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2024 ACC/AHA Guideline for the Management of Lower Extremity Peripheral Artery Disease

21 Jan, 2025 | 12:44h | UTC

Introduction:
This summary highlights key points from the 2024 ACC/AHA guideline on managing patients with lower extremity peripheral artery disease (PAD). It addresses diagnosis, risk stratification, and treatment strategies to reduce major adverse cardiovascular events (MACE) and major adverse limb events (MALE), focusing on four clinical subsets of PAD—asymptomatic PAD, chronic symptomatic PAD, chronic limb-threatening ischemia (CLTI), and acute limb ischemia (ALI). Its overarching goal is to optimize cardiovascular risk reduction, preserve limb function, and improve quality of life (QOL).

Key Recommendations:

Clinical Assessment and Diagnosis
- Perform a thorough history and physical examination in patients at risk of PAD (e.g., older adults, those with diabetes, hypertension, dyslipidemia, smokers, or known atherosclerosis).
- Measure the ankle-brachial index (ABI) to establish the diagnosis of PAD; use toe-brachial index (TBI) for patients with noncompressible arteries.
- Obtain imaging (e.g., duplex ultrasound, CT angiography, MR angiography) when planning revascularization or in cases with inconclusive ABI.
Risk Factor Management (Guideline-Directed Medical Therapy)
- Antiplatelet and Antithrombotic Therapy:
  - Recommend single antiplatelet therapy (e.g., aspirin or clopidogrel) for symptomatic PAD to reduce MACE.
  - Consider low-dose rivaroxaban (2.5 mg twice daily) plus low-dose aspirin in patients at low bleeding risk to reduce MALE.
- Lipid-Lowering Therapy:
  - Initiate high-intensity statin therapy in all patients with PAD to reduce cardiovascular and limb events.
  - Add ezetimibe or a PCSK9 inhibitor if LDL-C levels remain above target (≥70 mg/dL).
- Blood Pressure Control:
  - Target a systolic blood pressure <130 mm Hg in patients with PAD; ACE inhibitors or angiotensin-receptor blockers can further reduce cardiovascular risk.
- Diabetes Management:
  - Optimize glycemic control, especially in CLTI; newer agents (e.g., SGLT2 inhibitors, GLP-1 receptor agonists) can reduce cardiovascular risk in PAD with type 2 diabetes.
- Smoking Cessation:
  - Strongly advise cessation of all forms of tobacco and nicotine; offer pharmacotherapy (e.g., varenicline, bupropion, nicotine replacement) and behavioral counseling.
Exercise Therapy
- Supervised Exercise Therapy (SET):
  - A cornerstone of care for patients with claudication to improve walking performance and quality of life.
  - Generally performed 3 times per week for at least 12 weeks in a supervised setting (e.g., cardiac rehab facility).
- Structured Community-Based (Home-Based) Programs:
  - Include regularly prescribed walking regimens, with periodic clinical follow-up and coaching to promote adherence.
Revascularization for Chronic Symptomatic PAD
- Initial Approach:
  - Offer revascularization (endovascular, surgical, or hybrid) if patients have functionally limiting claudication that fails to improve with medical therapy and structured exercise.
- Endovascular vs. Surgical:
  - Select a strategy based on lesion characteristics, availability of adequate vein conduit, and patient comorbidities.
  - Combining revascularization with supervised exercise generally yields better functional outcomes.
- Common Femoral Disease:
  - Surgical endarterectomy remains a highly durable option.
  - Endovascular approaches can be considered for select cases, particularly where surgical risk is high or anatomy is favorable.
Management of Chronic Limb-Threatening Ischemia (CLTI)
- Team-Based Care:
  - Collaborate with vascular specialists, podiatrists, wound-care experts, and other clinicians for optimal outcomes.
- Revascularization Goals:
  - Prevent amputation, heal wounds, and reduce rest pain.
  - Both endovascular and surgical methods can be effective; selection depends on anatomy, available vein conduit, and patient risk profile (e.g., the BEST-CLI and BASIL-2 trials guide decisions).
- Adjunctive Wound Care:
  - Use local wound management (e.g., debridement, negative pressure therapy, offloading) to facilitate healing.
  - Treat infection aggressively; urgent revascularization plus antibiotics is essential.
- Pressure Offloading:
  - Custom footwear and casts/shoes reduce plantar pressure and help prevent or heal foot ulcers.
Acute Limb Ischemia (ALI)
- Immediate Recognition:
  - Suspect ALI in patients with sudden onset of pain, pallor, pulselessness, paresthesia, and paralysis.
  - Determine limb viability (categories I–III) rapidly.
- Treatment:
  - Begin anticoagulation (e.g., IV unfractionated heparin) unless contraindicated.
  - Urgent revascularization (surgical embolectomy, catheter-directed thrombolysis, or mechanical thrombectomy) for salvageable limbs.
  - Monitor for compartment syndrome and consider fasciotomy if needed.
Preventive Foot Care
- Educate patients on self-inspection, daily hygiene, and protective footwear.
- Screen regularly for high-risk conditions (neuropathy, calluses, deformities, infection).
- Promptly address any foot lesions to avoid progression to ulceration, infection, or gangrene.
Longitudinal Follow-Up
- Schedule regular visits to monitor:
  - Cardiovascular risk factor control (lipids, blood pressure, glycemic targets, smoking).
  - Lower extremity symptoms, functional status, and foot health.
  - Need for repeat ABI, duplex ultrasound, or imaging after revascularization to detect restenosis.
- Reinforce adherence to structured exercise, medication regimens, and foot care strategies.

Conclusion:
These recommendations underscore the importance of personalized, multidisciplinary care that addresses both cardiovascular and limb-related outcomes in patients with lower extremity PAD. A combination of comprehensive risk-factor modification, supervised or structured exercise programs, and strategic use of revascularization can significantly reduce the risk of major limb loss, improve symptoms, and enhance QOL. Ongoing follow-up is critical to detect disease progression, optimize therapy, and maintain patient engagement in preventative care.

Reference:
2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024; DOI: https://doi.org/10.1161/CIR.0000000000001251

Management of Cervical Artery Dissection: Key Points From the AHA Scientific Statement

21 Jan, 2025 | 11:05h | UTC

Introduction:
This document summarizes the American Heart Association (AHA) scientific statement on cervical artery dissection (CAD), an important cause of ischemic stroke, especially in younger and middle-aged adults. Cervical artery dissection often presents with nonspecific symptoms—such as headache, neck pain, or partial Horner syndrome—but can lead to serious neurological deficits. Early recognition, targeted imaging, appropriate acute treatment, and well-informed decisions on antithrombotic therapy are essential to optimize patient outcomes.

