Archives

RCT: Early Restrictive vs Liberal Oxygen Strategy in Severe Trauma – No Significant Outcome Difference

22 Dec, 2024 | 17:21h | UTC

Background: The Advanced Trauma Life Support (ATLS) guidelines recommend providing supplemental oxygen to severely injured patients in the early phase after trauma, although the evidence base is limited. Observational research suggests that liberal oxygen administration may raise the risk of death and respiratory complications. Therefore, the TRAUMOX2 trial examined whether an 8-hour restrictive oxygen strategy (targeting an SpO₂ of 94%) could improve outcomes compared with a liberal strategy (12–15 L/min or FiO₂ 0.6–1.0) initiated prehospital or upon trauma center admission.

Objective: To determine whether an early restrictive oxygen approach, as compared with a liberal approach, reduces the composite outcome of death and/or major respiratory complications (pneumonia or ARDS) within 30 days in severely injured adults.

Methods: This investigator-initiated, international, multicenter, open-label, randomized controlled trial enrolled patients aged 18 years or older with blunt or penetrating trauma requiring full trauma team activation and anticipated hospital stay of at least 24 hours. Randomization occurred either prehospital or upon trauma center arrival in a 1:1 ratio to restrictive (lowest dose of oxygen to maintain SpO₂ at 94%) versus liberal therapy (12–15 L/min via nonrebreather mask or FiO₂ 0.6–1.0). The intervention lasted 8 hours, with all other management per standard care. The primary outcome—death or major respiratory complications (pneumonia per CDC criteria or ARDS per the Berlin definition)—was evaluated by blinded assessors within 30 days. Statistical analyses employed logistic regression, adjusted for stratification variables.

Results: Among 1979 randomized patients, 1508 completed the study (median age, 50 years; Injury Severity Score [ISS], 14). The composite primary outcome occurred in 16.1% (118/733) of restrictive-group patients and 16.7% (121/724) of liberal-group patients (odds ratio, 1.01; 95% CI, 0.75–1.37; p=0.94). Mortality alone (8.6% vs 7.3%) and major respiratory complications alone (8.9% vs 10.8%) showed no significant differences between groups. Adverse and serious adverse events were similar, except atelectasis was less frequent in the restrictive group (27.6% vs 34.7%).

Conclusions: In severely injured trauma patients, an 8-hour restrictive oxygen strategy did not significantly reduce death or major respiratory complications compared with a liberal strategy. Both approaches produced similar 30-day outcomes. Nevertheless, restricting oxygen may limit atelectasis and could be a reasonable alternative to giving high-flow oxygen to all trauma patients.

Implications for Practice: Clinicians may choose to target approximately 94% SpO₂ in the early trauma phase without compromising major outcomes. This approach potentially avoids the risks of hyperoxia, though no definitive survival benefit was identified. Pragmatic implementation of a conservative oxygen strategy seems feasible in diverse prehospital and hospital settings.

Study Strengths and Limitations: Notable strengths include multicenter design, randomized enrollment in prehospital and in-hospital settings, and blinded outcome assessment. Limitations include postrandomization exclusions of patients with minor injuries, a relatively short intervention period (8 hours), and an overall open-label design. These factors, along with lower-than-expected event rates, may have limited the power to detect differences in mortality. Commentary from https://bit.ly/bottomline_traumox2 also highlights that the median ISS of 14 indicates moderate rather than extremely severe trauma, possibly contributing to the modest event rates.

Future Research: Large-scale studies with extended intervention durations and targeted subgroups (e.g., severe traumatic brain injury) could clarify optimal oxygen thresholds in trauma care. Ongoing trials with larger sample sizes may better capture smaller but clinically meaningful differences in mortality or complications.

Reference: Arleth T, Baekgaard J, Siersma V, et al. Early Restrictive vs Liberal Oxygen for Trauma Patients: The TRAUMOX2 Randomized Clinical Trial. JAMA. Published online December 10, 2024. DOI: http://doi.org/10.1001/jama.2024.25786

 

---

Large Language Models for Structured Reporting in Radiology: Past, Present, and Future

21 Dec, 2024 | 14:12h | UTC

Introduction/Context: Structured reporting (SR) has been a topic of discussion for decades as a way to standardize and improve the quality of radiology reports. Although there is evidence that SR can reduce errors and enhance guideline adherence, widespread adoption remains limited. Large language models (LLMs), transformer-based and trained on large volumes of text, have emerged as a promising solution to automate and facilitate structured radiology reporting. This narrative review provides an overview of LLM-based SR, while also discussing limitations, regulatory challenges, and future applications.

Key Points/Findings/Recommendations:

1. Application of LLMs in Structured Reporting: Studies focus on models such as GPT-3.5 and GPT-4, showing promising results in converting free-text radiology reports into structured formats, including multilingual capabilities.
2. Main Advantages:
   • Consistency and improved standardization of reports.
   • Potential to reduce errors and enhance comprehensiveness.
   • Streamlining the use of predefined templates and formats.
3. Multilingual and Translational Capabilities: Research shows that several LLMs can process reports in different languages, promoting broader global collaboration.
4. Technical Limitations: Hallucination (fabricated content), terminology inconsistencies, and misinterpretations remain hurdles to large-scale adoption.
5. Regulatory and Privacy Challenges: Proprietary model opacity and a lack of regulated pathways pose difficulties for safely integrating these systems into clinical practice.

Implications for Practice:

• Automation and Efficiency: LLMs can streamline the reporting process, reduce typing effort, and facilitate standardized descriptions, offering efficiency gains.
• System Integration: Incorporation of LLMs into radiology systems (PACS, RIS) could help with documentation and report formatting, improving communication across teams.
• Broader Clinical Perspective: Standardized reports may enhance information sharing and potentially patient safety, especially in multidisciplinary settings.

Limitations/Considerations:

• Hallucination: Even advanced models may generate inaccurate or fictitious content unrelated to the evidence.
• Lack of Transparency: Proprietary models often do not disclose their training data or algorithms, hindering external validation.
• Evolving Regulations: The European Union and other countries are developing AI-specific legal frameworks. Meeting safety, reliability, and transparency requirements is critical for clinical use.
• Availability of Open-Source Models: While open-source models offer more regulatory flexibility, they still require significant validation and refinement for clinical application.

Conclusion: LLMs have significant potential to transform structured radiology reporting, offering increased efficiency and accuracy. However, regulatory issues, model opacity, and current technical limitations must be addressed before these tools can be safely and effectively integrated into clinical practice. Future research should explore clinical acceptance of LLM-generated reports, compare them to radiologist-produced reports, and investigate how these models can be best integrated into existing systems.

Sources and Links:

• Busch, F., Hoffmann, L., dos Santos, D.P. et al. Large language models for structured reporting in radiology: past, present, and future. Eur Radiol (2024). https://doi.org/10.1007/s00330-024-11107-6

 

---

Meta-Analysis: Endovascular Therapy for Vertebrobasilar Occlusion Improves Functional Outcomes

19 Dec, 2024 | 22:56h | UTC

Background: Acute vertebrobasilar artery occlusion (VBAO) is associated with high mortality and severe neurological deficits. Previous randomized trials of endovascular therapy (EVT) for VBAO have shown inconsistent results, leaving uncertainty about its efficacy across different patient subgroups.

Objective: To determine whether EVT confers improved 90-day functional outcomes compared with standard medical therapy alone in patients with acute VBAO and to explore treatment effect heterogeneity in prespecified subgroups.

Methods: This individual patient data meta-analysis included all four major randomized controlled trials (ATTENTION, BAOCHE, BASICS, BEST) that enrolled patients with VBAO treated within 24 hours of estimated onset. Participants received either EVT or best medical therapy. The primary outcome was a favorable functional status at 90 days (modified Rankin Scale [mRS] score 0–3). Secondary outcomes included functional independence (mRS 0–2), distribution of mRS scores (shift analysis), symptomatic intracranial hemorrhage (sICH), and all-cause mortality at 90 days.

Results: Among 988 patients (556 EVT; 432 control), median age 67 years, EVT significantly increased the proportion achieving mRS 0–3 (45% vs 30%; adjusted odds ratio [aOR] 2.41, 95% CI 1.78–3.26) and mRS 0–2 (35% vs 21%; aOR 2.52, 95% CI 1.82–3.48). EVT improved the overall distribution of functional outcomes (aOR for mRS shift 2.09, 95% CI 1.61–2.71) and reduced 90-day mortality (36% vs 45%; aOR 0.60, 95% CI 0.45–0.80). Although sICH was more common with EVT (5% vs <1%; aOR 11.98, 95% CI 2.82–50.81), the net clinical benefit remained strongly in favor of EVT. Subgroup analyses showed broadly consistent benefit, though the advantage was uncertain for patients with mild baseline severity (NIHSS <10).

