Daily Anesthesiology Research Analysis
A multicentre phase 3 RCT (PRIME-AIR) tested a perioperative lung expansion bundle in open abdominal surgery, achieving high protocol adherence and higher intraoperative PEEP exposure. New translational work shows microtubule-modulating drugs bidirectionally alter isoflurane sensitivity and emergence in mice, and a comprehensive population PK model of IV lidocaine with metabolite kinetics proposes fat-free mass–based dosing to rapidly attain target concentrations.
Summary
A multicentre phase 3 RCT (PRIME-AIR) tested a perioperative lung expansion bundle in open abdominal surgery, achieving high protocol adherence and higher intraoperative PEEP exposure. New translational work shows microtubule-modulating drugs bidirectionally alter isoflurane sensitivity and emergence in mice, and a comprehensive population PK model of IV lidocaine with metabolite kinetics proposes fat-free mass–based dosing to rapidly attain target concentrations.
Research Themes
- Perioperative lung protection and postoperative pulmonary complications
- Precision anesthetic dosing and pharmacokinetic/pharmacodynamic modeling
- Drug–microtubule interactions influencing anesthetic sensitivity
Selected Articles
1. Perioperative lung expansion and pulmonary outcomes after open abdominal surgery versus usual care in the USA (PRIME-AIR): a multicentre, randomised, controlled, phase 3 trial.
In this multicentre phase 3 RCT of adults undergoing major open abdominal surgery at intermediate/high PPC risk, adherence to a perioperative lung expansion bundle was high (72–98%). The intervention increased intraoperative mean PEEP relative to usual care; 751 participants were analyzed in the mITT cohort.
Impact: A large, rigorously conducted NIH-funded RCT addressing PPC mitigation can influence perioperative ventilation bundles and standard practice in open abdominal surgery.
Clinical Implications: Supports structured, individualized intraoperative lung expansion strategies with demonstrable implementation fidelity. Pending full outcome details, programs can emulate high-adherence protocols and PEEP titration strategies in at-risk open abdominal surgeries.
Key Findings
- Multicentre phase 3 RCT enrolled 794 patients; mITT analysis included 751 (379 intervention, 372 usual care).
- Adherence to bundle components was high (72–98%).
- Intervention group received higher intraoperative mean PEEP (reported mean 7.5 cmH2O) than usual care.
- Eligibility targeted ARISCAT ≥26 and BMI <35 kg/m² for elective open abdominal surgeries ≥2 hours.
Methodological Strengths
- Multicentre randomized phase 3 design with NIH funding and mITT analysis.
- High protocol adherence and standardized intraoperative management bundle.
Limitations
- Abstract does not report definitive PPC outcome effect sizes in the provided excerpt.
- Generalizability limited to BMI <35 kg/m² and open abdominal procedures ≥2 hours; blinding of intraoperative teams is inherently challenging.
Future Directions: Report detailed PPC severity and incidence outcomes, subgroup effects (e.g., ARISCAT strata), and implementation across diverse BMI and laparoscopic populations.
2. Population Pharmacokinetics of IV Lidocaine and its Metabolites in Adult Surgical Patients.
In 98 adult surgical patients with 1,520 samples, lidocaine followed a 3-compartment model; metabolites MEGX and GX fit 2-compartment models. Clearance was 45.9 L/h with a 60% postoperative decrease, and simulations support fat-free mass–based dosing to target 1.5 mg/L rapidly.
Impact: Provides a clinically actionable joint parent–metabolite PK model with dosing guidance using fat-free mass, enabling safer, target-driven perioperative lidocaine use.
Clinical Implications: Adopt fat-free mass–based bolus/infusion regimens to achieve ~1.5 mg/L rapidly while accounting for postoperative clearance reductions, fluid shifts, and body composition.
Key Findings
- Lidocaine PK fit a 3-compartment model; MEGX and GX each fit 2-compartment models.
- Typical lidocaine clearance was 45.9 L/h and decreased by 60% postoperatively; central volume 25.2 L.
- Intercompartmental clearances: 142 L/h and 5.81 L/h; volumes 44.4 L and 29.3 L; peripheral V1 expanded with intraoperative fluids.
- FFM-based dosing (2.5 mg/kg over 30 min, then 2 mg/kg over 1 h, then 1.5 mg/kg/h) rapidly achieved a 1.5 mg/L target.
Methodological Strengths
- Rich sampling (1,520 concentration–time points) with joint parent–metabolite modeling.
- Allometric scaling with both total body mass and fat-free mass; simulation of clinical dosing regimens.
Limitations
- Surgical cohorts limited to donor nephrectomy and cholecystectomy; external validation pending.
- No concurrent pharmacodynamic endpoints or clinical outcomes to define optimal target concentrations.
Future Directions: Externally validate the model across diverse surgeries, hepatic/renal phenotypes, and integrate PK-PD to refine target concentrations and safety thresholds.
3. Microtubule-modulating drugs alter sensitivity to isoflurane in mice.
Chronic exposure to microtubule-active agents altered isoflurane sensitivity and timing: epothilone D and vinblastine increased sensitivity (leftward EC50), morphine decreased sensitivity (rightward EC50), and paclitaxel modestly decreased sensitivity. Vinblastine shortened induction latency and morphine prolonged it; both shortened emergence versus saline.
Impact: Reveals a mechanistic link between microtubule modulation and anesthetic responsiveness with practical implications for patients on MT-targeting chemotherapy or prolonged opioids.
Clinical Implications: Consider altered MAC-like requirements and induction/emergence profiles in patients chronically exposed to microtubule agents or opioids; titrate isoflurane cautiously and monitor depth closely.
Key Findings
- Epothilone D and vinblastine increased isoflurane sensitivity (EC50 0.75 and 0.74 vs saline 0.97–0.98).
- Morphine reduced sensitivity (EC50 1.16 vs saline 0.97–0.98); paclitaxel caused a modest rightward shift (EC50 1.05).
- At 1.2% isoflurane, morphine prolonged induction latency (275±50 s) and vinblastine shortened it (96.5±26 s) vs saline (211±39 s).
- Emergence latency was shorter with morphine (58±20 s) and vinblastine (98±43 s) than saline (176±50 s).
Methodological Strengths
- Controlled chronic drug exposure with quantitative EC50 estimation using LORR dose–response.
- Assessment of both induction and emergence latency at fixed isoflurane concentration.
Limitations
- Male CD1 mouse model limits generalizability to humans and females.
- LORR is a surrogate for consciousness and may not capture all anesthetic endpoints; mechanistic assays were not performed.
Future Directions: Translate findings to human pharmacology with clinical MAC assessments in chemotherapy and chronic opioid populations; explore cellular MT metrics and neural circuitry mechanisms.