A New Solution for Routine Endoscopic Aerosol-Generating Procedures (AGPs) in the COVID-19 Pandemic.

INTRODUCTION: There is urgent need to find a swift and cheap way to safely perform routine endoscopic procedures during the otolaryngological and anesthesiological practice. We want to share our experience of a novel device, inspired by the pediatric head box experience. MATERIALS AND METHODS: Five otolaryngologists and four anesthesiologists were asked to visualize the glottic plane by using the device. A total of 15 attempts was allowed to reach the vocal folds within 60 seconds after entering the box. Student's t-test for unpaired samples was used to compare groups. RESULTS: Transnasal laryngoscopy through our endobox could be successfully performed by all the physicians involved and the mean number of attempts before visualizing and passing the glottis for the first time was 2.8 (range 1-5) in the otolaryngologists' group versus 3.2 (range 1-6) in the anesthesiologists' group (P=0.583). Out of the 15 attempts, the group of otolaryngologists reached the glottis 10.2 times, on average, against 9.7 in the other group (P=0.692). CONCLUSIONS: Our endobox seems a practical and feasible strategy to control droplets diffusion during standard ear, nose, and throat and anesthesiological practice.

Use of Fluoride as a Marker Solute to Quantify the Current Effective Delivered Dose in Continuous Renal Replacement Therapy: An "in vitro" Study.

BACKGROUND: The current effective delivered dose is a quality indicator for continuous renal replacement therapy. Its periodic assessment might enable physicians to deliver personalised treatments. Yet, its quantification as by extracorporeal urea clearance (Cl) is cumbersome and thus often neglected in routine practice. The aim of this in vitro study is to demonstrate the non-inferior effectiveness of assessing the current effective delivered dose using a simpler, cheaper and faster approach based on measurement of fluoride rather than urea extracorporeal Cl. METHODS: We compared urea and fluoride removal in 3 post-dilution continuous veno-venous haemofiltration (CVVH) and 3 continuous veno-venous haemodialysis (CVVHD) in vitro experimental models. Experiments ran for 180 min, using 3 L of human blood, heparin anticoagulation and a machine dose of 30 mL/kg/h. Urea and fluoride were measured in the inflow, outflow and effluent lines to compare sieving coefficients (SC), saturation coefficients (SA) and transmembrane Cls. RESULTS: In CVVH, the median SC values were 1.06 (1.02-1.07) and 1.02 (1.01-1.04) for fluoride and urea, respectively (discrepancy of 4.3%), while transmembrane convective Cls were 31.28 (30.01-31.31) mL/kg/h and 30.30 (29-31.85) mL/kg/h (discrepancy of 3.13%), respectively. In CVVHD, the median SA values were 1.01 (0.96-1.02) and 1 (0.95-1.01) for fluoride and urea, respectively (discrepancy of 1.6%), while transmembrane dialytic Cls were 30.26 (29.52-31.32) mL/kg/h and 31.16 (30-31.75) mL/kg/h (discrepancy of -2.97%), respectively. CONCLUSION: Fluoride transmembrane removal was close to that observed with urea, in terms of SC, SA and transmembrane Cl. Fluoride seems as much accurate as urea in assessing the current effective delivered dose during both CVVH and CVVHD and might therefore be adopted for dose measurement. Besides accuracy, fluoride bedside assessment could present many advantages over urea, particularly in terms of availability, costs, time requirement and rapidity of assessment.

Comparison of neostigmine vs. sugammadex for recovery of muscle function after neuromuscular block by means of diaphragm ultrasonography in microlaryngeal surgery: A randomised controlled trial.