Conclusions: EVT for acute VBAO significantly improves functional outcomes and reduces mortality despite a higher sICH risk. These results support EVT as a standard consideration in appropriately selected patients with moderate-to-severe VBAO. The benefit’s magnitude is comparable to that seen in anterior circulation large vessel occlusions, although caution is advised in mild cases and those with extensive baseline infarction.

Implications for Practice: Clinicians should consider EVT for most patients presenting with acute VBAO. While sICH risk is increased, the substantial improvements in function and survival justify its use in suitable candidates. Careful imaging and clinical assessment remain critical for optimal patient selection.

Study Strengths and Limitations: Strengths include a pooled individual patient dataset from all major VBAO EVT trials, allowing detailed subgroup analyses. Limitations involve early trial termination, underrepresentation of women, predominance of Asian populations, and exclusion of patients with very mild symptoms or large baseline infarcts, potentially limiting generalizability.

Future Research: Further trials are needed to define EVT’s role in patients with mild symptoms, isolated vertebral occlusion, large infarcts, or those presenting beyond 24 hours. Additional studies should assess real-world applicability and diverse patient populations.

Reference: Nogueira RG, et al. Endovascular therapy for acute vertebrobasilar occlusion (VERITAS): a systematic review and individual patient data meta-analysis. DOI: http://doi.org/10.1016/S0140-6736(24)01820-8

 

---

Guideline: Doxycycline Postexposure Prophylaxis to Reduce Bacterial STI Incidence in High-Risk Populations

19 Dec, 2024 | 22:32h | UTC

Introduction: This summary presents key recommendations from the 2024 Centers for Disease Control and Prevention (CDC) guidelines on using doxycycline postexposure prophylaxis (doxyPEP) to prevent bacterial sexually transmitted infections (STIs), including syphilis, gonorrhea, and chlamydia. Targeting men who have sex with men (MSM) and transgender women with at least one bacterial STI in the past 12 months, these guidelines aim to reduce recurrence rates and improve sexual health outcomes through timely prophylactic intervention.

Key Recommendations:

1. Offer doxyPEP counseling to MSM and transgender women with a recent bacterial STI history, addressing the benefits, harms, and uncertainties of prophylactic doxycycline use.
2. Advise eligible patients to take a single 200 mg dose of doxycycline as soon as possible (ideally within 72 hours) following condomless oral, anal, or vaginal sexual exposure to reduce their subsequent STI risk.
3. Reinforce periodic screening (every 3–6 months) for STI markers, including syphilis and HIV serologies, as well as nucleic acid amplification tests for gonorrhea and chlamydia at relevant anatomical sites.
4. Integrate doxyPEP into comprehensive sexual health services that include risk-reduction counseling, condom use, recommended immunizations, and linkage to HIV preexposure prophylaxis (PrEP) or HIV care, thereby enhancing overall prevention strategies.
5. Consider extending doxyPEP to other high-risk groups, including heterosexual individuals with recurrent STIs, guided by clinical judgment and shared decision-making.
6. Monitor and address adverse events, particularly gastrointestinal symptoms, and acknowledge the potential for antimicrobial resistance. Continued vigilance is warranted given the risk of resistance in commensal flora and key STI pathogens, such as Neisseria gonorrhoeae.
7. Assess social and ethical dimensions of doxyPEP implementation, ensuring equitable access and minimizing potential harms, including stigma or intimate partner violence related to prophylaxis disclosure.

Conclusion: Implementing doxyPEP for MSM and transgender women who have experienced a recent bacterial STI can substantially lower the incidence of recurrent infections. By combining prophylactic doxycycline with routine surveillance, comprehensive preventive services, and careful consideration of resistance patterns, clinicians may enhance patient care and strengthen STI control efforts. Further investigation is needed to establish efficacy in cisgender women, transgender men, nonbinary persons, and other populations at risk. Longer-term, population-based studies focused on antimicrobial resistance and community-level effects will help guide sustainable and equitable use of this prevention strategy.

Reference: Flores J, Davis AM, Hazra A. Doxycycline Postexposure Prophylaxis to Prevent Bacterial Sexually Transmitted Infection. JAMA. Published online December 19, 2024. DOI: http://doi.org/10.1001/jama.2024.24540

 

---

Review: New and Emerging Treatments for Major Depressive Disorder

19 Dec, 2024 | 22:21h | UTC

Introduction: This is a summary of a review on new and emerging treatments for major depressive disorder (MDD), a globally prevalent condition with substantial morbidity and socioeconomic burden. While conventional monoaminergic antidepressants often provide benefit, many patients do not achieve remission, leading to treatment-resistant depression. Novel approaches, including psychedelics (psilocybin, ketamine/esketamine), anti-inflammatory agents, opioid modulators, neuropeptides, botulinum toxin injections, and various neuromodulatory techniques (newer forms of transcranial magnetic stimulation and light-based therapies), are under investigation. This summary highlights their potential efficacy, tolerability, and current limitations.

Key Recommendations:

1. Ketamine and Esketamine: Consider these as adjunctive treatments for patients with refractory MDD, given their rapid antidepressant and anti-suicidal effects. Carefully monitor for blood pressure elevations and potential habituation. Long-term cost-effectiveness and sustained benefits remain uncertain.
2. Psychedelics (Psilocybin, Ayahuasca): Psilocybin-assisted therapy may produce rapid symptom improvement, but scalability, required therapeutic support, and possible increases in suicidality raise concern. Ayahuasca shows early promise, yet lacks robust long-term data and standardized administration protocols.
3. Neuromodulation (rTMS, TBS, Accelerated TMS, Light Therapy): Repetitive transcranial magnetic stimulation (rTMS) and its variants (theta burst stimulation, accelerated protocols) demonstrate modest efficacy with good tolerability. Bright light therapy may enhance neuromodulation outcomes. Optimal protocols and positioning in treatment pathways are not well established.
4. Anti-inflammatory and Other Agents: Preliminary findings suggest potential adjunctive roles for minocycline, NSAIDs, statins, omega-3 fatty acids, and a buprenorphine-samidorphan combination. However, larger, high-quality trials are needed to confirm their efficacy and safety profiles.
5. Onabotulinumtoxin A: A single glabellar injection may confer antidepressant effects, but the underlying mechanism and durability are unclear. Methodological issues, including difficulties with blinding, limit strong recommendations.
6. More Invasive Interventions (DBS, MST): Deep brain stimulation (DBS) and magnetic seizure therapy (MST) are invasive approaches supported by limited evidence, restricting their use to highly refractory cases. The balance of benefit, risk, and resource intensity remains uncertain.

Conclusion: Although these emerging treatments offer potential avenues beyond traditional antidepressants, most remain investigational. Key challenges include limited comparative data, uncertain long-term outcomes, and scaling difficulties. Further rigorous research, including head-to-head trials, long-term follow-ups, and clarity regarding optimal psychotherapeutic support, is required. As evidence matures, these novel interventions may become more integrated into standard care, potentially improving outcomes for patients with difficult-to-treat MDD.

Reference: Njenga C, Ramanuj PP, Magalhães FJC, Pincus HA. New and emerging treatments for major depressive disorder. BMJ. 2024;386:e073823. DOI: https://doi.org/10.1136/bmj-2022-073823

 

---

Review: Nonsurgical Management of Chronic Venous Insufficiency

19 Dec, 2024 | 16:45h | UTC

Introduction: This summary highlights key points from a recent review on the nonsurgical management of chronic venous insufficiency, a condition characterized by persistent venous hypertension leading to edema, skin changes, and venous ulcers. Chronic venous insufficiency is influenced by both structural factors (e.g., venous reflux, obstruction) and functional elements (e.g., obesity, impaired calf-muscle pump). While interventional procedures may improve symptoms in patients with significant structural abnormalities, most cases require comprehensive nonsurgical strategies targeting venous hypertension and improving quality of life.

Key Recommendations:

1. Comprehensive Assessment: Distinguish between structural and functional components of venous disease. Structural issues may warrant endovenous procedures, whereas functional insufficiency (e.g., due to obesity, weak calf muscles) requires behavioral and medical interventions.
2. Compression Therapy (Class 1A for Venous Ulcers): Use tailored compression stockings or wraps to reduce venous pressure, alleviate swelling, and aid ulcer healing. Compression levels above 30 mm Hg can facilitate healing, but lower levels (20–30 mm Hg) may improve adherence.
3. Lifestyle Modifications: Implement weight reduction measures in obese patients to lower central venous pressure and improve venous return. Consider evaluating and managing obstructive sleep apnea or cardiac dysfunction that may elevate venous pressure.
4. Exercise and Leg Elevation: Encourage exercises that strengthen calf and foot muscles, thereby enhancing the venous pump function and reducing stasis. Advise regular leg elevation to alleviate edema and discomfort.
5. Medication Review: Assess current medications (e.g., calcium-channel blockers, gabapentinoids) that may cause edema and consider alternatives. Avoid unnecessary diuretics unless true volume overload is confirmed.
6. Venous Interventions for Structural Lesions (Class IB for Varicose Veins): In patients with symptomatic varicose veins and axial reflux, procedural interventions (e.g., endovenous ablation, sclerotherapy, or surgical stripping) can be more effective than long-term compression alone. Early intervention may expedite ulcer healing in selected cases.
7. Cautious Use of Venoactive Agents: Although certain supplements (e.g., flavonoids, horse chestnut) are widely available, current guidelines provide only weak recommendations, with limited evidence for clinically meaningful outcomes.