Key Recommendations:

Epidemiology and Risk Factors
- CAD accounts for up to 25% of ischemic strokes in adults under 50 years of age, with a slightly higher incidence in men but lower peak age in women.
- Risk factors include genetic predispositions (eg, connective tissue disorders), anatomic variants (elongated styloid process, vascular tortuosity), minor cervical trauma, and comorbidities such as hypertension or fibromuscular dysplasia.
Diagnosis and Imaging
1. Clinical Suspicion
  - Suspect CAD in younger adults with new or worsening neck pain, headache, pulsatile tinnitus, partial Horner syndrome, or cranial nerve involvement, especially if there is a history of recent minor neck trauma or manipulation.
  - Up to 8%–12% of patients may have isolated neck or head pain with no initial ischemic signs.
2. Imaging Modalities
  - Magnetic Resonance Imaging (MRI)/Magnetic Resonance Angiography (MRA): High-resolution, fat-suppressed T1-weighted sequences are useful for detecting intramural hematoma.
  - Computed Tomography Angiography (CTA): Good sensitivity and specificity for luminal abnormalities and can detect intraluminal thrombus. Avoid false positives by distinguishing imaging artifacts from true double lumens or intimal flaps.
  - Conventional Digital Subtraction Angiography (DSA): Historically the gold standard but reserved for equivocal cases because of procedure-related risks (eg, iatrogenic dissection).
  - Ultrasound with Color Doppler: Operator-dependent but helpful for serial follow-up of vessel remodeling.
3. Additional Diagnostic Testing
  - Connective Tissue Disorders: Consider genetic counseling if physical exam, family history, or recurrent dissections suggest a monogenic disorder (eg, vascular Ehlers-Danlos).
  - Screening for Fibromuscular Dysplasia (FMD): Patients with CAD, especially those with hypertension or evidence of FMD in other vascular beds, may warrant renal artery imaging.
  - Aortic and Intracranial Imaging: Aortic root dilation and cerebral aneurysms may be more prevalent in CAD; consider advanced imaging (eg, MRA) based on clinical judgment.
Hyperacute and Acute Stroke Management
1. Intravenous Thrombolysis (IVT):
  - IVT (alteplase or tenecteplase) remains reasonable for otherwise eligible acute ischemic stroke patients, with no specific evidence of higher hemorrhagic risk in CAD. Caution is advised if there is intracranial extension of the dissection or other significant bleeding risk factors.
2. Mechanical Thrombectomy:
  - Recommended for large-vessel occlusion in CAD patients who meet standard thrombectomy criteria. Tandem lesions (extracranial dissection and intracranial occlusion) can be addressed via retrograde (intracranial first) or antegrade (extracranial first) approach, with similar overall outcomes reported.
3. Acute or Subacute Stenting:
  - May be considered in selected cases of severe flow-limiting stenosis leading to distal hypoperfusion or in persistent ischemia despite optimal medical therapy. Stenting in tandem occlusions can improve reperfusion but carries added risks (in-stent restenosis, stent thrombosis, or need for dual antiplatelet therapy).
Antithrombotic Therapy for Secondary Stroke Prevention
1. Rationale for Early Treatment:
  - Artery-to-artery embolization underpins most CAD-related ischemic events. Early initiation of antithrombotics (ideally within the first 24–72 hours) reduces further embolic risk.
2. Choice of Agent: Antiplatelet vs Anticoagulant
  - When to Prefer Anticoagulation:
    - Patients with high-risk imaging features: severe stenosis (>50%–70%), intraluminal thrombus, occlusion, multiple or early recurrent dissections.
    - Traditional option is heparin bridging to Vitamin K antagonist (target INR ≈2–3), but direct oral anticoagulants (DOACs) can be considered based on patient profile and preference.
  - When to Prefer Antiplatelet Therapy:
    - Patients with lower stroke risk (no significant stenosis, no intraluminal thrombus) or higher bleeding risk (large infarct, hemorrhagic transformation, intradural extension).
    - Aspirin monotherapy is typical; a short course of dual antiplatelet therapy (aspirin + clopidogrel) for 21–90 days can be considered if minor stroke/TIA criteria apply and bleeding risk is acceptable.
3. Practical Start-Up and Monitoring:
  - Begin therapy as soon as deemed safe, ideally after hemorrhagic complications are excluded.
  - For VKA: bridge with heparin (IV unfractionated or low–molecular-weight) for at least 5 days until INR is therapeutic for ≥24 hours.
  - Regularly monitor clinical response and, if relevant, INR in anticoagulated patients.
4. Duration of Therapy:
  - Minimum 3–6 months of antithrombotics, with vessel imaging at follow-up (eg, 3 or 6 months) to assess for healing or persistent dissection.
  - Decisions to extend antithrombotic therapy past the 6-month mark may be considered in the context of an individual’s overall vascular risk factor profile and in the context of neuroimaging features as remodeling occurs.
  - Consider extended or indefinite therapy (often antiplatelet) if persistent stenosis, high-risk anatomic factors, or recurrent dissections occur.
Risk of Recurrent Dissection and Lifestyle Precautions
- Recurrence rates range from 1% to 2% per year but are higher in the first few months post-dissection. Fibromuscular dysplasia and younger age are associated with increased recurrence risk.
- It is reasonable to advise patients to avoid high-risk neck activities (eg, contact sports, extreme neck manipulation) for 1–6 months or until imaging confirms vessel healing. In those with a known connective tissue disorder or recurrent dissection, lifelong caution is appropriate.
Follow-Up Imaging and Management of Dissecting Aneurysms
- Recanalization most often occurs by 6–12 months; persistent occlusions or stenoses beyond 12 months rarely recanalize further.
- Dissecting aneurysms form or enlarge in some cases but seldom rupture. Antithrombotic choice does not appear to affect aneurysm resolution rates.
- Endovascular or surgical interventions are reserved for enlarging or symptomatic aneurysms causing compression or other complications.

Conclusion: Cervical artery dissection warrants vigilant clinical recognition, prompt imaging, and individualized treatment strategies. Early antithrombotic therapy—whether anticoagulation or antiplatelet—plays a critical role in preventing stroke. Decisions should reflect both the patient’s hemorrhagic risk and the presence of imaging features predictive of stroke. Mechanical thrombectomy and, in selected cases, stenting are viable acute interventions for high-risk presentations. Although recurrences are uncommon, thoughtful follow-up imaging, patient education, and avoidance of high-risk neck activities are central to minimizing future dissections and optimizing outcomes.

Reference: Yaghi S, Engelter S, Del Brutto VJ, Field TS, Jadhav AP, Kicielinski K, Madsen TE, Mistry EA, Salehi Omran S, Pandey A, Raz E, on behalf of the American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Peripheral Vascular Disease. Treatment and Outcomes of Cervical Artery Dissection in Adults: A Scientific Statement From the American Heart Association. Stroke. 2024;55(3). DOI: https://doi.org/10.1161/STR.0000000000000457

Network Meta-analysis: Oseltamivir Fails to Improve Key Outcomes in Nonsevere Influenza

20 Jan, 2025 | 11:17h | UTC

Background: Influenza causes significant respiratory morbidity and can lead to severe complications, especially in high-risk individuals. Current guidelines endorse antiviral therapy, yet the evidence for reducing mortality, hospital admission, and symptom duration in nonsevere cases remains controversial. Recent recommendations have often focused on neuraminidase inhibitors (e.g., oseltamivir), despite uncertainties regarding clinical impact and adverse effects. An editorial accompanying this study underscores the need to reexamine routine antiviral use, especially oseltamivir, given minimal benefit observed in outpatient populations.

