Daily Respiratory Research Analysis
A randomized crossover trial shows intramuscular naloxone reverses fentanyl-induced apnea more efficiently than intranasal dosing, with immediate implications for overdose response. A 60,042-patient validation demonstrates a multimarker calculator markedly improves short-term mortality risk stratification in acute pulmonary embolism vs ESC guidance. Surveillance and animal transmission studies identify emergent H3N3 avian influenza viruses with human-receptor binding and efficient droplet transm
Summary
A randomized crossover trial shows intramuscular naloxone reverses fentanyl-induced apnea more efficiently than intranasal dosing, with immediate implications for overdose response. A 60,042-patient validation demonstrates a multimarker calculator markedly improves short-term mortality risk stratification in acute pulmonary embolism vs ESC guidance. Surveillance and animal transmission studies identify emergent H3N3 avian influenza viruses with human-receptor binding and efficient droplet transmission in guinea pigs, underscoring zoonotic risk.
Research Themes
- Acute respiratory and overdose therapeutics
- Thromboembolism risk stratification and clinical decision tools
- Zoonotic respiratory viruses and pandemic preparedness
Selected Articles
1. A comparison of intramuscular (Zimhi) and intranasal naloxone (Narcan) in reversal of fentanyl-induced apnea: a randomized, crossover, open-label trial.
In a randomized crossover trial in volunteers, intramuscular naloxone (5 mg) required fewer doses than intranasal naloxone (4 mg) to reverse fentanyl-induced apnea, with no serious adverse events. Findings were consistent in opioid-naïve and chronic opioid users, supporting IM delivery for rapid reversal.
Impact: This trial directly informs overdose response by comparing real-world naloxone products and routes, showing superior effectiveness of IM dosing for restoring breathing. It provides high-quality evidence likely to influence EMS protocols and community naloxone kit recommendations.
Clinical Implications: Overdose response programs and EMS protocols should consider prioritizing IM naloxone for rapid reversal of opioid-induced apnea, while future work evaluates optimized IN formulations/doses. Training and kits may need updating to ensure timely IM access in community settings.
Key Findings
- IM naloxone (5 mg) required fewer doses than IN naloxone (4 mg) to reverse fentanyl-induced apnea (median 1.5 vs 2 doses; p=0.0002) in opioid-naïve participants.
- Efficacy superiority of IM over IN naloxone was also observed in chronic opioid users.
- No serious adverse events occurred; mild-to-moderate withdrawal and muscle rigidity were observed, with rigidity more frequent after IN.
- Rescue IV naloxone was rarely needed (1 participant).
Methodological Strengths
- Randomized crossover design with standardized fentanyl-induced apnea model
- Objective, clinically relevant primary endpoint (return of adequate ventilation) and inclusion of opioid-naïve and chronic users
Limitations
- Open-label design and controlled research-unit setting may limit generalizability to out-of-hospital overdoses
- Sample size is modest, and the exact number in the chronic user cohort is not specified in the abstract
Future Directions: Pragmatic EMS and community-based trials comparing IM vs optimized IN dosing, pharmacokinetic-pharmacodynamic modeling across body types and substances, and implementation studies assessing time-to-ventilation and survival outcomes.
Severe opioid-induced respiratory depression (OIRD) can be treated with intranasal (IN) or intramuscular (IM) naloxone. It is relevant to compare their efficacy and determine the optimal strategy to restore breathing following OIRD. In this open label, crossover, one-on-one randomized trial, conducted in a research unit of an academic medical center, we compared the required number of IM (5 mg/0.5 mL) versus IN (4 mg/0.1 mL) naloxone doses following 10 µg/kg intravenous fentanyl-induced apnea in opioid-naïve participants and participants who chronically use an opioid. After 2 min of apnea, IM or IN naloxone was given at 2 min intervals until return of adequate ventilation. The primary outcome was the number of naloxone doses needed to achieve full reversal of breathing. If necessary, rescue intravenous naloxone was administered. Eighteen opioid-naïve participants were randomized, 16 analyzed. The required median IM naloxone doses were 1.5 (IQR 1-2) versus 2 (1-3) for IN naloxone (p = 0.0002); one participant required rescue naloxone. No serious adverse events occurred. Similarly, in participants who chronically used an opioid, IM was more effective than IN naloxone. In these participants, adverse effects included muscle rigidity in the IN treated participants and mild to moderate withdrawal irrespective of treatment. Here we show the superiority of IM over IN naloxone in the number of doses required for full reversal of breathing following opioid-induced apnea. While the trial shows superiority for IM naloxone with products used in the community, we relate our findings to the higher naloxone plasma concentrations after IM naloxone compared to IN naloxone.
2. Acute pulmonary embolism: a multimarker calculator to predict short-term outcomes.
In 60,042 hemodynamically stable PE patients, a multimarker calculator integrating sPESI, natriuretic peptides, troponin, and concomitant DVT achieved markedly higher discrimination for 30-day mortality than the ESC model (C-statistic 0.79 vs 0.56). At a >10% predicted risk threshold, the calculator tripled the PPV for mortality vs ESC.
Impact: This large validation demonstrates clinically actionable improvement in short-term mortality risk stratification, enabling more precise decisions about monitoring intensity, escalation, and potential reperfusion strategies.
Clinical Implications: Emergency and hospital clinicians can incorporate a multimarker calculator to better identify intermediate-high risk PE patients, potentially improving triage, telemetry/ICU allocation, and timely consideration of reperfusion therapies.