Conclusion: Nonsurgical management of chronic venous insufficiency emphasizes reducing venous hypertension, improving calf muscle pump function, and addressing central factors such as obesity and cardiac conditions. By combining compression therapy, exercise, weight reduction, and appropriate medication adjustments, clinicians can alleviate symptoms, enhance patient comfort, and potentially improve wound healing. Procedural interventions remain essential adjuncts for selected structural abnormalities, but long-term functional management is key to sustained clinical benefit.

Reference: Fukaya E, Kolluri R. Nonsurgical Management of Chronic Venous Insufficiency. The New England Journal of Medicine. 2024;391:2350–2359. DOI: https://doi.org/10.1056/NEJMcp2310224

 

---

Review: Management of Atrial Fibrillation

18 Dec, 2024 | 14:22h | UTC

Introduction: This summary of a comprehensive review on atrial fibrillation (AF) focuses on an increasingly prevalent arrhythmia affecting more than 10 million adults in the United States. AF significantly elevates the risks of stroke, heart failure (HF), cognitive decline, and mortality. This guideline-based overview examines the pathophysiology, detection, prevention, and treatment strategies for AF, emphasizing risk factor modification, appropriate anticoagulation, and early rhythm control interventions to improve clinical outcomes and quality of life.

Key Recommendations:

1. Risk Factor and Lifestyle Modification: Implement weight reduction, regular exercise, optimal blood pressure control, smoking cessation, and reduced alcohol intake at all AF stages to prevent new-onset AF, reduce recurrences, and mitigate complications.
2. Screening and Diagnosis: Consider AF screening in high-risk patients using wearable devices or implantable loop recorders. Confirm suspected AF with electrocardiography and extended rhythm monitoring in those with cryptogenic stroke.
3. Stroke Prevention: Assess stroke risk using CHA2DS2-VASc. For patients with annual stroke risk ≥2%, initiate oral anticoagulation (preferably direct oral anticoagulants over warfarin) to lower stroke risk by up to 80%. Avoid aspirin monotherapy for AF-related stroke prevention due to inferior efficacy.
4. Early Rhythm Control: Begin rhythm control within one year of AF diagnosis, particularly in symptomatic patients or those with HF and reduced ejection fraction (HFrEF). Early use of antiarrhythmic drugs or catheter ablation can improve symptoms, cardiac function, and reduce hospitalizations.
5. Catheter Ablation: Utilize ablation as a first-line therapy in symptomatic paroxysmal AF to maintain sinus rhythm and prevent progression. In patients with AF and HFrEF, ablation enhances quality of life, improves left ventricular function, and lowers mortality and HF hospitalization rates.
6. Rate Control Strategies: For patients who are not candidates for rhythm control, use beta-blockers or nondihydropyridine calcium channel blockers to achieve satisfactory ventricular rate control. Consider atrioventricular nodal ablation plus pacemaker implantation if pharmacologic therapy is inadequate.
7. Staging and Long-Term Management: Recognize four AF stages (at risk, pre-AF, clinically apparent AF, and permanent AF) to tailor management. After ablation, continue anticoagulation for at least three months, then reassess stroke risk before considering discontinuation.
8. Addressing Inequities: Improve access to guideline-directed AF therapies, including ablation and specialized care, and address social determinants of health that influence disparities in diagnosis, treatment, and outcomes.

Conclusion: Guideline-directed AF management, encompassing comprehensive risk factor modification, appropriate anticoagulation, and timely rhythm control strategies, can reduce stroke incidence, improve HF outcomes, and prolong life. Catheter ablation is a key intervention for appropriate patients, especially those with symptomatic paroxysmal AF or HFrEF, while striving for equitable and evidence-based care across diverse populations remains a critical priority.

Reference: Ko D, Chung MK, Evans PT, et al. Atrial Fibrillation: A Review. JAMA. Published online December 16, 2024. doi: https://doi.org/10.1001/jama.2024.22451

 

---

Review: Diagnosis and Management of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

18 Dec, 2024 | 11:08h | UTC

Introduction: DRESS is a severe T-cell–mediated hypersensitivity reaction triggered by prolonged exposure to certain medications, characterized by extensive rash, fever, hematologic abnormalities (notably eosinophilia or atypical lymphocytosis), lymphadenopathy, and involvement of internal organs such as the liver, kidneys, and lungs. Common culprits include aromatic anticonvulsants, allopurinol, and specific antibiotics. Although relatively rare, DRESS accounts for a substantial proportion of severe cutaneous adverse drug reactions (SCARs) in hospitalized patients and can be life-threatening, with mortality rates around 5%. Its pathogenesis involves complex immune dysregulation, including Th2 predominance, possible viral reactivation (e.g., HHV-6), and genetic predispositions related to certain HLA alleles. Diagnosis typically relies on clinical criteria, such as the validated RegiSCAR scoring system, and on excluding other SCARs like Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP).

Key Recommendations:

• Identify and Discontinue the Culprit Drug: Prompt removal of the offending medication is the cornerstone of therapy.
• Supportive Care and Monitoring: Hospitalization, often in an intensive care setting, may be required for organ function support and close monitoring of disease progression. Regular assessment of liver enzymes, renal function, blood counts, and cardiac and pulmonary status is critical.
• Systemic Glucocorticoids: High-dose corticosteroids (e.g., prednisone 0.5–1 mg/kg/day) are first-line therapy. A gradual taper over 6–12 weeks is recommended to minimize relapse.
• Steroid-Sparing and Targeted Therapies: In refractory cases or when steroids are contraindicated, consider other immunosuppressants (e.g., cyclosporine, mycophenolate mofetil) or targeted biologic agents (e.g., anti–IL-5 therapies) to control persistent eosinophilia and organ involvement.
• Diagnostic Testing and Specialist Involvement: Although no single test confirms DRESS, dermatology or allergy/immunology consultation may help identify culprit drugs and safer therapeutic alternatives. Patch testing, delayed intradermal testing, and HLA genotyping can sometimes clarify drug causality.
• Long-Term Follow-Up: Patients require prolonged observation due to risks of relapse, potential autoimmune sequelae (e.g., thyroiditis, type 1 diabetes), and psychological distress. Ongoing multidisciplinary care and support are essential.

Conclusion: Early recognition of DRESS, prompt discontinuation of the offending drug, and initiation of systemic corticosteroids are key steps in management. Emerging therapies offer additional treatment options for severe or refractory cases. Long-term follow-up is vital to address relapses, organ damage, and autoimmune complications. A coordinated, multidisciplinary approach improves clinical outcomes and quality of life for affected patients.

Reference: Kroshinsky D, Cardones ARG, Blumenthal KG. Drug Reaction with Eosinophilia and Systemic Symptoms. New England Journal of Medicine. 2024;391:2242-2254. DOI: https://doi.org/10.1056/NEJMra2204547

 

---

RCT: A Single Dose of Ceftriaxone Reduces Early Ventilator-Associated Pneumonia in Acute Brain Injury Patients

17 Dec, 2024 | 12:26h | UTC

Background: Patients with acute brain injury are at increased risk for early ventilator-associated pneumonia (VAP), which can worsen their clinical course. Although short-term antibiotic prophylaxis has been considered, its utility remains uncertain. This study evaluated whether a single early dose of ceftriaxone could reduce the incidence of early VAP in these patients.

Objective: To determine if a single 2-g intravenous dose of ceftriaxone administered within 12 hours of intubation reduces the incidence of early VAP (day 2 to day 7 of mechanical ventilation) in comatose adults (Glasgow Coma Scale ≤12) requiring prolonged mechanical ventilation after acute brain injury.

Methods: This multicenter, randomized, double-blind, placebo-controlled, assessor-masked superiority trial was conducted in nine ICUs across eight French university hospitals. Patients with acute brain injury from trauma, stroke, or subarachnoid hemorrhage who required at least 48 hours of mechanical ventilation were enrolled. Participants received either ceftriaxone 2 g or placebo once, early after endotracheal intubation. All patients received standard VAP prevention measures, but no selective oropharyngeal or digestive decontamination. The primary endpoint was the incidence of early VAP confirmed by blinded assessors using standard clinical, radiological, and microbiological criteria.

