Daily Anesthesiology Research Analysis
Three studies with immediate relevance to anesthesiology and perioperative care stood out today. A randomized crossover trial in Nature Communications shows intramuscular naloxone reverses fentanyl-induced apnea with fewer doses than intranasal naloxone. A JAMA Network Open crossover RCT demonstrates preoxygenation using bag-valve mask with PEEP outperforms nonrebreather across adults (normal weight and overweight/obese) and children, while a mechanistic study in Advanced Science identifies NOX2
Summary
Three studies with immediate relevance to anesthesiology and perioperative care stood out today. A randomized crossover trial in Nature Communications shows intramuscular naloxone reverses fentanyl-induced apnea with fewer doses than intranasal naloxone. A JAMA Network Open crossover RCT demonstrates preoxygenation using bag-valve mask with PEEP outperforms nonrebreather across adults (normal weight and overweight/obese) and children, while a mechanistic study in Advanced Science identifies NOX2-driven ROS signaling as a key mediator of ventilator-induced lung injury that is mitigated by quercetin.
Research Themes
- Opioid overdose reversal strategies in anesthesiology and emergency settings
- Optimizing airway preoxygenation with PEEP across diverse patient groups
- Mechanistic targets (NOX2/ROS-CaMKII-ERK1/2) and antioxidant intervention in ventilator-induced lung injury
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, intramuscular naloxone (5 mg) reversed fentanyl-induced apnea with fewer doses than intranasal naloxone (4 mg) in opioid-naïve participants, with similar superiority in chronic opioid users. No serious adverse events occurred; adverse effects included transient rigidity with IN and mild–moderate withdrawal.
Impact: Findings directly inform first-line community and clinical overdose response, suggesting IM formulations may restore breathing faster and more reliably than IN in severe OIRD.
Clinical Implications: For suspected fentanyl-related apnea, prioritize IM naloxone when available, anticipate fewer repeat doses, and monitor for withdrawal. IN remains valuable where IM access is limited, but additional doses may be required.
Key Findings
- IM naloxone required fewer doses than IN to reverse fentanyl-induced apnea (median 1.5 vs 2; p=0.0002).
- Superiority of IM over IN was also observed in chronic opioid users.
- No serious adverse events; transient rigidity occurred with IN and mild–moderate withdrawal in both groups.
- Rescue IV naloxone was rarely needed.
Methodological Strengths
- Randomized crossover design controlling inter-individual variability.
- Standardized fentanyl-induced apnea model with predefined dosing intervals; inclusion of opioid-naïve and opioid-tolerant cohorts.
Limitations
- Open-label design may introduce performance bias.
- Controlled research-unit setting; generalizability to community overdoses and polysubstance exposures requires confirmation.
- Sample size for opioid-tolerant subgroup not detailed in abstract.
Future Directions: Pragmatic trials in prehospital/community overdose settings comparing time to adequate ventilation, need for repeat dosing, and outcomes across formulations and titration protocols.
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. The study was registered at https://doi.org/10.1186/ISRCTN21068708 .
2. Preoxygenation With and Without Positive End-Expiratory Pressure in Lung-Healthy Volunteers: A Randomized Clinical Trial.
Across adults (normal weight and overweight/obese) and children, BVM with PEEP produced higher end-expiratory oxygen (FeO2), better dependent-lung ventilation by electrical impedance tomography, and a longer oxygenation reserve index decay than nonrebreather masks. Results support prioritizing BVM+PEEP for preoxygenation.
Impact: Provides device-level evidence across age and body habitus groups to standardize preoxygenation protocols, potentially reducing desaturation during airway management.
Clinical Implications: When feasible, use BVM with PEEP for preoxygenation, especially in obese adults and children, to maximize oxygen stores and ventilate dependent regions; anticipate improved oxygen reserve during induction.
Key Findings
- BVM and BVM+PEEP yielded higher FeO2 than NRM in adults (NW and OW/OB) and children (all P<.001).
- BVM+PEEP improved dependent-lung ventilation versus NRM in adults (NW) and children (P=.03 and .002).
- In OW/OB adults, BVM+PEEP increased ORI at end-preoxygenation and prolonged time to ORI baseline vs NRM.
Methodological Strengths
- Crossover randomized design across three populations (normal weight adults, overweight/obese adults, children).
- Objective physiologic endpoints including FeO2, EIT ventilation distribution, and ORI; registered trial.
Limitations
- Volunteer study in lung-healthy participants; external validity to acutely ill patients requires confirmation.
- Short preoxygenation exposure (3 minutes) and immediate physiologic outcomes; no clinical desaturation endpoints.
Future Directions: Test BVM+PEEP in emergency and OR airway management among high-risk patients (e.g., hypoxic, critically ill) with clinical endpoints (desaturation rates, first-pass success).