Key Findings
- C-statistic for 30-day mortality: 0.79 for the multimarker calculator vs 0.56 for ESC (P<.001) in 60,042 stable PE patients.
- Improved discrimination was consistent in subsets with RV metrics and troponin (0.78 vs 0.66; P<.001) and after imputation (0.79 vs 0.66; P<.001).
- At a >10% predicted risk threshold, PPV for mortality was 15.7% vs 5.0% for the ESC model (P<.001).
Methodological Strengths
- Very large, prospective registry cohort with rigorous discrimination and calibration analyses
- Incorporates multi-dimensional biomarkers (clinical, cardiac biomarkers, DVT) with consistent performance across subsets
Limitations
- Observational registry design; residual confounding and missing biomarker data necessitated imputation
- Clinical impact (e.g., changes in management and outcomes) was not tested in a randomized implementation trial
Future Directions: Prospective impact and implementation trials integrating the calculator into EHR-driven workflows, decision support, and evaluating patient-centered outcomes and cost-effectiveness.
BACKGROUND AND AIMS: Risk stratification of patients with acute pulmonary embolism (PE) is critical to provide targeted interventions aimed at improving patients' outcomes. The objective of this study was to validate a multimarker prognostic calculator and compare its performance with that of the European Society of Cardiology (ESC) model. METHODS: The multimarker calculator estimates absolute risk of key outcomes for an individual patient based on the individual variables of the simplified Pulmonary Embolism Severity Index, natriuretic peptide levels, troponin levels, and concomitant lower limb deep vein thrombosis. Using data for haemodynamically stable patients with acute PE from the Registro Informatizado de la Enfermedad TromboEmbólica registry, the study compared the performance of the multimarker calculator and the ESC model using measures of discrimination and calibration. The primary outcome was 30-day all-cause mortality. RESULTS: A total of 60 042 stable patients with PE (mean age: 67 years, 51.8% female) were included. Compared with the ESC model, the multimarker calculator provided significant C-statistic improvement in the whole cohort (0.79 vs. 0.56; P < .001), in the group of 16 648 participants with available data for right ventricular function/size and troponin (0.78 vs. 0.66; P < .001), and after imputation of missing data (0.79 vs. 0.66; P < .001). At a calculator estimated risk of >10% to identify intermediate-high risk PE, the positive predictive value for mortality was 15.7% (vs. 5.0% for the ESC model; P < .001). CONCLUSIONS: In stable patients with acute PE, the use of a multimarker calculator substantially improved the risk stratification for mortality beyond that of the ESC model.
3. Characterization of emerging H3N3 avian influenza viruses in poultry in China.
Routine surveillance identified reassortant H3N3 avian influenza viruses in poultry that bind both avian- and human-type receptors. In vivo studies showed efficient replication in chickens, replication in mice, and respiratory droplet transmission in 4/6 viruses in guinea pigs, signaling zoonotic potential.
Impact: By combining genomics, receptor-binding, and mammalian transmission models, this study flags H3N3 strains with features associated with zoonotic risk, informing One Health surveillance and pandemic preparedness.
Clinical Implications: While not immediately changing clinical practice, the findings warrant heightened veterinary and public health surveillance, risk assessment, and pre-emptive countermeasure planning (e.g., candidate vaccine viruses) for H3 lineage threats.
Key Findings
- H3N3 viruses were complex reassortants; chicken/pigeon strains carried genes mainly from H3N8 and H10N3 lineages.
- Chicken/pigeon viruses replicated in multiple organs of chickens with shedding up to 13 days without causing death.
- Six tested viruses bound both avian- and human-type receptors; most of 17 tested replicated efficiently in mice.
- Four of six viruses transmitted efficiently via respiratory droplets in guinea pigs, indicating zoonotic potential.
Methodological Strengths
- Integrated genomic reassortment analysis with receptor-binding assays and multi-species in vivo models
- Assessment of respiratory droplet transmission in guinea pigs strengthens zoonotic risk inference
Limitations
- No human infections studied; ferret transmission/pathogenicity not reported
- Geographically and temporally limited sampling (China, 2022–2023) may not capture wider diversity
Future Directions: Ferret transmission/pathogenicity studies, expanded One Health surveillance across regions, antigenic characterization and candidate vaccine virus selection for H3N3.
Avian influenza viruses continue to challenge poultry and human health; therefore, careful surveillance and evaluation of emerging viruses are important for animal disease control and human influenza pandemic preparedness. In this study, we detected a series of H3N3 subtype avian influenza viruses in chickens, pigeons, and ducks during our routine surveillance and diagnosis between September 2022 and May 2023. We performed extensive analyses to fully understand the origins of these viruses and their risk to animals and humans. We found that the viruses were complex reassortants; the viruses from chickens and pigeons carry genes mainly derived from H3N8 viruses and H10N3 viruses, whereas the two duck viruses were reassortants of duck and wild bird viruses. The chicken and pigeon, but not duck, viruses replicated in multiple organs of chickens and were shed for up to 13 days, but none caused disease or death. Six of the viruses tested all bound to both avian- and human-type receptors. Seventeen viruses were tested in mice and most replicated efficiently but were not lethal. Six viruses were tested in guinea pigs, and four of them transmitted efficiently via respiratory droplets. Our study thus identified novel H3N3 avian influenza viruses and revealed their zoonotic potential, thereby emphasizing the importance of careful monitoring and control of H3 viruses in animals.