Results: Among 319 patients included in the analysis (162 ceftriaxone, 157 placebo), early VAP incidence was significantly lower with ceftriaxone (14%) compared to placebo (32%) (HR 0.60 [95% CI 0.38–0.95]; p=0.030). Patients receiving ceftriaxone had fewer overall VAP episodes, fewer ventilator and antibiotic exposure days, shorter ICU and hospital stays, and reduced 28-day mortality (15% vs 25%). No significant increase in resistant organisms or adverse events attributable to ceftriaxone was observed.

Conclusions: A single early dose of ceftriaxone significantly reduced early VAP risk in acute brain injury patients undergoing mechanical ventilation. This prophylactic approach may improve clinical outcomes without evident safety concerns.

Implications for Practice: Incorporating a single early ceftriaxone dose into VAP prevention protocols for brain-injured patients could mitigate early respiratory infections and potentially enhance clinical outcomes. Nonetheless, clinicians should remain cautious, considering overall antibiotic stewardship and the need for further evidence on long-term microbial resistance patterns.

Study Strengths and Limitations: Strengths include a robust, multicenter, double-blind, placebo-controlled design and blinded adjudication of VAP cases. Limitations include the lack of long-term assessment of the intestinal microbiota and antimicrobial resistance. Further investigation is required to confirm the safety profile regarding microbial ecology and to explore neurological outcomes in greater depth.

Future Research: Future studies should examine the long-term effects of this single-dose approach on resistance patterns, microbial flora, and functional neurological recovery.

Reference: Dahyot-Fizelier C, et al. Ceftriaxone to prevent early ventilator-associated pneumonia in patients with acute brain injury: a multicentre, randomised, double-blind, placebo-controlled, assessor-masked superiority trial. The Lancet Respiratory Medicine. 2024; DOI: http://doi.org/10.1016/S2213-2600(23)00471-X

 

---

RCT: Liberal vs Restrictive Transfusion Yields No Neurologic Outcome Benefit in Aneurysmal Subarachnoid Hemorrhage

16 Dec, 2024 | 11:26h | UTC

Background: Aneurysmal subarachnoid hemorrhage (SAH) is a critical neurologic condition associated with high morbidity and mortality. Anemia is common in this setting and may worsen cerebral oxygenation and outcomes. However, the impact of a liberal transfusion threshold compared with a restrictive approach on long-term neurologic outcomes has been uncertain.

Objective: To determine whether a liberal red blood cell transfusion strategy (transfusion at hemoglobin ≤10 g/dL) improves 12-month neurologic outcomes compared with a restrictive strategy (transfusion at hemoglobin ≤8 g/dL) in patients with aneurysmal SAH and anemia.

Methods: This was a multicenter, pragmatic, open-label, randomized controlled trial conducted at 23 specialized neurocritical care centers. Critically ill adults with a first-ever aneurysmal SAH and hemoglobin ≤10 g/dL within 10 days of admission were randomized to a liberal or restrictive transfusion strategy. The primary outcome was unfavorable neurologic outcome at 12 months, defined as a modified Rankin scale score ≥4. Secondary outcomes included the Functional Independence Measure (FIM), quality of life assessments, and imaging-based outcomes such as vasospasm and cerebral infarction. Outcome assessors were blinded to group allocation.

Results: Among 742 randomized patients, 725 were analyzed for the primary outcome. At 12 months, unfavorable neurologic outcome occurred in 33.5% of patients in the liberal group and 37.7% in the restrictive group (risk ratio 0.88; 95% CI, 0.72–1.09; p=0.22). There were no clinically meaningful differences in secondary outcomes. Mortality at 12 months was similar (approximately 27% in both arms). Radiographic vasospasm was more frequently detected in the restrictive group, though this did not translate into improved functional outcomes in the liberal arm. Adverse events and transfusion reactions were comparable between groups.

Conclusions: In patients with aneurysmal SAH and anemia, a liberal transfusion strategy did not lead to a significantly lower risk of unfavorable neurologic outcome at 12 months compared with a restrictive approach.

Implications for Practice: These findings suggest that routinely maintaining higher hemoglobin levels does not confer substantial long-term functional benefit. Clinicians may consider a more restrictive threshold (≤8 g/dL) to minimize unnecessary transfusions without compromising outcomes. Some skepticism toward adopting a more liberal transfusion policy is warranted given the lack of demonstrable benefit.

Study Strengths and Limitations: Strengths include the randomized, multicenter design, blinded outcome assessment, and a 12-month follow-up. Limitations include potential unmeasured subtle benefits, the inability to blind clinical teams, and the challenge of capturing all aspects of functional recovery with current measurement tools. Further research may clarify if more tailored transfusion strategies can yield modest but meaningful improvements.

Future Research: Future studies should evaluate intermediate hemoglobin thresholds, develop more sensitive measures of functional and cognitive recovery, and consider individualized transfusion strategies based on specific patient factors and biomarkers of cerebral ischemia.

Reference: English SW, et al. Liberal or Restrictive Transfusion Strategy in Aneurysmal Subarachnoid Hemorrhage. New England Journal of Medicine. Published December 9, 2024. DOI: http://doi.org/10.1056/NEJMoa2410962

 

---

Review: Enhancing Interpretability and Accuracy of AI Models in Healthcare

16 Dec, 2024 | 11:06h | UTC

Introduction: Artificial intelligence (AI) has shown remarkable potential in healthcare for improving diagnostics, predictive modeling, and treatment planning. However, the “black-box” nature of many high-performing AI models limits their trustworthiness and clinical utility. Challenges such as limited generalizability, variable performance across populations, and difficulty in explaining model decisions remain critical barriers to widespread adoption. This review synthesizes current evidence on AI models in healthcare, focusing on the interplay between model accuracy and interpretability. By highlighting these issues, we aim to guide healthcare professionals and researchers toward strategies that balance performance with transparency and reliability.

Key Recommendations:

1. Adopt Interpretable Models: Incorporate interpretable frameworks (e.g., LIME, SHAP, Grad-CAM) that allow clinicians to understand model outputs. Such techniques facilitate better acceptance of AI-driven diagnostics, reducing the risk of misinterpretations and erroneous clinical decisions.
2. Balance Accuracy and Transparency: Consider hybrid models that achieve high accuracy while maintaining a degree of explainability. Techniques that blend deep learning with simpler statistical or machine learning approaches can offer clinical insights into AI-derived predictions without substantially sacrificing performance.
3. Integrate Uncertainty Quantification: Employ methods that estimate uncertainty in AI predictions, providing clinicians with confidence intervals or probability distributions. This approach helps manage expectations, enabling safer decision-making in critical clinical scenarios.
4. Use Multimodal Data and Diverse Populations: Encourage the integration of multiple data sources—imaging, clinical notes, genomics—to improve model generalizability. Validate models on diverse patient cohorts to ensure robust performance across various healthcare environments and patient demographics.
5. Collaborative, User-Centered Development: Engage healthcare professionals in the model development process to ensure clinical relevance and usability. User-centered design can guide AI solutions that seamlessly fit into existing workflows and foster greater trust among end-users.

Conclusion: The path to fully leveraging AI in healthcare involves overcoming interpretability challenges while maintaining accuracy. Implementing interpretable, uncertainty-aware models validated on diverse datasets will enhance trust, foster responsible adoption, and ultimately improve patient outcomes. By focusing on both technological innovation and user-centered development, we can drive AI models toward safer, more transparent, and clinically beneficial applications.

Reference: Ennab M, Mcheick H. Enhancing interpretability and accuracy of AI models in healthcare: a comprehensive review on challenges and future directions. Frontiers in Robotics and AI. 2024;11:Article 1444763. DOI: https://doi.org/10.3389/frobt.2024.1444763

 

---

Guidelines for the Management of Hyperglycemic Crises in Adult Patients with Diabetes

15 Dec, 2024 | 13:18h | UTC

Introduction: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are critical, acute complications of type 1 and type 2 diabetes. Recent data show a global rise in DKA and HHS admissions, driven by factors such as psychosocial challenges, suboptimal insulin use, infection, and certain medications (e.g., SGLT2 inhibitors). This consensus report, developed by leading diabetes organizations (ADA, EASD, JBDS, AACE, DTS), provides updated recommendations on epidemiology, pathophysiology, diagnosis, treatment, and prevention of DKA and HHS in adults, aiming to guide clinical practice and improve outcomes.