BACKGROUND: Postoperative residual curarisation (PORC) is a risk directly related to the use of neuromuscular blocking agents during surgical procedures. Acceleromyography is distressing for conscious patients when assessing PORC. Diaphragm ultrasonography could be a valid alternative. OBJECTIVES: The primary objective was to achieve a 28% lower incidence of PORC in patients who, after rocuronium administration, received neostigmine or sugammadex at 30 min after surgery. To assess PORC, diaphragm ultrasonography was used, and thickening fractioning [the difference of thickness at the end of inspiration (TEI) and at the end of expiration (TEE), normalised for TEE (TEI - TEE/TEE)] was measured. PORC was defined as thickening fractioning of 0.36 or less. The secondary object was the comparison, in the two treatment groups, of the return to baseline thickening fractioning at 30 min after surgery (ΔTF30). DESIGN: Randomised, double-blind, single-centre study. SETTING: University Hospital Careggi, Florence, Italy. PATIENTS: Patients of American Society Anesthesiologists' physical status 1 or 2, 18 to 80 years, receiving rocuronium during microlaryngeal surgery. INTERVENTIONS: At the end of surgery participants were randomised to receive neostigmine (NEO group) or sugammadex (SUG group) as the reversal drug. Thickening fractioning and ΔTF30 were evaluated at baseline and at 0, 10 and 30 min after surgery. MAIN OUTCOME MEASURES: TEE and TEI at each time point. RESULTS: A total of 59 patients with similar demographic characteristics were enrolled. An association between lack of recovery (thickening fractioning ≤0.36) and drug treatment was only observed at 0 min (SUG vs. NEO, P < 0.05). Concerning ΔTF, at 30 min more patients in the SUG group returned to baseline than those in the NEO group (P < 0.001), after adjusting for side (P = 0.52), baseline thickening fractioning (P < 0.0001) and time of measurement (P < 0.01). CONCLUSION: We found an early (0 min) but not long-lasting (30 min) association between diaphragm failure and treatment allocation; a full recovery in baseline diaphragm function was observed only in patients receiving sugammadex. We cannot exclude that further differences have not been found due to interpatients variability in assessing diaphragm contractility by ultrasonography. TRIAL REGISTRATION: EudraCT Identifier: 2013-004787-62, Clinicaltrials.gov Identifier: NCT02698969.

Changes in ceftriaxone pharmacokinetics/pharmacodynamics during the early phase of sepsis: a prospective, experimental study in the rat.

BACKGROUND: Sepsis is characterized by the loss of the perm-selectivity properties of the glomerular filtration barrier (GFB) with consequent albuminuria. We examined whether the pharmacokinetics-pharmacodynamics (PK/PD) of ceftriaxone (CTX), an extensively protein-bound 3rd generation cephalosporin, is altered during early sepsis and whether an increase in urinary loss of bound-CTX, due to GFB alteration, can occur in this condition. METHODS: A prospective, experimental, randomized study was carried out in adult male Sprague-Dawley rats. Sepsis was induced by cecal ligation and puncture (CLP). Rats were divided into two groups: Sham-operated and CLP. CTX (100 mg i.p., equivalent to 1 g dose in humans) was administered in order to measure plasma and lung CTX concentrations at several time-points: baseline and 1, 2, 4 and 6 h after administration. CTX was measured by High Performance Liquid Chromatography (HPLC). The morphological status of the sialic components of the GFB barrier was assessed by lectin histo-chemistry. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA >90%) for 80 and 100% of Tfree > minimum inhibitory concentration (MIC) for 80 and 100% of dosing interval. MEASUREMENTS AND MAIN RESULTS: After CLP, sepsis developed in rats as documented by the growth of polymicrobial flora in the peritoneal fluid (≤1 × 101 CFU in sham rats vs 5 × 104-1 × 105 CFU in CLP rats). CTX plasma concentrations were higher in CLP than in sham rats at 2 and 4 h after administration (difference at 2 h was 47.3, p = 0.012; difference at 4 h was 24.94, p = 0.004), while lung penetration tended to be lower. An increased urinary elimination of protein-bound CTX occurred (553 ± 689 vs 149 ± 128 mg/L, p < 0.05; % of bound/total CTX 22 ± 6 in septic rats vs 11 ± 4 in sham rats, p < 0.01) and it was associated with loss of the GFB sialic components. According to Monte Carlo simulation a PTA > 90% for 100% of the dosing interval was reached neither for sham nor CLP rats using MIC = 1 mg/L, the clinical breakpoint for Enterobacteriacee. CONCLUSIONS: Sepsis causes changes in the PK of CTX and an alteration in the sialic components of the GFB, with consequent loss of protein-bound CTX. Among factors that can affect drug pharmacokinetics during the early phases of sepsis, urinary loss of both free and albumin-bound antimicrobials should be considered.

Effects of continuous renal replacement therapy on linezolid pharmacokinetic/pharmacodynamics: a systematic review.