Objective: To assess and compare the efficacy and safety of direct-acting antiviral medications (baloxavir, oseltamivir, laninamivir, zanamivir, peramivir, umifenovir, favipiravir, and amantadine) in treating patients with nonsevere influenza.

Methods: This systematic review and network meta-analysis included 73 randomized clinical trials (N=34,332) that evaluated antivirals vs placebo, standard care, or another antiviral. Eligible studies enrolled nonhospitalized patients with confirmed or suspected influenza. Outcomes included mortality, hospital admission, time to symptom alleviation, adverse events, and emergence of antiviral resistance. Risk of bias was assessed with a modified Cochrane tool, and the certainty of evidence was rated using the GRADE approach. Pooled estimates were generated with a frequentist random-effects model, focusing on both absolute risk differences and relative measures.

Results:

Mortality: Across all antiviral agents, there was high-certainty evidence of little or no effect on mortality in both low-risk and high-risk patients compared with standard care or placebo.
Hospital Admission: In low-risk patients, none of the antivirals significantly altered admission rates (high certainty). In high-risk patients, oseltamivir had little or no effect on hospitalization (high certainty), whereas baloxavir may reduce admissions (low certainty).
Time to Alleviation of Symptoms: Baloxavir shortened symptom duration by approximately one day (moderate certainty) without increasing adverse events. Oseltamivir and zanamivir likely produced smaller decreases (<1 day; moderate certainty). Umifenovir may also shorten symptoms (low certainty).
Adverse Events: Baloxavir did not increase treatment-related adverse events (high certainty) but may lead to viral resistance in around 10% of cases (low certainty). Oseltamivir probably increases adverse events such as nausea and vomiting (moderate certainty).
Serious Outcomes (ICU Admission, Duration of Hospitalization): Data were limited, with uncertainty regarding meaningful reductions in these measures.

Conclusions: Baloxavir may reduce hospital admissions for high-risk patients and significantly shorten symptom duration without notable treatment-related adverse events. Oseltamivir shows little effect on mortality or hospitalization for nonsevere influenza, with only modest (likely not clinically important) reductions in symptom duration and a higher rate of adverse events. Other antivirals either demonstrate uncertain clinical benefits or likely provide no major advantages in this patient population.

Implications for Practice: These findings suggest that routine use of oseltamivir for outpatients with nonsevere influenza should be reconsidered, especially in low-risk groups. Baloxavir appears favorable for high-risk patients, though clinicians should monitor potential drug resistance. Given the minimal impact on major outcomes and the cost considerations, prescribers should weigh the benefits and harms of these antivirals, aligning treatment decisions with patient risk profiles and clinical judgment.

Study Strengths and Limitations: Strengths include a comprehensive search, large pooled population, and rigorous GRADE-based analysis of certainty. Limitations involve low event rates for hospital admissions and mortality, limiting power for certain outcomes, and sparse data on some antivirals (e.g., amantadine). Additionally, few trials reported ICU admissions or mechanical ventilation needs, restricting conclusions about severe complications.

Future Research: Further high-quality studies should evaluate patient-important outcomes such as mechanical ventilation and severe complications in diverse populations. Investigations into combination strategies, alternative dosing, and resistance patterns would help clarify the long-term viability of baloxavir and other antivirals, particularly in high-risk cohorts.

Reference:

Gao Y, Zhao Y, Liu M, et al. Antiviral Medications for Treatment of Nonsevere Influenza: A Systematic Review and Network Meta-Analysis. JAMA Internal Medicine. Published online January 13, 2025. DOI: http://doi.org/10.1001/jamainternmed.2024.7193
Baghdadi JD, Grady D, Morgan DJ. The Limited Role for Antiviral Therapy in Influenza. JAMA Internal Medicine. Published online January 13, 2025. DOI: http://doi.org/10.1001/jamainternmed.2024.7258

Review: Management of Alcohol Withdrawal Syndromes in General Hospital Settings

14 Jan, 2025 | 12:33h | UTC

Introduction:
This summary provides an overview of a state-of-the-art review on identifying, assessing, and treating alcohol withdrawal syndromes among patients in general hospital settings. The rising prevalence of heavy alcohol use—and the sharp increase in hospital admissions for alcohol withdrawal during and after the COVID-19 pandemic—underscores the need for clear, evidence-based guidance. This review addresses the epidemiology, pathophysiology, clinical features, screening tools, and pharmacologic options for managing alcohol withdrawal. It also highlights nutritional considerations and the importance of preventing relapse to reduce readmissions and improve patient outcomes.

Key Recommendations:

Screening and Risk Stratification:
- Use brief, validated questionnaires (eg, Single Alcohol Screening Question or AUDIT-C) to identify at-risk alcohol use.
- Employ biomarker tests (eg, blood alcohol level, PEth, EtG) when possible to confirm recent intake and evaluate heavy use.
- Consider standardized risk scales (eg, PAWSS) to identify patients likely to develop severe withdrawal and guide treatment intensity.
Symptom Severity Assessment:
- Select a validated tool to monitor withdrawal progress (eg, CIWA-Ar).
- For patients with altered mental status or unreliable self-report, consider alternative scales (eg, BAWS or GMAWS) that rely more on objective signs.
Benzodiazepine Therapy:
- Continue to regard benzodiazepines (particularly long-acting agents like diazepam or chlordiazepoxide) as first-line therapy for prevention of seizures and delirium.
- In patients with liver dysfunction or advanced age, short-acting options (eg, lorazepam, oxazepam) may be safer.
- Symptom-triggered regimens can reduce total benzodiazepine exposure in lower-risk patients but require trained staff and structured protocols.
- Fixed-schedule or loading-dose regimens may be warranted in severe withdrawal cases or when symptom-triggered approaches prove insufficient.
Alternative and Adjunctive Pharmacotherapies:
- Phenobarbital: Offers GABA-enhancing and anti-glutamatergic effects, useful in severe or benzodiazepine-resistant withdrawal; consider ICU-level monitoring for high-risk patients.
- Alpha-2 Adrenergic Agonists (clonidine, dexmedetomidine): Adjunctive benefit for persistent autonomic instability (tachycardia, hypertension), but these agents do not prevent seizures or delirium if used alone.
- Antiseizure Medications (eg, carbamazepine, gabapentin, valproate): May aid in mild cases or adjunctively, but current evidence does not support them as stand-alone agents in severe withdrawal.
Nutritional Repletion and Thiamine Replacement:
- Aggressively treat thiamine deficiency (eg, IV thiamine 200–500 mg daily) to prevent or halt Wernicke-Korsakoff syndrome.
- Correct additional deficits (eg, folate, magnesium) for better overall recovery.
Relapse Prevention and Post-Acute Care:
- Initiate FDA-approved medications (eg, naltrexone or acamprosate) during admission to reduce relapse risk after discharge.
- Provide psychosocial support and referral to continuing addiction services (eg, specialty programs, peer support) to sustain recovery efforts.

Conclusion:
Effective management of alcohol withdrawal in hospital settings requires early recognition of at-risk patients, thoughtful risk stratification, and prompt pharmacologic intervention tailored to withdrawal severity and comorbid conditions. Benzodiazepines remain the mainstay therapy, though phenobarbital shows promise, particularly for resistant or severe cases. Adjunctive alpha-2 agonists help control hyperadrenergic symptoms, but do not replace core GABA-targeted therapies. By integrating nutritional repletion, addressing potential complications, and initiating relapse-prevention strategies, clinicians can reduce both the morbidity of acute withdrawal and the likelihood of future hospitalizations related to alcohol use.

