'pro' and 'con' discussion.After identifying 11 studies out of 104, only eight studies met the inclusion criteria. In total, 1335 patients were studied without any incidence of SSI. Causes of SSI are multifactorial. Therefore, 27 205 patients would be required (power = 90%, alpha = 0.05) to provide substantiated conclusions on safety of a single low dose of dexamethasone.Positively, many studies demonstrated showed convincing effects of low-dose dexamethasone on prevention of PONV and dose-dependent effects on post-operative pain and quality of recovery. Dexamethasone induces hyperglycaemia, but none of the studies demonstrated a concomitant SSI.Conversely, animal studies showed that high dose dexamethasone inhibits wound healing.A team approach of anaesthesiologists and orthopaedic surgeons is mandatory in order to balance the risk-benefit ratio of peri-operatively applied steroids for individual arthroplasty patients.We did not find evidence that a single low dose of dexamethasone contributes to SSI or wound healing impairment from the current studies. Cite this article: Wegener JT, Kraal T, Stevens MF, Hollman MW, Kerkhoffs GMMJ, Haverkamp D. Low-dose dexamethasone during arthroplasty: what do we know about the risks? EFORT Open Rev 2016;1:303-309. DOI: 10.1302/2058-5241.1.000039., Competing Interests: Conflict of Interest: None declared.

A patient suffered massive subcutaneous emphysema and bilateral tension pneumothoraces after receiving supplemental oxygen through an airway exchange catheter (AEC). Complications of AEC placement include misplacement, direct injury to the larynx, bronchi or lung, barotrauma related to oxygen supplementation, and a loss of airway. We review these complications and discuss the specific risks of supplementing oxygen using an AEC. We suggest measures to limit pressure from the oxygen source and warn against advancing an AEC too far into the tracheobronchial tree.

Purpose of Review: Ultrasound-guided regional anesthesia is a challenging, complex skill and requires competence in teaching. The aim of this study was to review current literature on identification of education and learning of ultrasound-guided regional anesthesia and to summarize recent findings on teaching concepts., Recent Findings: Several teaching programs have been described and implemented into daily routine. Factors relevant to current practice are the knowledge of sonoanatomy, the acquisition of manual skills, the teaching ability, and the feedback given to the trainee. Simulation is a rapidly growing field and is supported by the development of phantoms. Needle visualization is one of the core competencies that is necessary for successful ultrasound-guided procedures and could be supported by technical developments in the future to improve teaching concepts., Summary: Although a lot of key questions cannot be answered by the latest study results, some interesting findings were able to improve existing education programs. These results should be tailored to the individual need of a trainee, and the effects of improved training programs on patient safety and quality of care have to be investigated. The see one, do one, teach one approach is obsolete and should be abandoned.

Unlabelled: The reamer-irrigator-aspirator (RIA) is a device that has recently been developed to retrieve bone graft from the medullary canal of the femur and the tibia. As for most new surgical procedures, complications arise as part of the learning curve and/or imperfections in the design or technique. To increase awareness of potential complications and to prevent unnecessary harm to the patient, new complications need to be reported. We present case reports of 2 patients who developed severe intraoperative cardiac events presumably caused by excessive and rapid blood loss during RIA bone graft harvesting. This complication has not been described before. Increased awareness of excessive blood loss and subsequent cardiac events during an RIA procedure is warranted., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The imidazole ring is widespread in biologically active compounds, and hence imidazole-containing scaffolds are useful starting points for drug discovery programmes. We report the synthesis of a series of novel imidazole-containing compounds fused with either phenanthrene or phenanthroline, which show enhanced growth inhibitory potency against human colon, breast and melanoma cancer cell lines, as well as evidence of inhibition of the molecular chaperone heat shock protein 70 (Hsp70) pathway in cells, as shown by depletion of downstream oncogenic client proteins of the Hsp90 chaperone pathway, and induction of apoptosis.