IMPORTANCE: Optimal preoxygenation is critical in emergency medicine to prevent desaturation during airway management, especially in high-risk populations. Identifying the most effective preoxygenation device across diverse patient groups remains a clinical priority. OBJECTIVE: To compare the efficacy of 3 preoxygenation devices-nonrebreather mask (NRM), bag-valve mask (BVM), and BVM with positive end-expiratory pressure (BVM plus PEEP)-in lung-healthy volunteers. DESIGN, SETTING, AND PARTICIPANTS: This crossover randomized clinical trial was conducted from May 26 to 31, 2024, at Eurac Research, Bolzano, Italy. Volunteer participants included lung-healthy adults with normal weight (NM), adults with overweight or obesity (OW-OB), and children aged 6 to 12 years. EXPOSURES: Preoxygenation using each device (NRM, BVM, BVM plus PEEP) with 15 L/min of oxygen for a duration of 3 minutes in a randomized order. MAIN OUTCOMES AND MEASURES: The primary outcome was expiratory oxygen concentration (Feo2) at the end of preoxygenation. Secondary outcomes included ventilation in dependent lung regions assessed using electrical impedance tomography, noninvasive continuous monitoring of oxygenation status (oxygenation reserve index [ORI]) at the end of preoxygenation, and the time taken for ORI to return to baseline values. RESULTS: The study included 53 participants, 39 male (74%) and 14 female (26%), of whom 16 were adults with NW (mean [SD] age, 36 [11] years), 18 were adults with OW-OB (mean [SD] age, 45 [11] years), and 19 were children (mean [SD] age, 8 [3] years). Mean (SD) Feo2 at the end of preoxygenation was higher with BVM and BVM plus PEEP compared with NRM in adults with NW (72.1% [5.9%] and 75.6% [4.3%], respectively, vs 52.5% [6.1%]; P < .001), adults with OW-OB (65.8% [10.4%] and 73.0% [6.4%], respectively, vs 51.9% [6.1%]; P < .001), and children (64.6% [13.4%] and 67.5% [10.2%], respectively, vs 38.5% [7.5%]; P < .001). Ventilation in dependent lung regions was higher with BVM plus PEEP than NRM in adults with NW (BVM plus PEEP, 51.9 [9.3] vs NRM, 47.0 [5.7]; P = .03) and children (BVM plus PEEP, 53.0 [7.3] vs NRM, 47.7 [7.0]; P = .002). ORI at the end of preoxygenation was higher with BVM plus PEEP than with NRM in adults with OW-OB (BVM plus PEEP, 0.79 [0.13] vs NRM, 0.73 [0.13]; P < .001). Additionally, the mean (SE) time for ORI to return to baseline was longer with BVM plus PEEP compared with NRM in both adults with OW-OB (BVM plus PEEP, 196 [74] seconds vs NRM, 158 [53] seconds; P = .01) and children (BVM plus PEEP, 115 [59] seconds vs NRM, 62 [36] seconds; P < .001). CONCLUSIONS AND RELEVANCE: In this crossover randomized clinical trial, preoxygenation with PEEP was more effective than preoxygenation without PEEP, resulting in higher Feo2 values and improved ventilation in dependent lung regions. These findings suggest that BVM plus PEEP should be prioritized for preoxygenation in emergency settings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06370689.
3. Mechanical Stress Induced NOX2 Promotes Endothelial Dysfunction in Ventilator-Induced Lung Injury: Potential Treatment with Quercetin.
In murine VILI models and in vitro cyclic stretch, NOX2 was identified as the predominant ROS source disrupting endothelial junctions and activating CaMKII/ERK1/2 signaling. Antioxidant quercetin reduced ROS, preserved barrier proteins, mitigated lung injury, and improved survival, suggesting a translatable mechanistic target.
Impact: Defines a mechanistic axis (NOX2–ROS–CaMKII/ERK1/2) linking mechanical stress to endothelial dysfunction in VILI and identifies an accessible antioxidant intervention.
Clinical Implications: While preclinical, targeting NOX2-driven oxidative signaling or testing antioxidant strategies like quercetin could be explored adjunctively to lung-protective ventilation in high-risk patients.
Key Findings
- NOX2 identified as the main ROS source causing endothelial junction repression under high cyclic stretch and MV.
- ROS-dependent activation of CaMKII/ERK1/2 signaling mediates endothelial barrier disruption.
- Quercetin scavenged ROS, preserved junctional proteins, reduced VILI severity, and improved mouse survival.
- Transcriptomic similarities noted between VILI and CLP, supporting shared injury pathways.
Methodological Strengths
- Integrated in vivo (mouse MV) and in vitro high cyclic stretch models with convergent mechanistic readouts.
- Pathway validation (NOX2, CaMKII/ERK1/2) and pharmacologic rescue with an antioxidant; inclusion of omics analyses.
Limitations
- Preclinical models; human translational efficacy and dosing/safety of quercetin require clinical trials.
- Specificity of quercetin as an antioxidant vs targeted NOX2 inhibition was not directly compared.
Future Directions: Evaluate selective NOX2 inhibitors and antioxidant strategies in large-animal VILI and early-phase human studies; assess synergy with lung-protective ventilation protocols.
Mechanical ventilation (MV) is a treatment that helps people who are unable to breathe on their own. However, the use of MV leads to the development of ventilator-induced lung injury (VILI). Here, it is found that VILI with endothelial barrier disruption is accompanied by elevated reactive oxygen species (ROS) in mice. NADPH oxidase 2 (NOX2, also known as CYBB or gp91phox) is first examined to be the main source of ROS to repress endothelial junction. Besides, 20%-0.5 Hz high cyclic stretch (high CS) significantly increases NOX2 expression and inhibits endothelial junction protein expression. NOX2 activates the downstream Calcium-calmodulin (CaM)-dependent protein kinase II (CaMKII)/ Extracellular signal-regulated protein kinase 1/2 (ERK1/2) signaling pathway through the regulation of ROS. This pathway is confirmed by high MV stimulation in vivo and high CS in vitro. Of note, quercetin, as an antioxidant, is effective in preventing mechanical stretch-induced endothelial dysfunction by scavenging ROS. Omics data indicated that there is a similar gene expression pattern in cecal ligation and puncture (CLP) and VILI. Pre-administration of quercetin significantly improves the survival rate of mice via inactivating ROS/CaMKII/ERK1/2 axis. Quercetin pre-treatment not only preventes MV-induced lung injury but also attenuates existing inflammation-induced lung injury.