Reference:
Kast KA, Sidelnik SA, Nejad SH, Suzuki J. Management of alcohol withdrawal syndromes in general hospital settings. BMJ 2025;388:e080461. https://doi.org/10.1136/bmj-2024-080461

RCT: High-Flow Nasal Oxygen Noninferior to Noninvasive Ventilation for Most Acute Respiratory Failure Causes

13 Jan, 2025 | 13:11h | UTC

Background: Acute respiratory failure (ARF) arises from diverse etiologies and can manifest as hypoxemic or hypercapnic events. High-flow nasal oxygen (HFNO) and noninvasive ventilation (NIV) are common noninvasive respiratory support modalities, but robust comparative data in various ARF subgroups have been limited. Prior research suggests NIV may benefit chronic obstructive pulmonary disease (COPD) exacerbations and acute cardiogenic pulmonary edema (ACPE), yet for hypoxemic failure (including COVID-19 and immunocompromised populations), HFNO is often favored for its comfort and physiological advantages. The RENOVATE trial was designed to assess whether HFNO is noninferior to NIV for preventing intubation or death among five distinct groups of patients with ARF.

Objective: To determine if HFNO is noninferior to NIV in terms of the composite outcome of endotracheal intubation or death within seven days in patients with ARF, categorized into five subgroups: (1) nonimmunocompromised with hypoxemic ARF, (2) immunocompromised with hypoxemic ARF, (3) COPD exacerbation with respiratory acidosis, (4) ACPE, and (5) hypoxemic COVID-19.

Methods: This multicenter, adaptive, noninferiority randomized clinical trial enrolled 1800 hospitalized adults across 33 Brazilian centers. Patients were stratified by ARF etiology and randomized 1:1 to receive either HFNO or NIV. Treatment protocols allowed HFNO escalation to NIV (particularly for COPD or ACPE) if needed. The primary outcome was defined using a Bayesian hierarchical model with dynamic borrowing across subgroups; noninferiority was met if the posterior probability for an odds ratio (OR) below 1.55 reached ≥0.992. Predefined futility and superiority thresholds guided interim analyses, with a maximum sample size of 2000.

Results: Of 1800 randomized patients, 1766 completed the study (mean age 64 years; 40% women). The primary outcome (intubation or death by day 7) occurred in 39.0% (HFNO) vs 38.1% (NIV). HFNO was noninferior in four subgroups:

Nonimmunocompromised with hypoxemia: 32.5% vs 33.1% (OR 1.02; posterior probability of noninferiority 0.999).
COPD exacerbation with respiratory acidosis: 28.6% vs 26.2% (OR 1.05; probability 0.992).
ACPE: 10.3% vs 21.3% (OR 0.97; probability 0.997).
Hypoxemic COVID-19: 51.3% vs 47.0% (OR 1.13; probability 0.997).

The immunocompromised subgroup stopped enrollment early for futility; final results there did not confirm noninferiority (57.1% vs 36.4%; OR 1.07; probability 0.989). No significant differences in 28- or 90-day mortality emerged, although mortality rates were generally higher than in some previous trials. Comfort scores favored HFNO, and rates of serious adverse events were similar between groups.

Conclusions: In four of five ARF subgroups, HFNO met predefined noninferiority criteria compared with NIV regarding endotracheal intubation or death at seven days. However, immunocompromised patients with hypoxemic ARF remain an area of uncertainty, as do smaller subgroups (e.g., COPD) under non-borrowing analyses. Clinicians may consider HFNO as an alternative initial approach, recognizing that rescue NIV may still be necessary, particularly in COPD exacerbations.

Implications for Practice: These findings support using HFNO for a broad range of ARF etiologies as a first-line therapy. HFNO’s ease of use, patient comfort, and comparable safety profile may make it especially appealing. Nevertheless, clinicians should remain vigilant in immunocompromised patients and in COPD exacerbations when hypercapnia is pronounced. Potential cost variations between HFNO and NIV may influence real-world adoption, and local resources, staff expertise, and patient tolerance should guide final decisions.

Study Strengths and Limitations: Strengths include a large, diverse sample and a robust Bayesian adaptive design that allowed dynamic borrowing across subgroups. This approach increased precision but also introduced heterogeneity concerns. Some patient groups (particularly immunocompromised and COPD) were relatively small, limiting definitive conclusions in those strata. Additionally, early stopping for futility in immunocompromised patients curtailed full enrollment, and the trial compared HFNO only with face-mask NIV (rather than alternatives such as helmet CPAP).

Future Research: Further large-scale studies should refine whether HFNO can supplant NIV in COPD exacerbations and immunocompromised populations. Investigations on cost-effectiveness, patient-centered outcomes (comfort, quality of life), and comparative models (e.g., helmet NIV) are also warranted.

Reference:
• RENOVATE Investigators and the BRICNet Authors. High-Flow Nasal Oxygen vs Noninvasive Ventilation in Patients With Acute Respiratory Failure: The RENOVATE Randomized Clinical Trial. JAMA. Published online December 10, 2024. DOI: http://doi.org/10.1001/jama.2024.26244
• Frat JP, Le Pape S, Thille AW. Editorial: Is High-Flow Oxygen the Standard for All Patients With Acute Respiratory Failure? JAMA. Published online December 10, 2024. DOI: http://doi.org/10.1001/jama.2024.25906
• Freund Y, Vromant A. Editorial: Reevaluating Respiratory Support in Acute Respiratory Failure—Insights From the RENOVATE Trial and Implications for Practice. JAMA. Published online December 10, 2024. DOI: http://doi.org/10.1001/jama.2024.25869

Network Meta-Analysis: TMP-SMX May Need Reassessment as First-Line Therapy for PCP in People With HIV

13 Jan, 2025 | 10:25h | UTC

Background: Pneumocystis jirovecii pneumonia (PCP) remains a severe opportunistic infection in people living with HIV (PWH), especially those with low CD4 counts. Trimethoprim–sulfamethoxazole (TMP-SMX) is widely recommended as first-line therapy; however, its toxicity profile can limit use. Alternative regimens such as dapsone–trimethoprim, clindamycin–primaquine, atovaquone, and pentamidine have been explored, but comprehensive comparative data are scarce.

Objective: This systematic review and network meta-analysis aimed to compare the efficacy (treatment failure, mortality) and tolerability (treatment change due to toxicity) of PCP treatment regimens in PWH. The goal was to determine whether TMP-SMX maintains superiority across these outcomes or if alternative regimens offer similar efficacy with improved safety profiles.

Methods: Researchers systematically searched Embase, Medline, and CENTRAL (inception through 3 February 2024) for randomized controlled trials (RCTs) comparing at least two PCP treatment regimens in PWH. Independent reviewers screened titles/abstracts and performed full-text reviews. Data extraction included population demographics, treatment arms, outcomes (treatment failure, all-cause mortality, treatment change), and risk-of-bias assessments using the Cochrane Risk-of-Bias 2 tool. A network meta-analysis using a frequentist random-effects model was performed to integrate direct and indirect comparisons, estimating relative treatment effects (risk ratios with 95% confidence intervals) and generating rankings via the surface under the cumulative ranking curve (SUCRA).