Key Recommendations:

1. Diagnosis and Classification:
   • DKA is defined by hyperglycemia (>11.1 mmol/l [200 mg/dl] or known diabetes), elevated ketone levels (β-hydroxybutyrate ≥3.0 mmol/l), and metabolic acidosis (pH <7.3 or bicarbonate <18 mmol/l).
   • HHS is characterized by marked hyperglycemia, severe hyperosmolality (>320 mOsm/kg), significant dehydration, and minimal ketonaemia or acidosis.
   • Consider euglycemic DKA, especially with SGLT2 inhibitor use.
   • Classify DKA severity (mild, moderate, severe) to guide the setting of care.
2. Fluid and Electrolyte Management:
   • Initiate isotonic or balanced crystalloid solutions to restore intravascular volume, enhance renal perfusion, and reduce hyperglycemia.
   • Adjust fluids based on hydration, sodium levels, and glucose trends.
   • Add dextrose when glucose falls below ~13.9 mmol/l (250 mg/dl) to allow ongoing insulin therapy until ketoacidosis resolves.
   • Carefully monitor potassium and provide adequate replacement to prevent severe hypokalemia.
3. Insulin Therapy:
   • Start a continuous intravenous infusion of short-acting insulin as soon as feasible after confirming adequate potassium.
   • For mild or moderate DKA, subcutaneous rapid-acting insulin analogs may be used under close supervision.
   • Continue insulin until DKA resolves (pH ≥7.3, bicarbonate ≥18 mmol/l, β-hydroxybutyrate <0.6 mmol/l) or HHS improves (osmolality <300 mOsm/kg, improved mental status).
   • Overlap subcutaneous basal insulin by 1–2 hours before discontinuing intravenous insulin to prevent rebound hyperglycemia.
4. Additional Considerations:
   • Avoid routine bicarbonate; use only if pH <7.0.
   • Phosphate supplementation is not routinely recommended unless levels are severely low.
   • Identify and treat underlying precipitating causes (infection, psychological factors, medication-related triggers).
   • Address social determinants of health and mental health conditions to reduce recurrence.

Conclusion: By implementing these evidence-based recommendations—early diagnosis, structured fluid and insulin therapy, careful electrolyte management, and addressing precipitating factors—clinicians can improve patient care, reduce morbidity and mortality, and enhance the quality of life for adults experiencing DKA and HHS.

Reference: Umpierrez GE, Davis GM, ElSayed NA, et al. Hyperglycaemic crises in adults with diabetes: a consensus report. Diabetologia. 2024;67:1455–1479. DOI: http://doi.org/10.1007/s00125-024-05979-4

 

---

Noninferiority RCT: Omitting Sentinel-Lymph-Node Biopsy Maintains 5-Year Invasive Disease–Free Survival in Early-Stage Breast Cancer

13 Dec, 2024 | 15:15h | UTC

Background: While axillary surgical staging using sentinel-lymph-node biopsy has been a mainstay in early-stage breast cancer management, its necessity in clinically node-negative patients undergoing breast-conserving therapy has been called into question. With tumor biology increasingly guiding treatment decisions, reducing surgical interventions without compromising survival is a major goal.

Objective: To determine whether omitting sentinel-lymph-node biopsy in patients with clinically node-negative, T1 or T2 (≤5 cm) invasive breast cancer undergoing breast-conserving surgery is noninferior to performing sentinel-lymph-node biopsy in terms of 5-year invasive disease–free survival.

Methods: In this prospective, randomized, noninferiority trial, 5502 eligible patients were randomized in a 1:4 ratio to omission of axillary surgery versus sentinel-lymph-node biopsy. The per-protocol population included 4858 patients. All patients received whole-breast irradiation. Invasive disease–free survival, defined as time to any invasive disease event or death, was the primary endpoint. Noninferiority required a 5-year invasive disease–free survival rate ≥85% and a hazard ratio upper limit <1.271.

Results: After a median follow-up of 73.6 months, the 5-year invasive disease–free survival was 91.9% (95% CI, 89.9–93.5) in the omission group and 91.7% (95% CI, 90.8–92.6) in the sentinel-biopsy group (HR, 0.91; 95% CI, 0.73–1.14), meeting noninferiority criteria. Axillary recurrences were slightly higher in the omission group (1.0% vs. 0.3%), though without detrimental effects on overall survival. Patients who omitted axillary surgery experienced lower rates of lymphedema, better arm mobility, and less pain than those undergoing sentinel-lymph-node biopsy.

Conclusions: For appropriately selected patients with clinically node-negative, early-stage breast cancer undergoing breast-conserving surgery, omitting sentinel-lymph-node biopsy did not compromise 5-year invasive disease–free survival and yielded fewer surgical complications and better quality of life outcomes.

Implications for Practice: Omitting axillary staging may be considered in low-risk patients, particularly older individuals with small, hormone receptor-positive, HER2-negative tumors. However, clinicians should balance the lack of nodal information against potential alterations in adjuvant therapy decisions, especially regarding radiotherapy and systemic treatment recommendations.

Study Strengths and Limitations: Strengths include a large patient population, rigorous prospective randomization, and substantial follow-up. Limitations include a predominance of low-risk, small, HR-positive/HER2-negative tumors, potentially limiting generalizability. While omitting sentinel-lymph-node biopsy reduces surgical morbidity, the absence of nodal status may influence adjuvant treatment planning.

Future Research: Further studies should assess the applicability of omission strategies to younger patients, larger tumors, or more aggressive subtypes, and explore whether novel biomarkers or imaging methods can reliably guide treatment decisions without axillary surgery.

Reference: Reimer T, Stachs A, Veselinovic K, Kühn T, Heil J, Polata S, Marmé F, et al. Axillary Surgery in Breast Cancer — Primary Results of the INSEMA Trial. New England Journal of Medicine. 2024. DOI: http://doi.org/10.1056/NEJMoa2412063

 

---

Retrospective Cohort Study: As-Needed Blood Pressure Medications Associated With Increased AKI and Other Adverse Outcomes in Hospitalized Veterans

8 Dec, 2024 | 21:34h | UTC

Background: Inpatient asymptomatic blood pressure (BP) elevations are common, and clinicians frequently use as-needed BP medications to rapidly lower BP values. However, there is limited evidence supporting this practice, and abrupt BP reductions may increase the risk of ischemic events, including acute kidney injury (AKI).

Objective: To examine whether as-needed BP medication use during hospitalization is associated with increased risk of AKI and other adverse outcomes compared to no as-needed use.

Methods: This retrospective cohort study used a target trial emulation and propensity score matching. Adults hospitalized for ≥3 days in non-ICU VA hospital wards from 2015-2020, who received at least one scheduled BP medication within the first 24 hours and had at least one systolic BP reading >140 mm Hg, were included. Patients were categorized into two groups: those receiving at least one as-needed BP medication (oral or IV) and those receiving only scheduled BP medications. The primary outcome was time-to-first AKI event. Secondary outcomes included a >25% drop in systolic BP within 3 hours and a composite of myocardial infarction (MI), stroke, or death.

Results: Among 133,760 veterans (mean age 71.2 years; 96% male), 21% received as-needed BP medications. As-needed BP medication use was associated with a 23% higher risk of AKI (HR=1.23; 95% CI, 1.18-1.29). The IV route showed a particularly pronounced AKI risk (HR=1.64). Secondary analyses indicated a 1.5-fold increased risk of rapid BP reduction and a 1.69-fold higher rate of the composite outcome (MI, stroke, death) among as-needed users.

Conclusions: In a large, national cohort of hospitalized veterans, as-needed BP medication use was associated with increased AKI risk and other adverse outcomes. These findings suggest that routine as-needed BP medication use for asymptomatic BP elevations may be harmful.

Implications for Practice: Clinicians should carefully reconsider the use of as-needed BP medications in the inpatient setting, especially in older individuals or those with significant cardiovascular risk. Given the lack of clear benefit and potential for harm, greater caution and potentially more conservative approaches are warranted.

Study Strengths and Limitations: Strengths include a large, nationally representative sample and robust analytic methods. Limitations include the retrospective design, potential residual confounding, and limited generalizability to non-veteran or surgical populations. While causal inferences cannot be made, the findings strongly support the need to question current practice.

Future Research: Prospective, randomized trials are needed to determine the optimal management of asymptomatic inpatient hypertension and to assess whether avoiding or reducing as-needed BP medication use improves clinical outcomes.

Reference: Canales MT, Yang S, Westanmo A, et al. As-Needed Blood Pressure Medication and Adverse Outcomes in VA Hospitals. JAMA Internal Medicine. Published online November 25, 2024. DOI: http://doi.org/10.1001/jamainternmed.2024.6213

 

---

RCT: FFR-Guided PCI Plus TAVI is Non-inferior and Superior to SAVR Plus CABG in Patients With Severe Aortic Stenosis and Complex Coronary Disease

8 Dec, 2024 | 21:22h | UTC

Background: Patients with severe aortic stenosis frequently present with concomitant complex coronary artery disease. Current guidelines recommend combined surgical aortic valve replacement (SAVR) and coronary artery bypass grafting (CABG) as first-line therapy. However, transcatheter aortic valve implantation (TAVI) and fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) have emerged as alternative treatments. Assessing their efficacy compared to SAVR plus CABG has been an unmet need.

Objective: To determine whether FFR-guided PCI plus TAVI is non-inferior and, if demonstrated, superior to SAVR plus CABG in patients with severe aortic stenosis and complex or multivessel coronary disease.