BACKGROUND: Major alterations in linezolid pharmacokinetic/pharmacodynamic (PK/PD) parameters might be expected in critically ill septic patients with acute kidney injury (AKI) who are undergoing continuous renal replacement therapy (CRRT). The present review is aimed at describing extracorporeal removal of linezolid and the main PK-PD parameter changes observed in critically ill septic patients with AKI, who are on CRRT. METHOD: Citations published on PubMed up to January 2016 were systematically reviewed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. All authors assessed the methodological quality of the studies and consensus was used to ensure studies met inclusion criteria. In-vivo studies in adult patients with AKI treated with linezolid and on CRRT were considered eligible for the analysis only if operational settings of the CRRT machine, membrane type, linezolid blood concentrations and main PK-PD parameters were all clearly reported. RESULTS: Among 68 potentially relevant articles, only 9 were considered eligible for the analysis. Across these, 53 treatments were identified among the 49 patients included (46 treated with high-flux and 3 with high cut-off membranes). Continuous veno-venous hemofiltration (CVVH) was the most frequent treatment performed amongst the studies. The extracorporeal clearance values of linezolid across the different modalities were 1.2-2.3 L/h for CVVH, 0.9-2.2 L/h for hemodiafiltration and 2.3 L/h for hemodialysis, and large variability in PK/PD parameters was reported. The optimal area under the curve/minimum inhibitory concentration (AUC/MIC) ratio was reached for pathogens with an MIC of 4 mg/L in one study only. CONCLUSIONS: Wide variability in linezolid PK/PD parameters has been observed across critically ill septic patients with AKI treated with CRRT. Particular attention should be paid to linezolid therapy in order to avoid antibiotic failure in these patients. Strategies to improve the effectiveness of this antimicrobial therapy (such as routine use of target drug monitoring, increased posology or extended infusion) should be carefully evaluated, both in clinical and research settings.

Glycocalyx and sepsis-induced alterations in vascular permeability.

Endothelial cells line the inner portion of the heart, blood vessels, and lymphatic vessels; a basal membrane of extracellular matrix lines the extraluminal side of endothelial cells. The apical side of endothelial cells is the site for the glycocalyx, which is a complex network of macromolecules, including cell-bound proteoglycans and sialoproteins. Sepsis-associated alterations of this structure may compromise endothelial permeability with associated interstitial fluid shift and generalized edema. Indeed, in sepsis, the glycocalyx acts as a target for inflammatory mediators and leukocytes, and its ubiquitous nature explains the damage of tissues that occurs distant from the original site of infection. Inflammatory-mediated injury to glycocalyx can be responsible for a number of specific clinical effects of sepsis, including acute kidney injury, respiratory failure, and hepatic dysfunction. Moreover, some markers of glycocalyx degradation, such as circulating levels of syndecan or selectins, may be used as markers of endothelial dysfunction and sepsis severity. Although a great deal of experimental evidence shows that alteration of glycocalyx is widely involved in endothelial damage caused by sepsis, therapeutic strategies aiming at preserving its integrity did not significantly improve the outcome of these patients.

Minocycline but not tigecycline is neuroprotective and reduces the neuroinflammatory response induced by the superimposition of sepsis upon traumatic brain injury.