The purpose of this study was to assess whether there was an agreement between quantitative cerebral blood flow (CBF) and arterial cerebral blood volume (CBVA) measurements by [(15)O]H2O positron emission tomography (PET) and model-free QUASAR MRI. Twelve healthy subjects were scanned within a week in separate MRI and PET imaging sessions, after which quantitative and qualitative agreement between both modalities was assessed for gray matter, white matter and whole brain region of interests (ROI). The correlation between CBF measurements obtained with both modalities was moderate to high (r(2): 0.28-0.60, P < 0.05), although QUASAR significantly underestimated CBF by 30% (P < 0.001). CBVA was moderately correlated (r(2): 0.28-0.43, P < 0.05), with QUASAR yielding values that were only 27% of the [(15)O]H2O-derived values (P < 0.001). Group-wise voxel statistics identified minor areas with significant contrast differences between [(15)O]H2O PET and QUASAR MRI, indicating similar qualitative CBVA and CBF information by both modalities. In conclusion, the results of this study demonstrate that QUASAR MRI and [(15)O]H2O PET provide similar CBF and CBVA information, but with systematic quantitative discrepancies., (Copyright © 2016 John Wiley & Sons, Ltd.)

This review summarizes current knowledge concerning incidence, risk factors, and mechanisms of perioperative nerve injury, with focus on local anesthetic-induced neurotoxicity. Perioperative nerve injury is a complex phenomenon and can be caused by a number of clinical factors. Anesthetic risk factors for perioperative nerve injury include regional block technique, patient risk factors, and local anesthetic-induced neurotoxicity. Surgery can lead to nerve damage by use of tourniquets or by direct mechanical stress on nerves, such as traction, transection, compression, contusion, ischemia, and stretching. Current literature suggests that the majority of perioperative nerve injuries are unrelated to regional anesthesia. Besides the blockade of sodium channels which is responsible for the anesthetic effect, systemic local anesthetics can have a positive influence on the inflammatory response and the hemostatic system in the perioperative period. However, next to these beneficial effects, local anesthetics exhibit time and dose-dependent toxicity to a variety of tissues, including nerves. There is equivocal experimental evidence that the toxicity varies among local anesthetics. Even though the precise order of events during local anesthetic-induced neurotoxicity is not clear, possible cellular mechanisms have been identified. These include the intrinsic caspase-pathway, PI3K-pathway, and MAPK-pathways. Further research will need to determine whether these pathways are non-specifically activated by local anesthetics, or whether there is a single common precipitating factor.

Potent, selective antitumour AhR ligands 5F 203 and GW 610 are bioactivated by CYPs 1A1 and 2W1. Herein we reason that DNA adducts' generation resulting in lethal DNA double strand breaks (DSBs) underlies benzothiazoles' activity. Treatment of sensitive carcinoma cell lines with GW 610 generated co-eluting DNA adducts (R(2)>0.7). Time-dependent appearance of γ-H2AX foci revealed subsequent DNA double strand breaks. Propensity for systemic toxicity of benzothiazoles steered development of prodrugs' hydrogels for localised delivery. Clinical applications of targeted therapies include prevention or treatment of recurrent disease after surgical resection of solid tumours. In vitro evaluation of 5F 203 prodrugs' activity demonstrated nanomolar potency against MCF-7 breast and IGROV-1 ovarian carcinoma cell lines., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Contemporary axillary brachial plexus block is performed by separate injections targeting radial, median, ulnar and musculocutaneous nerve. These nerves are arranged around the axillary artery, making ultrasound visualisation sometimes challenging. In particular, the radial nerve can be difficult to localise deep to the artery., Objectives: The primary aim of this study was to investigate which arm position optimises the visibility of the radial nerve. Secondary aims were the visibility and position of the other nerves during varying arm positions., Design: A prospective observational study., Setting: University teaching hospital, November 2012., Participants: Twenty volunteers, recruited by an advertisement on the Department's bulletin board. Inclusion criterion age more than 18 years., Exclusion Criteria: refusal of ultrasound examination, restricted shoulder movement, local infection, BMI greater than 30 kg m⁻²., Intervention: One anaesthesiologist performed bilateral ultrasound examinations of the axillary brachial plexus on 20 volunteers. Each arm was placed in different positions [shoulder (S) 90° or 180° abduction, elbow (E) 0° or 90° extension] and scans were performed proximally in the axilla, and additionally 5 cm distally to this point [proximal (P) vs. distal (D)], resulting in eight different scans stored for off-line analysis performed by two blinded anaesthesiologists., Main Outcome Measures: For radial, median, ulnar and musculocutaneous nerve, visibility was assessed on a six-point visibility scale. Distances and angles of the nerves relative to the axillary artery and distances relative to the skin were measured., Results: No significant differences between arm positions were found in the visibility score of radial (P = 0.359) and musculocutaneous nerves (P = 0.073). Visibility of the median nerve was improved in positions S90°/E0°/D and S180°/E0°/P (P = 0.02). The ulnar nerve was more visible in position S180°/E 0°/P and D (P = 0.007). The greatest distance between artery and radial nerve was 7.4 ± 4.7 mm at an angle of 120 ± 14° in position S180°/E 0°/D., Conclusion: The visibility of the radial nerve was not improved by varying positions of the arm. S180°/E0° provided the best overall visibility and accessibility of nerves., Trial Registration: https://www.toetsingonline.nl/to/ccmo&#95;search.nsf/Searchform?OpenForm Identifier: NL42116.018.12.