Results: Fourteen RCTs (1983–1996) with 1,788 participants across 27 treatment arms were included. No regimen demonstrated significant superiority over TMP-SMX in direct comparisons, although TMP-SMX outperformed atovaquone and trimetrexate plus folinic acid in reducing treatment failure. In the network analysis, clindamycin–primaquine, intravenous pentamidine, and TMP-SMX all had favorable SUCRA values for preventing treatment failure. For all-cause mortality, dapsone–trimethoprim and intravenous pentamidine ranked highest, while TMP-SMX was better than atovaquone in direct comparison. Notably, for tolerability, all alternative regimens tended to be safer than TMP-SMX, which ranked worst for toxicity. Inhaled pentamidine, trimetrexate plus folinic acid, and atovaquone were the best-tolerated therapies.

Conclusions: These findings suggest that TMP-SMX, although commonly used, might not be universally superior to all other regimens when balancing efficacy and safety in PWH with PCP. When the risk of renal or hematologic complications is high, considering clindamycin–primaquine or intravenous pentamidine may provide comparable efficacy with a more favorable safety profile. Inhaled pentamidine or atovaquone may offer good tolerability but should be carefully assessed for efficacy in moderate-to-severe disease.

Implications for Practice: When managing PCP in PWH, TMP-SMX may not always be the ideal standalone first-line choice, especially in patients at high risk for renal or hematologic complications. Clindamycin–primaquine and intravenous pentamidine could represent viable alternatives for clinicians seeking to balance efficacy with improved safety. Inhaled pentamidine or atovaquone may offer strong tolerability but should be carefully evaluated for their effectiveness in moderate-to-severe disease.

Study Strengths and Limitations: Strengths include a robust search strategy, strict inclusion criteria of RCTs, and the use of a network meta-analysis to integrate direct and indirect comparisons. Limitations involve the older timeframe of the included trials (most conducted before the modern ART era) and heterogeneous definitions of treatment failure, which may limit generalizability to broader contemporary clinical settings. Women and other high-risk populations were underrepresented, presenting another limitation.

Future Research: Contemporary RCTs should address the optimal dose and duration of TMP-SMX and alternative agents, include underrepresented groups (women, older adults, patients with renal impairment), and consider modern management of HIV and critical care practices. Ongoing investigations of novel agents like rezafungin may further refine first-line PCP treatment strategies.

Reference: Hatzl S, Posch F, Scholz L, … Bassetti M, Hoenigl M, Krause R. Comparative efficacy and safety of treatment regimens for Pneumocystis jirovecii pneumonia in people living with HIV: a systematic review and network meta-analysis of randomized controlled trials. Clinical Microbiology and Infection, Published online December 26, 2024. DOI: http://doi.org/10.1016/j.cmi.2024.12.024

2024 Focused Guideline Update on Corticosteroid Use in Sepsis, ARDS, and Community-Acquired Pneumonia

13 Jan, 2025 | 11:04h | UTC

Introduction: This summary presents the key points from a 2024 focused update of the guidelines on corticosteroid use for hospitalized adult patients with sepsis, acute respiratory distress syndrome (ARDS), and community-acquired pneumonia (CAP). Developed by a panel of international experts in critical care, endocrinology, and methodology, the update aims to incorporate new evidence into recommendations regarding dosage, duration, and timing of corticosteroid therapy. Pediatric-specific recommendations could not be made due to limited data.

Key Recommendations:

Sepsis and Septic Shock
- Conditional Recommendation: In adult patients with septic shock requiring vasopressor support, the panel suggests administering corticosteroids (typically hydrocortisone 200–300 mg/day IV for about 5–7 days, with or without fludrocortisone).
- Strong Recommendation Against High Dose/Short Duration: High-dose corticosteroids (> 400 mg/day hydrocortisone equivalent given for fewer than 3 days) are not recommended, as they confer increased risk of adverse effects without demonstrating benefit.
Acute Respiratory Distress Syndrome (ARDS)
- Conditional Recommendation: In adult patients hospitalized with ARDS (including those with COVID-19 ARDS), the panel suggests using corticosteroids (e.g., methylprednisolone, dexamethasone, or hydrocortisone) to lower short-term mortality and potentially reduce duration of mechanical ventilation. No specific agent or dosing regimen is mandated; choices should be guided by clinical judgment and patient context.
Community-Acquired Pneumonia (CAP)
- Strong Recommendation (Severe CAP): In adults hospitalized with severe bacterial CAP, the panel recommends corticosteroids (commonly moderate-dose IV hydrocortisone or methylprednisolone for 5–7 days). Recent data indicate a clear mortality benefit in these high-risk patients.
- No Recommendation (Less Severe CAP): For adults with less severe bacterial CAP, current evidence is inconclusive regarding mortality benefit. Although some findings suggest improvements in certain outcomes, the panel reached no consensus on whether corticosteroids should be routinely administered.

Conclusion: These updated guidelines emphasize the overall safety and potential survival benefits of corticosteroids in specific populations with critical illness, particularly those with septic shock, ARDS, or severe CAP. For each condition, the recommendations balance desirable effects—such as reduced mortality, organ dysfunction, and length of hospital stay—against possible harms, including hyperglycemia and neuromuscular weakness. Evidence remains insufficient to support pediatric guidance or clarify whether less severe CAP consistently merits treatment. Future research should address optimal dosing strategies, pediatric outcomes, long-term adverse effects, and potential cost-effectiveness across diverse healthcare settings.

Reference:
Chaudhuri, Dipayan MD, MSc, FRCPC, et al. 2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia. Critical Care Medicine 52(5): e219–e233, May 2024. DOI: http://dx.doi.org/10.1097/CCM.0000000000006172

Review: Heart Failure with Preserved Ejection Fraction

9 Jan, 2025 | 11:42h | UTC

Introduction: This summary reviews the 2025 New England Journal of Medicine article by Antonio Cannata, M.D., and Theresa A. McDonagh, M.D., which addresses the clinical syndrome of heart failure with preserved ejection fraction (HFpEF). The document describes its heterogeneous nature, diagnostic challenges, and emerging therapeutic approaches. Key objectives include emphasizing the importance of ruling out mimickers (e.g., respiratory disease or amyloidosis) and reviewing the evidence for guideline-directed therapies that reduce hospitalizations and improve quality of life.