OBJECTIVE: The development of sepsis in patients with traumatic brain injury increases mortality, exacerbates morphological and functional cerebral damage, and causes persistent neuroinflammation, including microglial activation. The administration of antibiotics possessing both antimicrobial and immunomodulatory activity might attenuate both sepsis and posttraumatic cerebral inflammation. We compared the potential therapeutic efficacy of two tetracyclines, minocycline and the newer generation tigecycline, on functional neurobehavioral impairment and regional histopathological damage in an experimental model of combined traumatic brain injury and sepsis. DESIGN: Prospective, experimental animal study. SETTING: University Research Laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Controlled cortical impact was used to induce traumatic brain injury and cecal ligation and puncture for sepsis. Immediately following injury, animals were treated with minocycline (45 mg/kg intraperitoneal), tigecycline (7.5 mg/kg intraperitoneal), or saline every 12 hours for 3 days. MEASUREMENTS AND MAIN RESULTS: The development of sepsis and cerebral inflammatory response were evaluated, respectively, by 1) growth of peritoneal microorganisms and clinical variables and 2) tumor necrosis factor-α expression in the perilesional cortex. To assess posttraumatic outcome, vestibulomotor and cognitive function were evaluated at different time points for 14 days post injury whereupon animals were killed and cerebral tissue analyzed for lesion volume, regional hippocampal (CA1/CA3) cell death, and microglial activation in the perilesional cortex, lesion core zone, and choroid plexus. Treatment with both antibiotics reduced microorganism growth, body weight loss, and mortality but had no effect on vestibulomotor or cognitive function. Minocycline alone attenuated postinjury cortical lesion volume, hippocampal CA3 neuronal cell loss, tumor necrosis factor-α expression, and the extent of microglial activation and infiltration. CONCLUSIONS: The significantly heightened mortality caused by the superimposition of sepsis upon traumatic brain injury can be reduced by administration of both antibiotics but only minocycline can decrease the extent of cell death in selectively cortical and hippocampal brain regions, via, in part, a reduction in cerebral inflammation.

Worrisome trend of new multiple mechanisms of linezolid resistance in staphylococcal clones diffused in Italy.

In order to assess the frequency of clinically relevant linezolid-resistant staphylococcal isolates, and the role of linezolid in maintaining and coselecting multiple resistance mechanisms (cfr, 23S rRNA, L3/L4 mutations), a prospective Italian study was performed from 2010 to 2011 to confirm the diffusion of three major multidrug-resistant clones (ST2, ST5, ST23).

Variations in Microcirculatory and Hemodynamic Parameters during Oncological Demolitive-Reconstructive Head and Neck Surgery: A Protocol for an Observational Study.

(1) Background: Oncological demolitive-reconstructive surgeries in the head and neck region cause significant stress on patients' biohumoural, cardiac, and vascular systems, leading to disturbances in macrocirculatory and microcirculatory parameters. Traditional monitoring addresses the symptoms, but not the underlying cause. Microcirculatory assessments complement macrocirculatory monitoring, and bladder-catheter-based technology offers a better representation of central microcirculation. Flap reconstruction surgeries involve demolitive and reconstructive phases, requiring optimal tissue perfusion. The literature lacks a consensus on macro-microcirculation coupling, and there is no agreement on the use of vasopressors during head and neck surgeries. Evidence-based guidelines are lacking, resulting in variations in vasopressor administration. (2) Methods: This is a 12-month observational, prospective study conducted in a single center. It aims to evaluate the impact of macro-microcirculation coupling on clinical complications in head and neck surgery. All consecutive patients undergoing oncologic surgery requiring flap reconstruction and meeting the inclusion criteria will be enrolled. The study will utilize standard hemodynamic monitoring and bladder catheterization for measuring urine output and temperature. (3) Conclusions: The study aims to evaluate the coupling of macro- and microcirculation in head and neck surgeries, assess hemodynamic parameters and microcirculatory changes, and investigate their association with postoperative complications. The results can enhance patient care and surgical outcomes.

A 5-year experience with midline catheters in the management of major head and neck surgery patients.

BACKGROUND: In the perioperative management of major head and neck surgery (HNS) patients, the performance of midline catheters (MCs) has been never tested. We present here our 5-year experience by reporting MC-related complications and by identifying the preoperative risk factors associated with their development. METHODS: Clinical variables were extracted and the dwell time, the number, and the type of postprocedural complications of MCs were retrieved. Complications were classified into major (needing MCs removal and including catheter-related bloodstream infection or deep vein thrombosis or catheter occlusion) and into minor (accidental dislodgement, leaking, etc.). Descriptive statistics and logistic regression models were used in order to identify the predictors of complications. RESULTS: A total of 265 patients were included, with a mean age of 67.4 years. Intraprocedural complications occurred in 1.1% of cases, while postprocedural complications occurred in 13.9% of cases (12.05/1000 days), but they were minor in more than 7.0% (5.4/1000 catheter-days). There were 19 minor complications (7.1% or 5.4/1000 catheter-days) while 18 (7%, 5.1/1000 catheter-days) patients experienced at least one major complication. Female sex (OR = 1.963, 95% CI 1.017-3.792), insertion in the right arm (OR = 2.473, 95% CI 1.150-5.318), and an ACE-27 score >1 (OR = 2.573, 95% CI 1.295-5.110) were independent predictors of major complications. CONCLUSIONS: MCs appear to represent an effective option in the setting of major HNS. The identification of patients most at risk for MC-related complications should prompt a postoperative watchful evaluation.