Background: The neuropathy of type II diabetes mellitus (DM) is increasing in prevalence worldwide. We aimed to test the hypothesis that in a rodent model of type II DM, neuropathy would lead to increased neurotoxicity and block duration after lidocaine-induced sciatic nerve block when compared with control animals., Methods: Experiments were carried out in Zucker diabetic fatty rats aged 10 weeks (early diabetic) or 18 weeks (late diabetic, with or without insulin 3 units per day), and age-matched healthy controls. Left sciatic nerve block was performed using 0.2 ml lidocaine 2%. Nerve conduction velocity (NCV) and F-wave latency were used to quantify nerve function before, and 1 week after nerve block, after which sciatic nerves were used for neurohistopathology., Results: Early diabetic animals did not show increased signs of nerve dysfunction after nerve block. In late diabetic animals without insulin vs control animals, NCV was 34.8 (5.0) vs 41.1 (4.1) ms s(-1) (P<0.01), and F-wave latency was 7.7 (0.5) vs 7.0 (0.2) ms (P<0.01), respectively. Motor nerve block duration was prolonged in late diabetic animals, but neurotoxicity was not. Late diabetic animals receiving insulin showed intermediate results., Conclusions: In a rodent type II DM model, nerves have increased sensitivity for short-acting local anaesthetics without adjuvants in vivo, as evidenced by prolonged block duration. This sensitivity appears to increase with the progression of neuropathy. Our results do not support the hypothesis that neuropathy due to type II DM increases the risk of nerve injury after nerve block., (© The Author 2014. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Glioblastoma multiforme (GBM) treatment includes temozolomide (TMZ) chemotherapy. O6-Methylguanine lesions are repaired by methylguanine-DNA methyltransferase (MGMT). Response to TMZ requires low MGMT and functional mismatch repair (MMR); resistance, conferred by MGMT or MMR deficiency, represents a barrier to successful treatment. TMZ analogs were synthesized, substituting N3-methyl with propargyl (1) or sulfoxide (2). MTT assays were conducted in SNB19 and U373 isogenic glioma cell lines (V = vector control; M = MGMT-transfected). TMZ potency was reduced >5-fold in SNB19M and U373M cells; in contrast, MGMT-expressing cells were equisensitive as vector controls to analogs 1 and 2 . GI50 values <50 μM of analogs 1 or 2 were detected in V cells possessing acquired TMZ resistance: SNB19VR (hMSH6 loss) and U373VR (MGMT upregulation). Analogs 1 and 2 inhibited MMR-deficient colorectal carcinoma cell growth (irrespective of p53); G2/M cell cycle arrest preceded apoptosis. γH2AX foci inferred the generation of DNA double-strand breaks by analogs 1 and 2 . Acridine orange-stained vesicles, intracellular punctate GFP-LC3 protein and double-membraned autophagosomes indicate that TMZ, 1 and 2 induce autophagy in apoptotis-resistant GBM cells. Analogs 1 and 2 elicit in vitro antitumor activity irrespective of MGMT, MMR and p53. Such imidazotetrazines may treat MGMT+ GBM and possess broader spectrum activity causing apoptosis and autophagy in malignancies which evade apoptosis., (© 2014 S. Karger AG, Basel.)

