Gabriele Melegari

Background: Gram-negative bacterial infections represent an increasingly relevant challenge in orthopedic surgery, particularly in complex patients exposed to major trauma, revision procedures, prolonged hospitalization, previous antimicrobial therapy, and intensive care. Although Gram-positive organisms remain predominant in prosthetic joint infections (PJIs) and fracture-related infections (FRIs), the emergence of multidrug-resistant (MDR) Gram-negative pathogens has important implications for perioperative management, antimicrobial prophylaxis, and treatment. Objective: This narrative review examines the epidemiology, pathogenesis, antimicrobial resistance, and management of Gram-negative orthopedic infections, with particular emphasis on issues relevant to anesthesiologists and intensive care physicians. Methods: A structured narrative literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science from database inception to July 2026, according to the principles of the Scale for the Assessment of Narrative Review Articles (SANRA). Original studies, systematic reviews, meta-analyses, guidelines, consensus statements, and relevant narrative reviews addressing Gram-negative infections in orthopedic surgery were considered. Results: Gram-negative pathogens account for a minority of orthopedic infections but become increasingly relevant in complex PJIs, FRIs, open fractures, revision surgery, and patients with substantial healthcare exposure. Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii are among the principal pathogens involved. Their clinical relevance is amplified by biofilm formation and increasingly complex antimicrobial resistance mechanisms. Perioperative antibiotic prophylaxis should remain individualized in patients colonized or previously infected with MDR Gram-negative organisms, avoiding indiscriminate broad-spectrum prophylaxis. Once infection is established, management requires adequate microbiological sampling, surgical source control, and susceptibility-guided antimicrobial therapy. New β-lactam/β-lactamase inhibitor combinations and cefiderocol have expanded therapeutic options against resistant Gram-negative pathogens; however, evidence specifically supporting cefiderocol for bone and joint infections remains limited. Conclusions: Gram-negative orthopedic infections represent an emerging challenge at the intersection of orthopedic surgery, infectious diseases, anesthesiology, and critical care. Early recognition of high-risk patients, individualized perioperative strategies, effective source control, resistance-guided antimicrobial therapy, and multidisciplinary management are essential.

Background: Pancreatic stone protein (PSP) has been proposed as a prognostic biomarker in sepsis, but its comparative performance versus C-reactive protein (CRP) and procalcitonin (PCT) remains uncertain. Methods: We performed a meta-analysis of direct within-study paired AUC comparisons between PSP and CRP and/or PCT in critically ill adults with sepsis, septic shock, or acute infection-related conditions in whom sepsis development or clinically relevant adverse outcomes were prospectively evaluated. Differences in AUC (ΔAUC) were pooled using random-effects models. The principal conservative analysis included one comparison per independent cohort and comparator. Results: Seven studies comprising 803 unique participants contributed 21 paired comparisons. In the principal conservative analysis, PSP showed a higher prognostic AUC than CRP, with a pooled ΔAUC of 0.179 (95% CI 0.095–0.262; p < 0.001), although between-cohort heterogeneity was substantial (I² = 81.65%). Compared with PCT, the pooled ΔAUC was 0.153 (95% CI 0.114–0.193; p < 0.001), with no observed heterogeneity (I² = 0.00%). The mortality-only sensitivity analysis showed a similar pooled effect for PSP versus CRP (ΔAUC 0.17, 95% CI 0.08–0.26), with substantial heterogeneity persisting, and for PSP versus PCT (ΔAUC 0.153, 95% CI 0.114–0.193), with no observed heterogeneity. Exclusion of the clinically distinct intra-abdominal infection cohort (Michailides et al.) likewise did not materially change the PSP-versus CRP estimate (ΔAUC 0.166, 95% CI 0.077–0.256). The direction and approximate magnitude of the pooled effects were also preserved across alternative assumptions for the within-study correlation. Conclusions: Available comparative evidence suggests that PSP may have greater prognostic discrimination than CRP and PCT. The findings were broadly maintained across sensitivity analyses, but the limited number of independent cohorts and substantial heterogeneity in the CRP comparison warrant caution. Further prospective studies are required to confirm these findings and establish their clinical relevance. Trial registration: This systematic review was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420261340301).