Key Recommendations:

Diagnostic Steps:
- Confirm an ejection fraction ≥50% and evidence of diastolic dysfunction or raised filling pressures.
- Exclude confounding conditions (e.g., COPD, hypertrophic cardiomyopathy, cardiac amyloidosis) through imaging (echocardiography, cardiac MRI) and relevant laboratory tests (natriuretic peptides).
- Consider invasive hemodynamic assessment if the diagnosis remains unclear.
Initial Management:
1. Diuretics: Use loop diuretics or thiazides to relieve congestion and peripheral edema. Titrate to the lowest effective dose once euvolemia is achieved.
2. Blood Pressure and Comorbidity Control: Optimize antihypertensive therapy with agents such as renin–angiotensin–system (RAS) inhibitors or mineralocorticoid receptor antagonists (MRAs) to address underlying hypertension and other cardiovascular risk factors.
Specific Pharmacotherapies:
- SGLT2 Inhibitors: Empagliflozin and dapagliflozin reduce the composite risk of cardiovascular death or heart-failure hospitalization, primarily by lowering hospitalization rates.
- RAS Blockade (ACE Inhibitors/ARBs/ARNIs): Although large trials did not show a clear mortality benefit, some studies indicated fewer hospitalizations.
- MRAs (e.g., Spironolactone, Finerenone): Evidence for HFpEF is mixed, though a recent trial (FINEARTS-HF) supports the potential role of finerenone in reducing hospitalization in patients with left ventricular ejection fraction ≥40%.
- GLP-1 Receptor Agonists: Agents like semaglutide (and the dual GIP/GLP-1 agonist tirzepatide) showed improvements in weight reduction, exercise tolerance, and quality of life in patients with HFpEF and obesity, suggesting an emerging cardiometabolic strategy.
- Beta-Blockers: Widespread use in HFpEF often relates to other comorbidities, but trials have not demonstrated significant outcome benefits specifically for preserved ejection fraction.
Adjunct Therapies and Devices:
- Pulmonary Artery Pressure Monitoring (CardioMEMS): Can help guide diuretic adjustments and has shown reductions in hospitalizations for heart failure across ejection-fraction ranges.
- Interatrial Shunt Devices: Trials so far have not shown conclusive benefits and may pose increased risk in patients with higher ejection fractions.
Lifestyle and Comorbidity Management:
- Address obesity, type 2 diabetes, and physical inactivity through dietary and exercise interventions.
- Evaluate for sleep-disordered breathing, as optimizing respiratory status can improve symptoms and reduce hospitalizations.

Conclusion: HFpEF is a complex syndrome often associated with obesity, hypertension, and other coexisting conditions that contribute to clinical variability. While no single agent has definitively reduced mortality, trials have shown meaningful reductions in hospitalizations and improvements in quality of life, especially with SGLT2 inhibitors and, in obese patients, GLP-1 receptor agonists. Ongoing research into pathophysiology-driven therapies may enhance future outcomes. For now, clinicians should employ a multimodal approach targeting volume status, cardiometabolic health, and comorbidity control to optimize management.

Reference:
Cannata A, McDonagh TA. Heart Failure with Preserved Ejection Fraction. New England Journal of Medicine. 2025;392:173–184.
DOI: https://doi.org/10.1056/NEJMcp2305181

Meta-Analysis: Tailored Hydration Strategies Decrease CI-AKI and MACE in Coronary Angiography

6 Jan, 2025 | 13:00h | UTC

Background: Contrast-induced acute kidney injury (CI-AKI) poses a considerable burden on patients undergoing coronary angiography or percutaneous coronary intervention (PCI). Beyond the direct tubular toxicity of iodine contrast, several risk factors, including chronic kidney disease (CKD) and hemodynamic instability, further increase the likelihood of renal damage. Although guideline-based prevention strategies recommend peri-procedural intravenous hydration, the optimal volume and method remain unclear.

Objective: This meta-analysis aimed to determine whether patient-tailored intravenous fluid administration (using parameters other than body weight alone) can reduce the incidence of CI-AKI, as well as major adverse cardiovascular events (MACE), compared with conventional non-tailored hydration protocols in patients undergoing coronary angiography and/or PCI.

Methods: A systematic review of randomized controlled trials (RCTs) was performed, including 13 studies and 4,458 participants. Tailored hydration strategies encompassed left ventricular end-diastolic pressure (LVEDP)-guided infusion, diuresis-driven matched replacement (RenalGuard®), bioimpedance vector analysis, central venous pressure, or inferior vena cava ultrasound measurements. These were compared against standard non-tailored fluid protocols. The primary outcome was CI-AKI (variously defined but measured within 7 days), and secondary outcomes included MACE, all-cause mortality, and renal replacement therapy (RRT).

Results: Across 12 RCTs (n=3,669), tailored hydration significantly reduced CI-AKI rates (risk ratio 0.56, 95% CI [0.46–0.69], p<0.00001; I²=26%). Ten studies (n=3,377) revealed lower MACE incidence in the tailored hydration arm (RR=0.57, 95% CI [0.42–0.78], p=0.0005; I²=12%). A significant reduction in all-cause mortality (RR=0.57, 95% CI [0.35–0.94], p=0.03) and RRT requirement (RR=0.51, 95% CI [0.29–0.89], p=0.02) was also observed, with no significant increase in pulmonary edema. Subgroup analyses (e.g., CKD) supported the overall benefit of individualizing fluid regimens.

Conclusions: Tailored hydration strategies appear superior to standard approaches in lowering the risk of CI-AKI, MACE, mortality, and RRT after coronary angiography or PCI. Although LVEDP-guided protocols are simple to implement and effective, the RenalGuard® system may offer additional benefits in selected populations, albeit at higher cost and complexity.

Implications for Practice: Clinicians should consider personalized hydration based on physiological or hemodynamic parameters to optimize fluid volume, reduce renal injury, and potentially improve clinical outcomes. Nevertheless, practical challenges include access to specialized equipment and the need for close monitoring in some techniques.

Study Strengths and Limitations: This systematic review highlights consistent treatment effects across diverse RCTs and methods. However, potential biases due to lack of blinding, varying CI-AKI definitions, and limited head-to-head comparisons among tailored approaches constrain definitive conclusions. The small sample size of certain studies and underpowered subgroup analyses also limit the generalizability of findings.

Future Research: Further large-scale trials are warranted to compare various tailored protocols directly, focusing on cost-effectiveness, ease of implementation, and patient-centered endpoints. Ongoing investigations, such as the NEPTUNE trial, aim to clarify whether combining multiple parameters (like LVEDP and contrast volume/eGFR ratio) yields optimal renal protection.

Reference: Cossette F, Trifan A, Prévost-Marcotte G, et al. Tailored Hydration for the Prevention of Contrast-Induced Acute Kidney Injury After Coronary Angiogram or PCI: A Systematic Review and Meta-Analysis. American Heart Journal. Published online January 4, 2025. DOI: http://doi.org/10.1016/j.ahj.2025.01.002

Meta-analysis: Therapeutic-Dose Heparin Improves 28-Day Mortality in COVID-19 Hospitalized Patients

6 Jan, 2025 | 12:00h | UTC

Background: High rates of thrombotic events and systemic inflammation among COVID-19 hospitalized patients led researchers to test whether intensified anticoagulation strategies could reduce morbidity and mortality. Previous trials yielded conflicting results, partly due to varying doses of anticoagulants—prophylactic, intermediate, or therapeutic—and heterogeneous patient severity. This comprehensive investigation, conducted by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, aimed to clarify the benefits and risks of escalated anticoagulation dosing in patients hospitalized for COVID-19.

Objective: To estimate whether higher-dose anticoagulation (therapeutic or intermediate) improves 28-day all-cause mortality compared with lower-dose anticoagulation (prophylactic or intermediate), and to evaluate secondary outcomes, including progression to mechanical ventilation, thromboembolic events, and major bleeding.

