Pharmacokinetic parameters of CAZ-AVI in the normal lung and in models of pneumonia: lessons for treatment optimization in critical care.

The spread of multidrug-resistant Gram-negative bacterial infections is a significant issue for worldwide public health. Gram-negative organisms regularly develop resistance to antibiotics, especially to ß-lactam antimicrobials, which can drastically restrict the number of therapies. A third-generation cephalosporin and the non-ß-lactam ß-lactamase inhibitor avibactam, which exhibits broad-spectrum ß-lactamase inhibition in vitro, are combined to form ceftazidime-avibactam (CAZ-AVI). In this narrative review, we summarize data on pharmacokinetic (PK) parameters for CAZ-AVI in both animal and human models of pneumonia, as well as in healthy individuals. We assessed current literature performing an extensive search of the literature, using as search words 'CAZ-AVI', 'pharmacokinetics', 'pneumonia', 'lung', and 'epithelial lining fluid'. Overall, lung exposure studies of CAZ-AVI revealed that the epithelial lining fluid penetration ranges between 30% and 35% of plasma concentration. Despite the fair lung penetration of CAZ-AVI, this antimicrobial agent has a pivotal role in managing patients with multi-drug resistant Gram-negative pneumonia, however further studies are needed to better assess its PK profile.

Nutrition support for critically ill patients during the COVID-19 pandemic: the Italian SIAARTI survey.

BACKGROUND: Critically ill, COVID-19 patients are characterized by a hypermetabolic state and a reduced food intake and are at high risk of malnutrition and lean body mass loss. An appropriate metabolic-nutritional intervention aims to reduce complications and improve the clinical outcomes. We conducted a cross-sectional, multicenter, observational, nationwide online survey involving Italian Intensivists to assess the nutritional practices in critically ill patients with COVID-19. RESULTS: A group of experts in nutrition of the Italian Society of Anaesthesia Analgesia Resuscitation and Intensive Care (SIAARTI) developed a 24-item questionnaire; the 9000 members of the Society were invited to participate through emails and social networks. Data was collected from June 1 to August 1, 2021. A total of 545 responses were collected: 56% in northern, 25% in central, and 20% in southern Italy. Artificial nutrition support is directly handled by intensivists in > 90 of the cases; the nutritional status is assessed as suggested by the guidelines in more than 70% of the cases, and a form of nutrition support is started within the first 48 h from ICU admission by > 90% of the respondents. Nutritional targets are reached in 4-7 days in > 75% of the cases, mainly by the enteral route. Indirect calorimetry, muscle ultrasound, and bioimpedance analysis are used by a limited part of the interviewees. Only about a half of the respondents reported the nutritional issues in the ICU discharge summary. CONCLUSIONS: This survey among Italian Intensivists during the COVID-19 epidemic showed how the beginning, progression, and route of nutritional support adhere to international recommendations, while recommendations on the tools to set the target and monitor the efficacy of the metabolic support are less followed.

KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.

Effectiveness of home-based preoperative pulmonary rehabilitation in COPD patients undergoing lung cancer resection.

OBJECTIVE: To investigate the effectiveness of a home-based preoperative rehabilitation program for improving preoperative lung function and surgical outcome of patients with chronic obstructive pulmonary disease (COPD) undergoing lobectomy for cancer. METHODS: This was a prospective, observational, single-center study including 59 patients with mild COPD who underwent lobectomy for lung cancer. All patients attended a home-based preoperative rehabilitation program including a minimum of 3 sessions each week for 4 weeks. Each session included aerobic and anaerobic exercises. Participants recorded the frequency and the duration of exercise performed in a diary. The primary end point was to evaluate changes in lung function including predicted postoperative (PPO) forced expiratory volume in 1 second (FEV1), 6-minute walking distance test (6MWD), PPO diffusing capacity for carbon monoxide (DLCO) %, and blood gas analysis values before and after the rehabilitation program. Postoperative pulmonary complications were recorded and multivariable analysis was used to identify independent prognostic factors (secondary end point). RESULTS: All patients completed the 4-week rehabilitation program. Thirteen of 59 (22%) patients (Group A) performed <3 sessions per week (mean sessions per week: 2.3±1.3); 46 of 59 (78%) patients (Group B) performed ⩾3 sessions per week (mean sessions per week: 3.5±1.6). The comparison of PPO FEV1% and 6MWD before and after rehabilitation showed a significant improvement only in Group B. No significant changes in PPO DLCO% or in blood gas analysis values were seen. Nine patients presented postoperative pulmonary complications, including atelectasis (n = 6), pneumonia (n = 1), respiratory failure (n = 1), and pulmonary embolism (n = 1). Group A presented higher number of postoperative pulmonary complications than Group B (6 vs 3; p = 0.0005). Multivariate analysis showed that the number of weekly rehabilitation sessions was the only independent predictive factor (p = 0.001). CONCLUSIONS: Our simple and low-cost rehabilitation program could improve preoperative clinical function in patients with mild to moderate COPD undergoing lobectomy and reduce postoperative pulmonary complications. All patients should be motivated to complete at least 3 rehabilitation sessions per week in order to obtain significant clinical benefits. Our preliminary results should be confirmed by larger prospective studies.