Methods: This international, multicenter, prospective, open-label, non-inferiority randomized controlled trial included patients aged ≥70 years with severe aortic stenosis and complex coronary disease who were deemed suitable for either percutaneous or surgical treatment by a Heart Team. Participants were randomized (1:1) to FFR-guided PCI plus TAVI or SAVR plus CABG. The primary endpoint was a composite of all-cause mortality, myocardial infarction, disabling stroke, clinically driven target-vessel revascularization, valve reintervention, and life-threatening or disabling bleeding at 1 year.

Results: Among 172 enrolled patients, 91 were assigned to FFR-guided PCI plus TAVI and 81 to SAVR plus CABG. At 1 year, the primary endpoint occurred in 4% of patients in the PCI/TAVI group versus 23% in the SAVR/CABG group (risk difference –18.5%; 90% CI –27.8 to –9.7; p<0.001 for non-inferiority; p<0.001 for superiority). The difference was driven mainly by lower all-cause mortality (0% vs 10%, p=0.0025) and reduced life-threatening bleeding (2% vs 12%, p=0.010).

Conclusions: In patients with severe aortic stenosis and complex coronary artery disease, FFR-guided PCI plus TAVI was non-inferior and in fact superior to SAVR plus CABG at 1 year, predominantly due to lower mortality and serious bleeding events.

Implications for Practice: These findings suggest that a percutaneous strategy may be a viable and potentially preferable alternative to surgery in selected patients. Nevertheless, given this is the first trial of its kind, cautious interpretation is advised, and routine adoption should await further corroboration.

Study Strengths and Limitations: Strengths include a randomized, multicenter design and standardized endpoint assessment. Limitations involve early trial termination resulting in a smaller sample size and the use of a single TAVI device type, limiting generalizability.

Future Research: Larger trials with longer follow-up, evaluation of other TAVI prostheses, and broader patient populations are needed to validate these findings and determine the optimal patient selection criteria.

Reference: Kedhi E, et al. TransCatheter aortic valve implantation and fractional flow reserve-guided percutaneous coronary intervention versus conventional surgical aortic valve replacement and coronary bypass grafting for treatment of patients with aortic valve stenosis and complex or multivessel coronary disease: The Lancet. 2024. DOI: http://doi.org/10.1016/S0140-6736(24)02100-7

 

---

Prospective Cohort: Combined CRP, LDL Cholesterol, and Lipoprotein(a) Levels Predict 30-Year Cardiovascular Risk in Women

8 Dec, 2024 | 20:58h | UTC

---

Nonrandomized Phase 1b–2 Study: CAR T-cell Therapy Obecabtagene Autoleucel Effective with Low Severe Toxicity in Adult B-cell ALL

4 Dec, 2024 | 12:04h | UTC

Background: Relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) in adults has a poor prognosis, with current therapies often requiring allogeneic stem-cell transplantation for durable responses. CAR T-cell therapies targeting CD19 have shown promise but are associated with significant toxic effects.

Objective: To evaluate the efficacy and safety of obecabtagene autoleucel (obe-cel), a novel autologous 41BB-ζ anti-CD19 CAR T-cell therapy designed to reduce toxic effects and improve persistence, in adults with relapsed or refractory B-cell ALL.

Methods: In this nonrandomized, phase 1b–2 multicenter study, 127 adults aged 18 years or older with relapsed or refractory CD19-positive B-cell ALL received at least one infusion of obe-cel. The primary endpoint was overall remission (complete remission or complete remission with incomplete hematologic recovery) in cohort 2A (patients with morphologic disease). Secondary endpoints included event-free survival, overall survival, and safety assessments.

Results: Among the 94 patients in cohort 2A (median follow-up of 20.3 months), overall remission occurred in 77% (95% CI, 67–85%), with 55% achieving complete remission and 21% achieving complete remission with incomplete hematologic recovery. The prespecified null hypotheses were rejected (P < 0.001). In the total infused population, the median event-free survival was 11.9 months (95% CI, 8.0–22.1), and the median overall survival was 15.6 months (95% CI, 12.9–NE). Grade 3 or higher cytokine release syndrome occurred in 2.4% of patients, and grade 3 or higher immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 7.1%.

Conclusions: Obe-cel demonstrated a high incidence of durable responses with a low incidence of severe immune-related toxic effects in adults with relapsed or refractory B-cell ALL.

Implications for Practice: Obe-cel may offer an effective CAR T-cell therapy option with manageable toxicity for adult patients with relapsed or refractory B-cell ALL. However, long-term benefits and direct comparisons with existing therapies require further investigation. Clinicians should consider the potential advantages but remain cautious given the lack of randomized controlled data.

Study Strengths and Limitations: Strengths include the multicenter design and substantial patient population. Limitations involve the nonrandomized, single-arm design without a control group, and potential bias from patients who did not receive the infusion due to disease progression or manufacturing failures. Additionally, longer follow-up is needed to fully assess durability and late-onset toxicities.

Future Research: Further studies are warranted to compare obe-cel directly with standard therapies in randomized controlled trials, assess long-term outcomes, and explore its efficacy in earlier lines of treatment or in combination with other modalities.

Reference: Roddie C, Sandhu KS, Tholouli E, Logan AC, Shaughnessy P, Barba P, Ghobadi A, et al. Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia. New England Journal of Medicine. Published November 27, 2024. DOI: http://doi.org/10.1056/NEJMoa2406526

 

---

RCT: Nivolumab Plus Ipilimumab Extends Progression-Free Survival in MSI-H or dMMR Metastatic Colorectal Cancer

4 Dec, 2024 | 11:51h | UTC

Background: Patients with microsatellite-instability–high (MSI-H) or mismatch-repair–deficient (dMMR) metastatic colorectal cancer typically experience poor outcomes with standard chemotherapy. Previous nonrandomized studies suggested that combining nivolumab with ipilimumab may offer clinical benefits in this population.

Objective: To evaluate the efficacy and safety of nivolumab plus ipilimumab compared with chemotherapy in patients with MSI-H or dMMR metastatic colorectal cancer who had not received prior systemic treatment for metastatic disease.

Methods: In this phase 3, open-label, randomized trial, 303 patients with unresectable or metastatic MSI-H or dMMR colorectal cancer were assigned in a 2:2:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies. The primary endpoint assessed in this interim analysis was progression-free survival (PFS) of nivolumab plus ipilimumab versus chemotherapy in patients with centrally confirmed MSI-H or dMMR status.

Results: At a median follow-up of 31.5 months, nivolumab plus ipilimumab significantly improved PFS compared to chemotherapy (P<0.001). The 24-month PFS was 72% (95% CI, 64–79) with nivolumab plus ipilimumab versus 14% (95% CI, 6–25) with chemotherapy. The restricted mean survival time at 24 months was 10.6 months longer with the combination therapy. Grade 3 or 4 treatment-related adverse events occurred in 23% of patients receiving nivolumab plus ipilimumab and 48% of those receiving chemotherapy.

Conclusions: First-line treatment with nivolumab plus ipilimumab significantly prolonged progression-free survival compared to chemotherapy in patients with MSI-H or dMMR metastatic colorectal cancer, with a lower incidence of high-grade treatment-related adverse events.

Implications for Practice: The combination of nivolumab and ipilimumab may represent a new standard of care for first-line treatment in MSI-H or dMMR metastatic colorectal cancer. However, clinicians should weigh the benefits against potential immune-related adverse events, and long-term survival benefits remain to be fully established.

Study Strengths and Limitations: Strengths include the randomized, phase 3 design and central confirmation of MSI-H or dMMR status. Limitations involve the open-label design, potential bias in patient-reported outcomes, underrepresentation of certain populations, and immature overall survival data.

Future Research: Further studies are needed to compare nivolumab plus ipilimumab directly with nivolumab monotherapy and to assess long-term overall survival benefits and quality of life in diverse patient populations.

Reference: Andre T, et al. Nivolumab plus Ipilimumab in Microsatellite-Instability–High Metastatic Colorectal Cancer. New England Journal of Medicine. 2024;391(21):2014–2026. DOI: http://doi.org/10.1056/NEJMoa2402141

 

---

RCT: Transcatheter Edge-to-edge Repair Improves Outcomes in Severe Tricuspid Regurgitation

29 Nov, 2024 | 12:37h | UTC

Background: Severe tricuspid regurgitation (TR) is linked to poor quality of life and increased mortality. Traditional medical therapy offers limited symptom relief, and surgical options carry high risks. Transcatheter tricuspid valve therapies like transcatheter edge-to-edge repair (T-TEER) have emerged as less invasive alternatives, but their impact on patient outcomes needs further exploration.

Objective: To determine if T-TEER combined with optimized medical therapy (OMT) enhances patient-reported outcomes and clinical events compared to OMT alone in patients with severe, symptomatic TR.