Methods: This prospective meta-analysis included randomized trials comparing higher- versus lower-dose anticoagulation for hospitalized COVID-19 patients. Investigators collected trial-level summary data, focusing primarily on heparins. Dosing categories—therapeutic, intermediate, and prophylactic—were predefined. The main outcome was 28-day mortality; secondary outcomes included progression to invasive mechanical ventilation (IMV), venous or arterial thrombotic events, and major hemorrhage. Data were analyzed using a fixed-effects model, with odds ratios (ORs) pooled across trials.

Results: Overall, 22 trials (over 11 000 total participants) contributed data, primarily evaluating heparins. For therapeutic versus prophylactic-dose heparin, 28-day mortality was significantly reduced (OR, 0.77; 95% CI, 0.64–0.93), especially among patients requiring low-flow oxygen or no supplemental oxygen. Therapeutic dose reduced thromboembolic events (OR 0.48; 95% CI, 0.36-0.64) but increased major bleeding (OR 1.90; 95% CI, 1.19-3.05) compared to prophylactic dose. In contrast, when therapeutic was compared to intermediate-dose heparin, the summary OR for 28-day mortality was 1.21 (CI, 0.93–1.58), suggesting a potential trend toward higher mortality that did not reach statistical significance. Intermediate versus prophylactic-dose comparisons revealed no conclusive mortality difference (OR, 0.95; CI, 0.76–1.19). Across all higher-dose arms, thromboembolic events decreased, while the risk of major bleeding increased, underscoring the delicate risk–benefit balance. Subgroup analyses by respiratory support level, D-dimer, and baseline severity did not indicate strong interaction effects, although sample sizes were limited in more severe illness subgroups.

Conclusions: Therapeutic-dose heparin reduces 28-day mortality relative to prophylactic-dose in hospitalized patients with COVID-19, mainly among those not requiring invasive ventilation. Mortality was similar or potentially worse when therapeutic was compared to intermediate-dose. Clinicians must weigh the lower rate of thrombotic complications against the higher bleeding risk, particularly in critically ill patients.

Implications for Practice: Although higher anticoagulant dosing appears beneficial for certain hospitalized COVID-19 patients, especially those with mild to moderate respiratory compromise, individualized assessment remains key. Current guidelines broadly recommend prophylactic dosing for the critically ill and suggest considering higher doses only in carefully selected patients. Evolving viral variants and changes in standard of care further complicate direct application of these findings to present-day hospital settings.

Study Strengths and Limitations: Strengths include prospective planning, collaboration with multiple trials, and a large pooled sample. Limitations encompass heterogeneity in dose definitions, partial reliance on published data where individual-level parameters could not be fully harmonized, and potential temporal changes in COVID-19 clinical profiles. Moreover, bleeding severity beyond major hemorrhage was not universally reported, limiting robust safety assessments.

Future Research: Further studies should focus on individualized anticoagulant strategies that consider biomarkers (for example, D-dimer) and evolving treatment protocols. Investigations examining optimal timing, duration, and post-discharge management will help refine anticoagulation practices.

Reference:

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Anticoagulation Among Patients Hospitalized for COVID-19: A Systematic Review and Prospective Meta-analysis. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-00800

Shappell CN, Anesi GL. Anticoagulation for COVID-19: Seeking Clarity and Finding Yet More Gray. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-03244

Avian Influenza A(H5N1) Outbreak Among US Farm Exposures: Clinical Findings and Early Treatment Outcomes

2 Jan, 2025 | 17:01h | UTC

Background: Highly pathogenic avian influenza A(H5N1) has reemerged in the United States with documented infections in poultry and dairy cows since 2021. From March through October 2024, 46 human cases were identified, most of whom were workers engaged in poultry depopulation or dairy-farm activities where infected or presumably infected animals were present.

Objective: To characterize the clinical presentations, exposure settings, and outcomes of individuals with laboratory-confirmed H5N1 infection and to investigate potential routes of transmission, disease severity, and risk to public health.

Methods: Using a standardized case-report form, data were collected on exposure history, symptom onset, and use of personal protective equipment (PPE). Respiratory and conjunctival swabs from symptomatic persons underwent real-time RT-PCR for H5 subtyping at both state laboratories and the Centers for Disease Control and Prevention (CDC). Genetic sequencing was performed on available samples. Investigators also monitored close household contacts to evaluate the risk of secondary transmission. An additional hospitalized patient with no identifiable exposure source was detected through routine influenza surveillance.

Results: Of the 46 adult case patients, 20 were exposed to infected poultry, 25 to infected or presumably infected dairy cows, and 1 had unknown exposure. Among the 45 occupationally exposed patients, illness was mild, with no hospitalizations or deaths. Conjunctivitis was present in 93% of cases; 49% reported fever, and 36% had respiratory symptoms. Fifteen patients had only conjunctivitis, highlighting the utility of conjunctival specimens for detection. Early antiviral therapy with oseltamivir was common, initiated at a median of two days after symptom onset. No additional cases were found among 97 closely monitored household contacts, indicating no evidence of sustained human-to-human transmission. Genetic analyses revealed clade 2.3.4.4b viruses, with some genotypic differences between poultry-related (D1.1 genotype) and cow-related (B3.13 genotype) infections.

Conclusions: In this observational study, H5N1 infections in US adults were generally mild, self-limited, and predominantly associated with conjunctivitis. The absence of critical illness or fatalities contrasts with historical reports of more severe H5N1 disease. Although no ongoing person-to-person transmission was documented, continued vigilance is warranted, given the virus’s potential for rapid adaptation.

Implications for Practice: Occupational health measures, such as consistent PPE use (especially eye protection), timely surveillance, and prompt antiviral treatment, may reduce the impact of H5N1 infections among exposed workers. Clinicians should consider conjunctival sampling for symptomatic patients with relevant animal contact. Policy efforts should focus on improving biosecurity practices in both poultry and dairy settings.

Study Strengths and Limitations: Strengths include systematic surveillance, robust laboratory testing of both respiratory and conjunctival specimens, and early antiviral administration. Limitations involve possible underreporting of mild or asymptomatic cases, incomplete details on exposure duration, and limited data on specific routes of cow-to-human transmission.

Future Research: Further studies should explore viral evolution in cows, the significance of raw milk as a transmission vehicle, and the potential for more severe infections, as highlighted by sporadic reports of severe H5N1 illness worldwide.

Reference: Garg S, Reinhart K, Couture A, Kniss K, Davis CT, Kirby MK, Murray EL, et al. Highly Pathogenic Avian Influenza A(H5N1) Virus Infections in Humans. New England Journal of Medicine. Published December 31, 2024. Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2414610

Editorial: Ison MG, Marrazzo J. The Emerging Threat of H5N1 to Human Health. New England Journal of Medicine. Published December 31, 2024. Link: https://www.nejm.org/doi/full/10.1056/NEJMe2416323

AGA Clinical Practice Update on Managing Portal Vein Thrombosis in Cirrhotic Patients: Expert Review

3 Jan, 2025 | 10:00h | UTC

Introduction: This summary highlights key recommendations from an AGA expert review on portal vein thrombosis (PVT) in cirrhotic patients. PVT is common in cirrhosis, with an estimated five-year incidence of around 11%, and may worsen portal hypertension and elevate mortality. Management is challenging because of limited evidence, the potential complications of both PVT and anticoagulation, and significant heterogeneity regarding clot characteristics, host factors, and cirrhosis severity. This review presents the latest guidance on identifying clinically relevant PVT, selecting anticoagulation, and considering endovascular interventions, including TIPS (transjugular intrahepatic portosystemic shunt).