The influence of psychological interventions on surgical outcomes: a systematic review.

BACKGROUND: An amplified and/or prolonged surgical stress response might overcome the organs' functional reserve, thus leading to postoperative complications. The aim of this systematic literature review is to underline how specific psychological interventions may contribute to improve surgical outcomes through the positive modulation of the surgical stress response in surgical patients. METHODS: We conducted a comprehensive literature search in the Cochrane Register of Controlled Trials, PubMed, EMBASE, Scopus, PsycINFO, and CINAHL databases. Only studies published in English from Jan 2000 to Apr 2022 and reporting pain and/or anxiety among outcome measures were included in the review. The following psychological interventions were considered: (1) relaxation techniques, (2) cognitive-behavioral therapies, (3) mindfulness, (4) narrative medicine, (5) hypnosis, and (6) coping strategies. RESULTS: Among 3167 records identified in the literature, 5 papers were considered eligible for inclusion in this review because reporting the effects that psychological features have on neurochemical signaling during perioperative metabolic adaptation and those metabolic and clinical effects that the psychological interventions had on the observed population. CONCLUSION: Our findings confirm that psychological interventions may contribute to improve surgical outcomes via the positive influence on patients' metabolic surgical stress response. A multidisciplinary approach integrating physical and non-physical therapies can be considered a good strategy to successfully improve surgical outcomes in the perioperative period.

Hearing outcomes and patient satisfaction after stapes surgery: local versus general anaesthesia.

Objective: Otosclerosis is a frequent ear disorder causing a stapedo-ovalar ankylosis and conductive hearing loss. Stapedoplasty, performed under both general (GA) and local anaesthesia (LA), is the most advisable surgical solution. Auditory recovery relies on the patient's conditions and on the intervention itself. The aim of our work was to compare hearing outcomes with stapedoplasty performed under GA or LA and to investigate patients' compliance to both methods. Methods: Fifty-five otosclerotic patients underwent stapedoplasty both under GA (32/55) and LA (23/55). Pre- and post-operative air and bone tone audiometry threshold values as well as the air-bone gap and its closure score, were analysed. All patients filled in a satisfaction questionnaire regarding their concern and level of appreciation of the type of anaesthesia. Results and conclusions: Our data show that the auditory results with stapedoplasty are good and do not differ between LA and GA. Even considering the advantages and limits of the two methods, one cannot favour one or the other type of anaesthesia. Finally, the patient's satisfaction cannot be considered a criterion of choice, since this was found to be high in both cases.

Sepsis induces albuminuria and alterations in the glomerular filtration barrier: a morphofunctional study in the rat.

INTRODUCTION: Increased vascular permeability represents one of the hallmarks of sepsis. In the kidney, vascular permeability is strictly regulated by the 'glomerular filtration barrier' (GFB), which is comprised of glomerular endothelium, podocytes, their interposed basement membranes and the associated glycocalyx. Although it is likely that the GFB and its glycocalyx are altered during sepsis, no study has specifically addressed this issue. The aim of this study was to evaluate whether albuminuria--the hallmark of GFB perm-selectivity--occurs in the initial stage of sepsis and whether it is associated with morphological and biochemical changes of the GFB. METHODS: Cecal ligation and puncture (CLP) was used to induce sepsis in the rat. Tumor necrosis factor (TNF)-alpha levels in plasma and growth of microorganisms in the peritoneal fluid were evaluated at 0, 3 and 7 hours after CLP or sham-operation. At the same times, kidney specimens were collected and structural and ultrastructural alterations in the GFB were assessed. In addition, several components of GFB-associated glycocalyx, syndecan-1, hyluronan (HA) and sialic acids were evaluated by immunofluorescence, immunohistochemistry and lectin histochemistry techniques. Serum creatinine and creatinine clearance were measured to assess kidney function and albuminuria for changes in GFB permeability. Analysis of variance followed by Tukey's multiple comparison test was used. RESULTS: Septic rats showed increased TNF-alpha levels and growth of microorganisms in the peritoneal fluid. Only a few renal corpuscles had major ultrastructural and structural alterations and no change in serum creatinine or creatinine clearance was observed. Contrarily, urinary albumin significantly increased after CLP and was associated with diffuse alteration in the glycocalyx of the GFB, which consisted in a decrease in syndecan-1 expression and in HA and sialic acids contents. Sialic acids were also changed in their structure, exhibiting a higher degree of acetylation. CONCLUSIONS: In its initial phase, sepsis is associated with a significant alteration in the composition of the GFB-associated glycocalyx, with loss of GFB perm-selectivity as documented by albumin leakage into urine.