Methods: In this multicenter, prospective, randomized (1:1) trial, 300 adults with severe, symptomatic TR despite stable OMT were enrolled from 24 centers in France and Belgium between March 2021 and March 2023. Participants were randomized to receive either T-TEER plus OMT or OMT alone. The primary outcome was a composite clinical endpoint at 1 year, including changes in New York Heart Association (NYHA) class, patient global assessment (PGA), or occurrence of major cardiovascular events. Secondary outcomes encompassed TR severity, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, and a composite of death, tricuspid valve surgery, KCCQ improvement, or hospitalization for heart failure.

Results: At 1 year, 74.1% of patients in the T-TEER plus OMT group improved in the composite endpoint versus 40.6% in the OMT-alone group (P < .001). Massive or torrential TR persisted in 6.8% of the T-TEER group compared to 53.5% of the OMT group (P < .001). The mean KCCQ score was higher in the T-TEER group (69.9 vs 55.4; P < .001). The win ratio for the composite secondary outcome was 2.06 (95% CI, 1.38-3.08; P < .001). No significant differences were observed in major cardiovascular events or cardiovascular death between groups.

Conclusions: Adding T-TEER to OMT significantly reduces TR severity and improves patient-reported outcomes at 1 year in patients with severe, symptomatic TR, without increasing adverse events.

Implications for Practice: T-TEER may offer a valuable addition to OMT for selected patients with severe TR, enhancing symptoms and quality of life. However, the absence of significant differences in hard clinical endpoints and the open-label design suggest cautious interpretation. Clinicians should weigh the benefits against potential biases in patient-reported outcomes.

Study Strengths and Limitations: Strengths include the randomized design and multicenter participation, enhancing the study’s validity. Limitations involve the open-label design without a sham control, potentially introducing bias in subjective outcomes. The short follow-up period and selective patient population based on anatomical suitability for T-TEER may limit generalizability.

Future Research: Longer-term studies are necessary to assess T-TEER’s impact on survival and heart failure hospitalization. Comparative studies of different transcatheter devices and investigations into optimal patient selection criteria are also recommended.

Reference: Donal E, Dreyfus J, Leurent G, et al. Transcatheter Edge-to-Edge Repair for Severe Isolated Tricuspid Regurgitation: The Tri.Fr Randomized Clinical Trial. JAMA. Published online November 27, 2024. DOI: http://doi.org/10.1001/jama.2024.21189

 

---

Management of Adult Sepsis in Resource-Limited Settings: A Global Delphi-Based Consensus

24 Dec, 2024 | 13:35h | UTC

Introduction: This summary presents key points from a recent expert consensus on managing adult sepsis under limited-resource conditions, where patients may lack access to an ICU bed, advanced monitoring technologies, or sufficient staffing. The statements were developed through a Delphi process involving an international panel of clinicians, aiming to complement existing sepsis guidelines by focusing on pragmatic approaches and context-specific adaptations. These consensus statements address unique challenges such as limited diagnostic tests, alternative strategies for hemodynamic monitoring, and management of sepsis in areas with tropical infections.

Key Recommendations:

1. Location of Care and Transfer
   • When an ICU bed is unavailable, care can be provided in a non-ICU setting if minimum monitoring (neurological status, blood pressure, peripheral perfusion) is ensured.
   • Before transferring a patient, ensure airway patency, initiate intravenous fluids and antimicrobials, and maintain safe transport conditions.
   • Incorporate telemedicine or phone consultation with critical care specialists whenever feasible.
2. Diagnostic Considerations
   • Employ screening tools (e.g., qSOFA) in areas with limited resources, acknowledging its diagnostic constraints.
   • Use clinical parameters like altered mental state, capillary refill time (CRT), and urine output to gauge tissue perfusion when lactate measurement is unavailable.
   • Insert an indwelling urinary catheter in septic shock to monitor urine output accurately, balancing infection risks against close monitoring needs.
3. Hemodynamic Management
   • Rely on clinical indicators (CRT, urine output) to guide fluid resuscitation when serum lactate is not accessible.
   • Use fluid responsiveness tests (e.g., passive leg raising, pulse pressure variation) if advanced hemodynamic monitoring is impractical.
   • Consider balanced solutions such as Ringer’s lactate or Hartmann’s solution for fluid resuscitation.
   • Recognize that patients with tropical infections (e.g., malaria, dengue) may require cautious fluid volumes to avoid overload.
   • Initiate epinephrine if norepinephrine or vasopressin is unavailable, and use vasopressors through peripheral lines if central access cannot be established.
4. Antimicrobial Therapy
   • Administer antibiotics without delay (ideally within one hour) in suspected sepsis or septic shock.
   • In severe infections of parasitic origin (e.g., malaria), start antiparasitic agents promptly.
   • In settings where laboratory investigations are limited, begin broad-spectrum antimicrobial coverage when infection cannot be ruled out.
   • De-escalate or discontinue therapy based on clinical improvement, declining white blood cell counts, and adequate source control.
5. Respiratory Support
   • For acute hypoxemic respiratory failure in septic patients, noninvasive ventilation (NIV) can be used if high-flow nasal oxygen is not available, provided close monitoring for potential failure is ensured.

Conclusion: These consensus-based statements offer practical guidance for clinicians treating sepsis in resource-limited environments. By adapting globally accepted recommendations and incorporating alternative strategies—such as clinical markers of perfusion, use of peripheral vasopressors, and prioritizing immediate antimicrobial therapy—these principles aim to improve patient outcomes where healthcare resources are scarce. Further research and context-specific adaptations will be essential to address remaining uncertainties and refine these expert recommendations.

Reference:
Thwaites, L., Nasa, P., Abbenbroek, B. et al. Management of adult sepsis in resource-limited settings: global expert consensus statements using a Delphi method. Intensive Care Medicine (2024). https://doi.org/10.1007/s00134-024-07735-7

 

---

Review: Chronic Hand Eczema

29 Nov, 2024 | 12:28h | UTC

Introduction: Hand eczema is a highly prevalent inflammatory skin condition and one of the most common work-related disorders, with a lifetime prevalence of approximately 15%. In up to two-thirds of affected individuals, the disease becomes chronic—persisting for more than three months or recurring multiple times within a year—leading to substantial personal and occupational disability. This review by Weidinger and Novak synthesizes current knowledge on the epidemiology, risk factors, clinical features, diagnosis, mechanisms, and management of chronic hand eczema, highlighting the need for further research to enhance prevention and treatment strategies.

Key Recommendations:

1. Risk Factor Identification: Recognize major risk factors, including current or past atopic dermatitis, dry skin, and occupational exposure to irritants and allergens. Occupational history is crucial, as hand eczema is prevalent in high-risk professions such as health care, hairdressing, and cleaning.
2. Diagnosis and Assessment: Diagnose chronic hand eczema based on history and clinical features, considering differential diagnoses like psoriasis and tinea manus. Patch testing is recommended to identify contact allergens, especially in cases unresponsive to initial therapy.
3. Patient Education and Prevention: Implement structured education on skin care, avoidance of trigger factors, and use of protective measures. Emphasize primary to tertiary prevention strategies, including workplace interventions and rehabilitation programs.
4. Topical Therapies: Initiate treatment with topical glucocorticosteroids for anti-inflammatory effect. Use calcineurin inhibitors as second-line therapy, particularly for patients refractory to steroids or requiring long-term treatment. The topical pan-Janus kinase inhibitor delgocitinib is approved for moderate to severe chronic hand eczema unresponsive to corticosteroids.
5. Phototherapy: Consider short-term phototherapy (4–8 weeks) with options like PUVA or narrow-band UVB for patients inadequately controlled with topical treatments.
6. Systemic Therapies: For severe cases unresponsive to topical treatments, systemic retinoids such as alitretinoin are first-line therapy. Off-label use of immunosuppressants like ciclosporine, methotrexate, and azathioprine may be considered. Systemic immunomodulatory therapies approved for atopic dermatitis, including dupilumab and Janus kinase inhibitors, show promise, especially in atopic hand eczema.
7. Adjunctive Measures: Encourage the use of emollients for skin barrier repair and recommend avoidance of harmful exposures. Patient self-management is crucial, including appropriate hand hygiene and use of protective gloves.

Conclusion: By adopting these evidence-based management strategies, clinicians can improve patient care by reducing symptoms, preventing disease progression, and enhancing quality of life for individuals with chronic hand eczema. Early identification of risk factors, comprehensive patient education, and individualized treatment plans are essential to mitigate the substantial personal and socioeconomic burden of this condition.

Reference: Weidinger S, Novak N. Hand eczema. The Lancet. 2024. DOI: http://doi.org/10.1016/S0140-6736(24)01810-5

 

---

RCT: Adjunctive Middle Meningeal Artery Embolization Reduces Reoperation in Subdural Hematoma

24 Nov, 2024 | 13:53h | UTC

Background: Subacute and chronic subdural hematomas are common neurosurgical conditions with a high recurrence rate after surgical evacuation, affecting 8% to 20% of patients. Middle meningeal artery embolization (MMAE) is a minimally invasive procedure targeting the blood supply to these membranes. Preliminary studies suggest that adjunctive MMAE may reduce hematoma recurrence, but its impact on reoperation risk remains unclear.