G-quadruplex (G4) interacting agents are a class of ligands that can bind to and stabilise secondary structures located in genomic G-rich regions such as telomeres. Stabilisation of G4 leads to telomere architecture disruption with a consequent detrimental effect on cell proliferation, which makes these agents good candidates for chemotherapeutic purposes. RHPS4 is one of the most effective and well-studied G4 ligands with a very high specificity for telomeric G4. In this work, we tested the in vitro efficacy of RHPS4 in astrocytoma cell lines, and we evaluated whether RHPS4 can act as a radiosensitising agent by destabilising telomeres. In the first part of the study, the response to RHPS4 was investigated in four human astrocytoma cell lines (U251MG, U87MG, T67 and T70) and in two normal primary fibroblast strains (AG01522 and MRC5). Cell growth reduction, histone H2AX phosphorylation and telomere-induced dysfunctional foci (TIF) formation were markedly higher in astrocytoma cells than in normal fibroblasts, despite the absence of telomere shortening. In the second part of the study, the combined effect of submicromolar concentrations of RHPS4 and X-rays was assessed in the U251MG glioblastoma radioresistant cell line. Long-term growth curves, cell cycle analysis and cell survival experiments, clearly showed the synergistic effect of the combined treatment. Interestingly the effect was greater in cells bearing a higher number of dysfunctional telomeres. DNA double-strand breaks rejoining after irradiation revealed delayed repair kinetics in cells pre-treated with the drug and a synergistic increase in chromosome-type exchanges and telomeric fusions. These findings provide the first evidence that exposure to RHPS4 radiosensitizes astrocytoma cells, suggesting the potential for future therapeutic applications., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Biophysical studies of ligand interactions with three human telomeric repeat sequences (d(AGGG(TTAGGG)n, n = 3, 7 and 11)) show that an oxazole-based 'click' ligand, which induces parallel folded quadruplexes, preferentially stabilises longer telomeric repeats providing evidence for selectivity in binding at the interface between tandem quadruplex motifs.

Background: Talar and calcaneal fractures and their treatment can cause severe postoperative pain. We hypothesized that a continuous peripheral nerve block (CPNB) would reduce pain scores more effectively than systemic analgesics, improve recovery, and lead to reduced length of stay (LOS)., Methods: Over a 3-year period patients undergoing open reduction and internal fixation (ORIF) of a talar or calcaneal fracture were retrospectively analyzed. Patients received a CPNB catheter preoperatively or intravenous patient-controlled analgesia (PCA) postoperatively. Primary endpoint was Numerical Rating Scale (NRS) scores on postoperative day 1. Secondary endpoints were NRS scores up to day 3, opioid requirement, analgesia-related side effects, intraoperative blood loss, infection, and LOS. Eighty-seven patients were analyzed; 70 with calcaneal fracture, 21 with talar fracture, 4 with both. In all, 40 patients received CPNB, 47 patients PCA., Results: Median NRS scores on day 1 were 1.0 (IQR 3) in the CPNB group and 2.0 (IQR 3) in the PCA group (ns). Median LOS for patients with CPNB was 5 days (IQR3) and PCA 4 days (IQR 2 ns). Blood loss and incidence of local infections were comparable in both groups. Opioid requirement was significantly increased in the PCA group (P < .01)., Conclusion: Significant advantages or disadvantages were not seen in either group. However, the PCA group required about 30-fold more opioids compared to the CPNB group on day 1, although that did not lead to an increased number of side effects., Level of Evidence: Level III, retrospective comparative series., (© The Author(s) 2014.)