Key Recommendations:

No Routine Screening: Asymptomatic patients with compensated cirrhosis do not require regular screening for PVT in the absence of suggestive clinical changes.
Imaging Confirmation: When Doppler ultrasound reveals suspected PVT, contrast-enhanced CT or MRI is recommended to confirm the diagnosis, exclude malignancy, and characterize clot extent and occlusion.
Hypercoagulability Testing: Extensive thrombophilia workup is not indicated unless there is family or personal history of thrombotic events, or associated laboratory abnormalities.
Intestinal Ischemia Management: Patients who develop PVT with evidence of intestinal ischemia should receive prompt anticoagulation and, ideally, multidisciplinary team care involving gastroenterology, hepatology, interventional radiology, hematology, and surgery.
Observation of Minor or Recent Thrombi: In cirrhotic patients without ischemia, with recent (<6 months) thrombi that are <50% occlusive, close imaging follow-up every three months is a reasonable option to track potential spontaneous clot regression.
Anticoagulation for Significant PVT: Consider anticoagulation for more extensive or obstructive (>50%) recent PVT, especially if the main portal vein or mesenteric vessels are involved. Candidates for liver transplantation and those with inherited thrombophilia may derive additional benefit.
Chronic Cavernous PVT: Anticoagulation is generally not advised in patients with long-standing (>6 months) complete occlusion and well-formed collateral channels.
Variceal Screening: Perform endoscopic screening or ensure prophylaxis for varices. Avoid delays in initiating anticoagulation, as timeliness is essential for better recanalization outcomes.
Choice of Anticoagulant: Vitamin K antagonists, low-molecular-weight heparin, and direct oral anticoagulants (DOACs) are all viable options in cirrhosis. DOACs may be appropriate in well-compensated (Child-Turcotte-Pugh class A or certain class B) cirrhosis but should be avoided in class C. Treatment selection should consider patient preferences, monitoring feasibility, and risk of bleeding.
Duration of Therapy: Reassess clot status with cross-sectional imaging every three months. Continue anticoagulation for transplant-eligible individuals who show partial or complete recanalization, and consider discontinuation in nonresponders after six months if futility is evident.
TIPS Revascularization: Portal vein revascularization using TIPS may be pursued in patients who have other TIPS indications (like refractory ascites or variceal bleeding) or to improve transplant feasibility by recanalizing portal flow.

Conclusion: PVT in cirrhosis remains a complex clinical issue requiring careful evaluation of clot extent, timing, and the potential need for transplantation. The recommendations presented here underscore prompt imaging, timely anticoagulation for high-risk thrombi, and individualized therapy based on Child-Turcotte-Pugh classification and bleeding risk. When necessary, multidisciplinary collaboration is key to achieving optimal patient outcomes. Prospective randomized trials and standardized classifications of PVT will be instrumental in refining future guidelines.

Reference:
Davis JPE, Lim JK, Francis FF, Ahn J. AGA Clinical Practice Update on Management of Portal Vein Thrombosis in Patients With Cirrhosis: Expert Review. Gastroenterology. 2024. DOI: http://doi.org/10.1053/j.gastro.2024.10.038

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

26 Dec, 2024 | 02:06h | 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:

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.
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.
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.
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.
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

Bayesian Network Meta-Analysis: Chlorpromazine IV/IM Emerges as a Top Choice for Acute Migraine Relief in the ED

25 Dec, 2024 | 11:18h | UTC

Background: Acute migraine is a prevalent cause of emergency department (ED) visits, necessitating prompt pain control. Although numerous drugs are available, there is debate about the most effective and safest options. Traditional pairwise meta-analyses fail to capture all treatment comparisons in a single framework, making network meta-analyses, particularly Bayesian, an appealing approach to inform clinical decision-making.

Objective: This systematic review and Bayesian network meta-analysis aimed to compare multiple pharmacologic therapies—single agents or combinations—for acute migraine relief in adults presenting to the ED. The goal was to identify those most likely to achieve adequate pain relief, reduce rescue medication use, and minimize significant adverse reactions.

Methods: The authors searched MEDLINE, Embase, and Web of Science from inception to February 9, 2024, for randomized controlled trials comparing any pharmacologic therapy to another or to placebo in ED patients with migraine. Four primary outcomes were analyzed: (1) adequate pain relief at two hours, (2) change in pain intensity at one hour, (3) need for rescue drug at two hours, and (4) significant adverse reaction (eg, sedation, akathisia, hypotension).

Results: Twenty-four to twenty-seven trials contributed to each outcome network. Chlorpromazine IV/IM was ranked highest for adequate pain relief (SUCRA=87.3%) and also significantly reduced the need for rescue medication (SUCRA=93.2%). Ibuprofen IV and valproate IV emerged among the least effective for pain relief, while dexamethasone IV was the most probable to cause fewer serious adverse reactions (SUCRA=79.5%). However, most comparisons were of low or very low certainty, limiting the strength of the findings.

Conclusions: Chlorpromazine IV/IM appears among the most effective single agents for acute migraine in the ED, although it may carry higher risks of sedation or hypotension. Certain analgesics (eg, ibuprofen IV, valproate IV, and possibly ketorolac IV/IM) demonstrated lower efficacy. Due to variability in trial size, dosing, and participant characteristics, the overall certainty of evidence remains limited.

Implications for Practice: Clinicians may consider parenteral chlorpromazine for rapid migraine relief, balancing its adverse event profile with potential efficacy. Dexamethasone’s lower probability of serious side effects could make it a complementary option. The findings highlight the need for individualized treatment, taking into account patient comorbidities and preferences.

Study Strengths and Limitations: This network meta-analysis offers a broad comparative perspective on diverse pharmacologic interventions for ED-based migraine management. Nonetheless, there is notable heterogeneity in study methodologies, small sample sizes, and sparse direct comparisons for many interventions, all of which reduce certainty in the estimates.

Future Research: Larger, more standardized trials are needed to confirm these results and directly compare drugs like chlorpromazine, prochlorperazine, and metoclopramide-NSAID combinations. Rigorous safety reporting is crucial to clarify adverse reaction risks for various agents, especially those with less available evidence.

Reference: deSouza IS, Anthony N, Thode H Jr, et al. Effectiveness and Safety of Pharmacologic Therapies for Migraine in the Emergency Department: A Systematic Review and Bayesian Network Meta-analysis. Annals of Emergency Medicine. DOI: http://doi.org/10.1016/j.annemergmed.2024.11.004

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

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

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:

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.
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.
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.
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.
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.
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.
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.
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

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:

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.
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.
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.
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

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

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

24 Dec, 2024 | 13:35h | UTC

Key Recommendations:

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.
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.
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.
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.
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.

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

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:

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.
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.
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.
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.
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.
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

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