Objective: To determine whether adjunctive MMAE reduces the risk of hematoma recurrence or progression leading to repeat surgery within 90 days compared to surgery alone in patients with symptomatic subacute or chronic subdural hematoma.

Methods: In this prospective, multicenter, randomized controlled trial, 400 patients aged 18 to 90 years with symptomatic subacute or chronic subdural hematoma requiring surgical evacuation were randomly assigned to receive either MMAE plus surgery (n=197) or surgery alone (n=203). The primary endpoint was hematoma recurrence or progression leading to repeat surgery within 90 days after the index treatment. The secondary endpoint was deterioration of neurologic function at 90 days, assessed using the modified Rankin Scale.

Results: Hematoma recurrence or progression requiring repeat surgery occurred in 8 patients (4.1%) in the MMAE plus surgery group versus 23 patients (11.3%) in the surgery-alone group (relative risk, 0.36; 95% CI, 0.11 to 0.80; P=0.008). Functional deterioration at 90 days was similar between groups (11.9% vs. 9.8%; risk difference, 2.1 percentage points; 95% CI, −4.8 to 8.9). Mortality at 90 days was 5.1% in the MMAE group and 3.0% in the control group. Serious adverse events related to the embolization occurred in 4 patients (2.0%), including disabling stroke in 2 patients.

Conclusions: Adjunctive MMAE combined with surgery significantly reduced the risk of hematoma recurrence or progression requiring reoperation within 90 days compared to surgery alone. However, there was no significant difference in neurologic functional deterioration, and the procedure was associated with procedural risks.

Implications for Practice: MMAE may be considered as an adjunct to surgical evacuation in patients with subacute or chronic subdural hematoma to reduce reoperation risk. Clinicians should carefully weigh the potential benefits against the risks of procedural complications, including stroke.

Study Strengths and Limitations: Strengths include the randomized controlled design and multicenter approach, enhancing generalizability. Limitations involve the open-label design, introducing potential bias since the primary endpoint was based on surgeon judgment. A substantial loss to follow-up (13.2%) could affect results, and the study was not powered to detect differences in mortality or serious adverse events.

Future Research: Further studies with larger sample sizes are needed to fully evaluate the safety and efficacy of MMAE, including long-term outcomes. Research should focus on optimizing patient selection and assessing the procedure’s impact on mortality and serious adverse events.

Reference: Davies JM, et al. Adjunctive Middle Meningeal Artery Embolization for Subdural Hematoma. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMoa2313472

 

---

Cohort Study: Oral Hormone Therapy and Tibolone Increase Cardiovascular Risk in Menopausal Women

28 Nov, 2024 | 18:42h | UTC

Background: Cardiovascular disease is the leading cause of mortality worldwide, with incidence in women increasing notably during the menopausal transition. Menopausal hormone therapy (MHT) effectively alleviates menopausal symptoms but has been associated with cardiovascular risks in previous studies. The impact of contemporary MHT formulations and administration routes on cardiovascular disease risk in women aged 50–58 remains unclear.

Objective: To assess the effect of different types of contemporary MHT on the risk of cardiovascular disease, focusing on various hormone combinations and administration methods.

Methods: This nationwide register-based emulated target trial included 919,614 Swedish women aged 50–58 years between 2007 and 2020 who had not used MHT in the previous two years. Participants were assigned to one of eight treatment groups—including oral and transdermal therapies—or to a non-initiator group. The primary outcomes were hazard ratios (HRs) for venous thromboembolism (VTE), ischemic heart disease (IHD), cerebral infarction, and myocardial infarction, analyzed separately and as a composite cardiovascular disease outcome.

Results: Among the participants, 77,512 were MHT initiators and 842,102 were non-initiators. During follow-up, 24,089 cardiovascular events occurred. In intention-to-treat analyses, tibolone was associated with an increased risk of cardiovascular disease (HR 1.52, 95% CI 1.11 to 2.08) compared with non-initiators. Initiation of tibolone or oral estrogen-progestin therapy was linked to a higher risk of IHD (HRs 1.46 and 1.21, respectively). A higher risk of VTE was observed with oral continuous estrogen-progestin therapy (HR 1.61), sequential therapy (HR 2.00), and estrogen-only therapy (HR 1.57). Per protocol analyses showed that tibolone use was associated with increased risks of cerebral infarction (HR 1.97) and myocardial infarction (HR 1.94).

Conclusions: Use of oral estrogen-progestin therapy was associated with increased risks of IHD and VTE, while tibolone was linked to higher risks of IHD, cerebral infarction, and myocardial infarction but not VTE. These findings underscore the varying cardiovascular risks associated with different MHT types and administration methods.

Implications for Practice: Clinicians should exercise caution when prescribing oral estrogen-progestin therapy or tibolone for menopausal symptom relief, considering the elevated cardiovascular risks. Alternative MHT options, such as transdermal therapies, may offer a safer profile and should be considered.

Study Strengths and Limitations: Strengths include the large, nationwide cohort and the emulated target trial design, which reduces selection bias and confounding. Limitations involve the lack of data on menopausal status, smoking, and body mass index, which may affect cardiovascular risk. Potential misclassification of exposure and adherence could also impact results.

Future Research: Further studies should investigate the cardiovascular effects of specific progestins within MHT formulations and explore the impact of different doses and durations of therapy.

Reference: Johansson T, Karlsson T, Bliuc D, et al. Contemporary menopausal hormone therapy and risk of cardiovascular disease: Swedish nationwide register based emulated target trial. BMJ. 2024;387:e078784. DOI: http://doi.org/10.1136/bmj-2023-078784

 

---

Review: Acute Respiratory Distress Syndrome

28 Nov, 2024 | 13:06h | UTC

Introduction: Acute respiratory distress syndrome (ARDS) is a severe inflammatory lung condition characterized by diffuse alveolar damage, leading to hypoxemia and respiratory failure. Since its initial description in 1967, the understanding and definition of ARDS have significantly evolved, integrating advances in basic science and clinical practice. A newly recommended global definition expands diagnostic criteria to enhance early recognition and management, especially in resource-limited settings. This review summarizes current insights into the epidemiology, pathophysiology, and evidence-based management of ARDS, highlighting key updates and future research priorities.

Key Recommendations:

1. New Global Definition of ARDS: Adoption of an expanded definition that includes patients receiving high-flow nasal oxygen (HFNO) support and allows diagnosis using pulse oximetry and thoracic ultrasonography. This makes ARDS identification feasible in diverse clinical environments, including those with limited resources.
2. Established Critical Care Interventions: Emphasis on early implementation of proven strategies such as low tidal volume ventilation (6 mL/kg predicted body weight) with plateau pressures ≤30 cm H₂O, prone positioning for patients with PaO₂/FiO₂ <150 mm Hg, and conservative fluid management after initial resuscitation. These interventions have consistently reduced mortality and are recommended as standard care.
3. Personalized Approaches and Phenotyping: Recognition of the heterogeneity in ARDS pathophysiology underscores the need for personalized treatment strategies. Identification of hyper-inflammatory and hypo-inflammatory phenotypes may guide targeted therapies and improve outcomes, although prospective validation is required.
4. Impact of COVID-19 on ARDS: Acknowledgment of the significant increase in ARDS incidence due to the COVID-19 pandemic. While COVID-19 ARDS shares similarities with traditional ARDS, notable differences in endothelial dysfunction and immune response highlight the necessity for tailored management approaches in these patients.
5. Pharmacologic Interventions: Updated guidelines provide conditional recommendations for the use of corticosteroids in ARDS, particularly in early moderate to severe cases. Ongoing research into pharmacologic agents such as statins, mesenchymal stromal cells, and other cell-based therapies shows potential but requires further clinical trials to establish efficacy.
6. Future Research Priorities: Identification of key areas for investigation, including the long-term sequelae of ARDS, optimization of non-invasive and invasive ventilation strategies, exploration of genetic and environmental risk factors, and development of rapid biomarker assays for real-time phenotyping and targeted therapy.

Conclusion: The evolving definition and understanding of ARDS aim to improve early detection and standardization of care across various clinical settings. Reinforcing established critical care interventions while advancing personalized and novel therapeutic approaches holds promise for reducing mortality and enhancing long-term patient outcomes. Continuous research into the pathophysiology and management of ARDS, enriched by insights from the COVID-19 pandemic, is essential to address ongoing challenges and improve patient care.

Reference: Wick KD, Ware LB, Matthay MA. Acute respiratory distress syndrome. BMJ. 2024;387:e076612. DOI: http://doi.org/10.1136/bmj-2023-076612

 

---

Review: Management of Degenerative Rotator-Cuff Disorders

28 Nov, 2024 | 12:48h | UTC

---