Evaluation of diaphragm thickening by diaphragm ultrasonography: a reproducibility and a repeatability study.

PURPOSE: We have focused on the two-dimensional (B-mode) and the time-motion (M-mode) analysis of the zone of apposition to determine the reliability of diaphragm ultrasonography in the clinical environment. METHODS: Ten healthy volunteers were enrolled and studied by three operators with different skills in ultrasonography. For every volunteer, each operator acquired three images of the diaphragm for each side, both in B-mode and in M-mode. Then a fourth operator calculated the thickening fraction (TF), by means of the formula TF = (TEI - TEE)/TEE (TEI is the thickness at end inspiration and TEE the thickness at end expiration). Afterwards, intraclass correlation coefficients (ICCs) were computed on TF to establish reproducibility and repeatability both in the B- and M-modes. A Coefficient of Repeatability or repeatability (CR) ≤ 0.3 was considered acceptable. RESULTS: Both B-mode (CRs 0.16-0.26) and M-mode (CRs 0.10-0.15) were sufficiently repeatable to assess TF, except for the less experienced operator (CRs B-Mode 0.20-0.32). Reproducibility was moderate to good between operators with CRs much narrower for the M-Mode (0.13-0.14). CONCLUSIONS: The results of our study have shown that diaphragm ultrasound is repeatable and reproducible when carried out by a radiologist or an intensivist with a basic curriculum in ultrasonography. The method is more accurate when using the M-mode for less experienced operators, and in this case, repeatability and reproducibility are not sufficient to make clinical decisions. No TF value lower than 36% was obtained using both techniques. This suggests the existence of a cut-off value that could be used as an initial tool to discriminate healthy subjects from those affected by diaphragmatic dysfunction. CLINICAL TRIAL REGISTRATION: EUDRACT 2015-004635-12.

Risk factors for difficult Laryngeal Mask Airway LMA-Supreme™ (LMAS) placement in adults: a multicentric prospective observational study in an Italian population.

BACKGROUND: Supraglottic airway devices (SADs) are precious tools for airway management in both routine and rescue situations; few studies have analyzed the risk factors for their difficult insertion. METHODS: The aim of this study was to identify the risk factors for difficult insertion for a specific SAD, the Laryngeal Mask Airway LMA-Supreme™ (LMAS). This was a prospective multicentric observational study on a cohort of Italian adult patients receiving general anesthesia for elective surgery. The possible causes of difficulty in LMAS placement (difficulty in insertion or unsatisfactory ventilation) were identified based on literature and on the opinion of international airway management experts. A dedicated datasheet was prepared to collect patients' data, including anthropometric-parameters and parameters for the prediction of difficult airway management, as well as technical choices for the use of LMAS. Data were analyzed to discover the risk factors for difficult LMAS placement and the association between each risk factor and the proportion of incorrect positioning was evaluated through the relative risk and its confidence interval. RESULTS: Four hundred thirty-two patients were enrolled; seventy required two or more attempts to insert the LMAS; nine required a change of strategy. At multivariate analysis, the following factors were significantly associated with difficult LMAS placement: Mallampati III-IV with either phonation or not; inter-incisor distance < 3 cm; reduced neck mobility; no administration of neuromuscular blocking agents (NMBAs). CONCLUSIONS: The alignment of the laryngeal and pharyngeal axes seems to facilitate the procedure, together with NMBA administration; on the contrary, Mallampati grade III-IV are associated with difficult LMAS placement.

Some Suggestions from PK/PD Principles to Contain Resistance in the Clinical Setting-Focus on ICU Patients and Gram-Negative Strains.