Role of a digital tool in preoperative lung resection surgery assessment.

The assessment of patients likely to undergo lung resection surgery is a multidisciplinary approach involving pulmonologists, surgeons and anaesthesiologists. In thoracic surgery, medical operability is also a calculation of postoperative lung function. A mobile application - PreParAPP MSD - to calculate postoperative lung function has been developed with the endorsement of the Italian Society of Anaesthesia, Analgesia and Intensive Care and with the unconditional support of MSD Italia. Thanks to a simple graphic interface, the calculation becomes fast and intuitive, while the possibility of storing and sharing data in an analytical and computerised way with other clinicians might help with the full assessment of patients without forcing them to undergo several medical examinations. These simple calculated parameters are performed by a minority of clinicians, generally anaesthesiologists. In our facility, there is a team involved in the perioperative evaluation of lung resection surgery (13 pulmonologists, 9 surgeons and 5 anaesthesiologists). In order to evaluate the possible Awareness towards postoperative lung function calculation better, we organised an internal survey with 27 clinicians who are members of such a team before and after the introduction of the PreParAPP MSD. It was found that after the introduction of PreParAPP MSD, the percentage of clinicians involved in postoperative lung function calculation rose from 18% to 70%. The implementation of a digital tool may help to improve guideline adherence, in accordance with other experiences in which such tools represented the start for various quality improvement purposes throughout the medical field.

Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders.

Pigmentary manifestations can represent an early clinical sign in children affected by Neurofibromatosis type 1 (NF1), Legius syndrome, and other neurocutaneous disorders. The differential molecular diagnosis of these pathologies is a challenge that can now be met by combining next generation sequencing of target genes with concurrent second-level tests, such as multiplex ligation-dependent probe amplification and RNA analysis. We clinically and genetically investigated 281 patients, almost all pediatric cases, presenting with either NF1 (n = 150), only pigmentary features (café au lait macules with or without freckling; (n = 95), or clinical suspicion of other RASopathies or neurocutaneous disorders (n = 36). The causative variant was identified in 239 out of the 281 patients analyzed (85.1%), while 42 patients remained undiagnosed (14.9%). The NF1 and SPRED1 genes were mutated in 73.3% and 2.8% of cases, respectively. The remaining 8.9% carried mutations in different genes associated with other disorders. We achieved a molecular diagnosis in 69.5% of cases with only pigmentary manifestations, allowing a more appropriate clinical management of these patients. Our findings, together with the increasing availability and sharing of clinical and genetic data, will help to identify further novel genotype-phenotype associations that may have a positive impact on patient follow-up.

Management of chest impalement injury.

PRESENTATION OF CASE: We will describe the case of a man who impaled himself on a greenhouse pole by falling off a ladder. DISCUSSION: The belated radiological exclusion of any spine and neck lesions forced the surgeons to operate with the patient supine and on a spine board, which prevented them from performing the classic thoracotomy and reaching the entry hole in the right scapula area. CONCLUSION: A double thoracotomy and the expedient of a haemostatic plug, positioned simultaneously with the extraction of the pole, allowed to control bleeding with absolute safety margins.

LMA® Protector™ versus traditional LMA to perform endobronchial ultrasound-guided transbronchial needle aspiration: a retrospective analysis.

BACKGROUND: The aim of this study was to evaluate the use of laryngeal mask airway (LMA)® Protector™ by comparison with traditional LMA for performing endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). METHODS: This was a retrospective observational single-center study including 143 patients who underwent EBUS-TBNA for mediastinal staging of lung cancer. Patients were retrospectively divided into two groups based on whether a traditional LMA (traditional LMA group) or LMA Protector was used. Anesthesiologist outcomes, diagnostic yield of EBUS-TBNA, and complications related to the procedure were computed for each group and statistically compared. RESULTS: LMA traditional group and LMA Protector group counted 70 and 73 patients, respectively. LMA traditional group versus LMA Protector group showed no significant difference on time of LMA insertion (120±25 vs. 118±39 s; P=0.49), reposition rates (18% vs. 16%; P=0.78); systolic pressure (140±55 vs. 118±37 mmHg; P=0.59); diastolic pressure (82±15 vs. 90±26 mmHg; P=0.39); heart rate (82±9.9 vs. 83±20 bpm; P=0.49); SpO2 values (93±21% vs. 92±14%; P=0.63); diagnostic accuracy (91.3% vs. 92%; P=0.95), and patients' complications as nausea (4% vs. 3%; P=0.61); vomiting (3% vs. 1%, P=0.96); gastric aspiration (7% vs. 1%; P=0.08); and sore throat (7% vs. 3%; P=0.22). Conversely, LMA traditional group versus LMA Protector group presented a longer procedural time (47±23 vs. 38±17 s; P=0.02), higher number of passage to biopsy target lesion (4±0.5 vs. 3.1±0.6; P=0.01); higher rate of balloon ultrasound rupture (11% vs. 1%; P=0.01). CONCLUSIONS: EBUS-TBNA conducted with LMA Protector is a useful strategy that reduced the procedural time and in theory ensured the comfort of patients. Our results should be confirmed by larger, prospective, randomized studies.