Background: We investigated whether early and serial plasma renin concentration (PRC) is associated with 1-year mortality in critically ill patients with COVID-19-related acute respiratory distress syndrome (ARDS). Methods: We conducted a single-center retrospective cohort study in a tertiary intensive care unit, including exclusively patients with COVID-19-related ARDS. PRC was measured at 72 h (T0), 120 h (T1), and 168 h (T2) after intensive care unit (ICU) admission. Chronic renin–angiotensin–aldosterone system (RAAS) inhibitors (ACEi/ARB) were discontinued on admission. The primary endpoint was 1-year mortality. Results: The analysis set included 104 mechanically ventilated patients with COVID-19-related ARDS and available 1-year outcome; 48/104 (46%) died within one year. Higher renin was associated with 1-year mortality at T0 (OR 1.94; p = 0.002), T1 (OR 1.69; p = 0.014), and T2 (OR 2.52; p < 0.001). Kaplan–Meier curves by renin tertiles showed significant separation at T0 and T2 (log-rank p < 0.001). In multivariable logistic regression, independent predictors were renin at T0 (adjusted OR 5.15; 95% CI 1.34–19.78; p = 0.017), PaO₂/FiO₂ ratio (P/F) at T0 (OR 0.02; p = 0.010), and procalcitonin (PCT) at T2 (OR 81.89; p = 0.020). Model discrimination was high (AUC 0.941). Conclusion: In patients with severe COVID-19-related ARDS, early renin (72 h) is independently associated with 1-year mortality, and serial trajectories provide additional prognostic information. Prospective multicenter validation is warranted.

Background: Regional anesthesia is a fundamental aspect of contemporary perioperative care. However, variability in practice, incomplete documentation, and inconsistent safety protocols continue to pose preventable risks. Although there are international checklist models for regional anesthesia and perioperative safety such as those developed by ASRA, ESAIC, and the WHO, Italy does not have a nationally endorsed checklist that is consensus-based and specifically tailored to local terminology, workflows, and legal requirements. Methods: To address this gap, we developed an evidence-based Locoregional Anesthesia Checklist (LRA Checklist) using established frameworks for healthcare checklist design. The development process included a needs assessment through a national survey of ESRA Italy members, a review of existing models, item drafting, expert consensus, and endorsement by the Board. We assessed content validity through a modified Delphi process involving 15 experts from the ESRA Italian Chapter Board. Additionally, we created a theoretical impact model to estimate the potential organizational and economic effects of implementing the checklist, using baseline institutional parameters. Results: Consensus was achieved for all checklist domains after two Delphi rounds, with minor edits to improve clarity, usability, and clinical relevance. The theoretical model indicates that adopting checklists may help reduce preventable complications, improve workflow, enhance documentation and traceability, and provide overall benefits to institutions in various scenarios. Conclusions: In conclusion, the LRA Checklist is a structured, consensus-based tool tailored for the Italian context, aimed at promoting safer and more standardized practices in regional anesthesia. To our knowledge, no prior Italian national consensus or checklist specifically dedicated to regional anesthesia has been formally published. Prospective multicenter studies are necessary to confirm its effectiveness in real-world settings and to quantify both clinical and economic outcomes.

Background: In head and neck reconstructive surgery, flap loss remains a major complication and continues to represent a significant challenge in perioperative management. Although free tissue transfer is widely used, unsatisfactory outcomes are still reported across different flap procedures. Anaesthetic management plays an important role in influencing flap perfusion through its effects on systemic haemodynamics, regional blood flow, and microcirculation. However, there is currently no consensus on universally acceptable haemodynamic targets, and the impact of intraoperative strategies appears to be highly application-specific. Materials and Methods: This narrative review was conducted in accordance with the 2019 SANRA guidelines. PubMed^® was used as the primary database for literature selection. Relevant studies addressing anaesthetic management in head and neck free flap surgery were reviewed, with a particular focus on intraoperative haemodynamic control, ischemia–reperfusion injury, fluid and transfusion management, vasoactive agents, and advanced monitoring techniques. Results: Ischemia–reperfusion injury represents a major mechanism of vascular compromise in free flap surgery and has a significant impact on microcirculatory perfusion. The literature suggests that several anaesthetic strategies—including goal-directed fluid therapy, cautious use of vasopressors, and advanced haemodynamic monitoring—may support intraoperative haemodynamic stability and improve flap perfusion. Nevertheless, the magnitude of haemodynamic improvement achievable with these strategies and their effect on graft survival vary according to patient characteristics, surgical factors, and flap type. Conclusions: Current evidence indicates that anaesthetic management has the potential to contribute to improved intraoperative haemodynamic control in head and neck free flap reconstruction, thereby supporting graft viability. However, haemodynamic targets and management strategies cannot be generalised and should be interpreted within specific clinical contexts. Rather than aiming for optimisation, future research should focus on defining acceptable clinical outcomes for individual applications and on evaluating whether achievable haemodynamic improvements are sufficient to reduce flap-related complications to clinically acceptable levels.