The containment of the phenomenon of resistance towards antimicrobials is a priority, especially in preserving molecules acting against Gram-negative pathogens, which represent the isolates more frequently found in the fragile population of patients admitted to Intensive Care Units. Antimicrobial therapy aims to prevent resistance through several actions, which are collectively known as "antimicrobial stewardship", to be taken together, including the application of pharmacokinetic/pharmacodynamic (PK/PD) principles. PK/PD application has been shown to prevent the emergence of resistance in numerous experimental studies, although a straight translation to the clinical setting is not possible. Individualized antibiotic dosing and duration should be pursued in all patients, and even more especially when treating intensive care unit (ICU) septic patients in whom optimal exposure is both difficult to achieve and necessary. In this review, we report on the available data that support the application of PK/PD parameters to contain the development of resistance and we give some practical suggestions that can help to translate the benefit of PK/PD application to the bedside.

TRPA1 mediates damage of the retina induced by ischemia and reperfusion in mice.

Oxidative stress is implicated in retinal cell injury associated with glaucoma and other retinal diseases. However, the mechanism by which oxidative stress leads to retinal damage is not completely understood. Transient receptor potential ankyrin 1 (TRPA1) is a redox-sensitive channel that, by amplifying the oxidative stress signal, promotes inflammation and tissue injury. Here, we investigated the role of TRPA1 in retinal damage evoked by ischemia (1 hour) and reperfusion (I/R) in mice. In wild-type mice, retinal cell numbers and thickness were reduced at both day-2 and day-7 after I/R. By contrast, mice with genetic deletion of TRPA1 were protected from the damage seen in their wild-type littermates. Daily instillation of eye drops containing two different TRPA1 antagonists, an oxidative stress scavenger, or a NADPH oxidase-1 inhibitor also protected the retinas of C57BL/6J mice exposed to I/R. Mice with genetic deletion of the proinflammatory TRP channels, vanilloid 1 (TRPV1) or vanilloid 4 (TRPV4), were not protected from I/R damage. Surprisingly, genetic deletion or pharmacological blockade of TRPA1 also attenuated the increase in the number of infiltrating macrophages and in the levels of the oxidative stress biomarker, 4-hydroxynonenal, and of the apoptosis biomarker, active caspase-3, evoked by I/R. These findings suggest that TRPA1 mediates the oxidative stress burden and inflammation that result in murine retinal cell death. We also found that TRPA1 (both mRNA and protein) is expressed by human retinal cells. Thus, it is possible that inhibition of a TRPA1-dependent pathway could also attenuate glaucoma-related retinal damage.

Postoperative pain after vitreo-retinal surgery is influenced by surgery duration and anesthesia conduction.

BACKGROUND: The control of postoperative pain (POP) is a key component of perioperative care. POP after vitreo-retinal surgery (VRS) has been under-investigated, and its incidence remains elusive. METHODS: In order to assess POP after VRS, the associated risk factors and efficacy of the analgesic protocol in use at our institution, we made a one-year retrospective study on patients undergoing VRS. Patients aged >18 years, ASA Class I-III undergoing VRS entered the study. POP was evaluated by measuring a Numerical Rating Scale (NRS), and analgesic consumption. RESULTS: A total of 782 patients entered the study. Patients received locoregional (LRA) or general anesthesia (GA) with supplemental block. Twenty-two percent of patients needed analgesics (acetaminophen in 97% of cases), mostly between two and six hours after surgery. The univariate analysis showed a positive association between POP and duration of surgery (P<0.0001) and glaucoma (P=0.04), and a negative association with age (P=0.008), analgesic administration at the end of surgery (P=0.005) and the intraoperative administration of remifentanil for surgery under LRA (P=0.02); sedation to execute the block for LRA did not reduce POP. Patients treated with GA with supplemental block had less pain compared to those treated with LRA with/without remifentanil (P=0.03, P=0.002, respectively). The multivariate analysis confirmed a positive correlation between POP and duration of surgery (P=0.0007) and a negative correlation with the intraoperative remifentanil administration during LRA (P=0.04), and with GA with supplemental block (P=0.01). CONCLUSIONS: The incidence of POP after VRS is low but not absent, especially for long procedures, it does not require postoperative opioids and can be modified by anesthesiologic choices.