In recent years, Transcranial Color Doppler (TCCD) has gained increasing recognition as a non-invasive neuromonitoring tool. However, there remains a strong tendency to view arterial TCCD as the ‘stethoscope for the brain,’ while the assessment of cerebral venous flow is still underrepresented in clinical protocols. This review aims to explore the emerging role of venous TCCD, particularly when combined with Internal Jugular Vein (IJV) ultrasound, in evaluating cerebral venous outflow in both critically ill and surgical patients. We conducted a narrative review of e-Pub articles from PubMed, MEDLINE, and Scopus, on the pathophysiological factors that impair cerebral venous drainage and their clinical implications in surgical and critical care settings. Based on this evidence, we developed two procedural algorithms that integrate established knowledge of cerebral venous hemodynamics with common clinical conditions affecting venous outflow, including internal jugular central venous catheter placement, mechanical ventilation, and pneumoperitoneum. The algorithms emphasize systematic monitoring of cerebral venous drainage, including assessment of internal jugular vein morphology and Rosenthal’s vein flow, to guide procedural optimization and minimize potential neurological complications. They were informed by validated frameworks, such as the RaCeVa protocol, and are illustrated through two representative clinical case scenarios. Cerebral venous congestion can be induced by multiple established risk factors, including mechanical ventilation, cardiovascular disease, elevated intra-abdominal pressure, the Trendelenburg position, and central venous catheterization. In selected patients, real-time venous TCCD monitoring, combined with IJV assessment, allows early detection of cerebral venous outflow impairment and guides timely hemodynamic and procedural adjustments in both surgical settings and critical care contexts. Venous TCCD neuromonitoring may help prevent intracranial hypertension and its consequent neurological complications. It can guide clinical decisions during procedures that may compromise cerebral venous drainage, such as mechanical ventilation, the placement of large-bore central venous catheters, or laparoscopic and robot-assisted surgeries. Further studies are warranted to validate this strategy and better define its role in specific high-risk clinical scenarios.

Background: Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection leading to organ dysfunction. Distinguishing sepsis from localized infection is crucial, as it guides clinical decision-making and biomarker interpretation. Biomarkers may support diagnosis, prognosis, and therapeutic choices, but their integration into practice remains debated. Methods: This narrative review was conducted in accordance with the SANRA (Scale for the Assessment of Narrative Review Articles) guidelines. A comprehensive literature search was performed in PubMed, Embase, and Cochrane CENTRAL (January 2000–September 2025). Studies evaluating sepsis-related biomarkers for diagnosis, prognostication, shock assessment, antimicrobial stewardship, and post-acute follow-up were considered. Findings: Established biomarkers such as procalcitonin (PCT), C-reactive protein (CRP), and lactate remain widely used for diagnosis, monitoring of inflammatory response, and assessment of severity. Emerging candidates include pancreatic stone protein (PSP), neutrophil gelatinase-associated lipocalin (NGAL), and monocyte HLA-DR (mHLA-DR), which may provide insights into infection dynamics, renal injury, and immune suppression, respectively. However, limitations in standardization and heterogeneous evidence hinder routine implementation. Interleukin-6 (IL-6), despite extensive study, shows limited specificity and inconsistent clinical applicability. Renin has been proposed as a marker of shock severity rather than infection. Comparative evidence highlights the need for stage-specific biomarker use across prehospital, emergency, ICU, and recovery phases. Conclusions: No single biomarker is universally applicable in sepsis. Their utility depends on timing, clinical setting, and patient phenotype. Combining classical and emerging biomarkers with point-of-care technologies and dynamic monitoring may enhance personalized management. Limitations include heterogeneity of evidence and lack of standardized thresholds. Future research should validate biomarker panels, integrate them into stewardship strategies, and explore their cost-effectiveness in clinical practice.

Background: The identification and clinical implementation of robust biomarkers are essential for improving diagnosis, prognosis, and treatment across a wide range of diseases. Pancreatic stone protein (PSP) has recently emerged as a promising candidate biomarker. Objective: This narrative review aims to provide an updated and comprehensive overview of the clinical applications of PSP in infectious, oncological, metabolic, and surgical contexts. Methods: We conducted a structured literature search using PubMed^®, applying the SANRA framework for narrative reviews. Boolean operators were used to retrieve relevant studies on PSP in a wide range of clinical conditions, including sepsis, gastrointestinal cancers, diabetes, and ventilator-associated pneumonia. Results: PSP has shown strong diagnostic and prognostic potential in sepsis, where it may outperform traditional markers such as CRP and PCT. It has also demonstrated relevance in gastrointestinal cancers, type 1 and type 2 diabetes, and perioperative infections. PSP levels appear to rise earlier than other inflammatory markers and may be less affected by sterile inflammation. Conclusion: PSP represents a versatile and clinically valuable biomarker. Its integration into diagnostic protocols could enhance early detection and risk stratification in critical care and oncology settings. However, widespread adoption is currently limited by the availability of point-of-care assay platforms.