Daily Anesthesiology Research Analysis
Three papers stand out today for anesthesiology and perioperative medicine: (1) a NIH HEAL morphine milligram equivalent (MME) calculator that standardizes opioid dose mapping across 29 opioids with PRISMA- and GRADE-based evidence synthesis; (2) a comprehensive meta-analysis showing remimazolam achieves similar procedural sedation success to active comparators while reducing respiratory and cardiovascular complications versus propofol; and (3) a large multicenter RCT showing nitric oxide during
Summary
Three papers stand out today for anesthesiology and perioperative medicine: (1) a NIH HEAL morphine milligram equivalent (MME) calculator that standardizes opioid dose mapping across 29 opioids with PRISMA- and GRADE-based evidence synthesis; (2) a comprehensive meta-analysis showing remimazolam achieves similar procedural sedation success to active comparators while reducing respiratory and cardiovascular complications versus propofol; and (3) a large multicenter RCT showing nitric oxide during cardiopulmonary bypass in infants does not improve 12‑month neurodevelopment or HRQOL.
Research Themes
- Standardization of opioid dose metrics in pain research
- Safety and efficacy of remimazolam for procedural sedation
- Neuroprotection strategies during pediatric cardiopulmonary bypass
Selected Articles
1. Standardizing research methods for opioid dose comparison: the NIH HEAL morphine milligram equivalent calculator.
This NIH HEAL-backed tool standardizes MME calculations using evidence-based conversion factors for 29 opioids, reproduces most CDC ratios, and extends coverage to additional opioids and formulations. It implements four standardized time-window methods and GRADE-rated evidence, enabling harmonized opioid dose mapping across research networks.
Impact: By providing a validated, transparent framework for MME conversion, this work removes a key barrier to meta-analysis and reproducibility in pain and perioperative opioid research.
Clinical Implications: Facilitates consistent opioid exposure reporting across trials and registries, improving comparability of perioperative analgesia studies and enabling more reliable dose–response and safety analyses.
Key Findings
- Created an NIH HEAL MME calculator with evidence-based mapping factors for 29 opioids.
- Systematic review (1949–2024) screened >170,050 articles; 24 studies informed conversion factors; evidence graded with modified GRADE.
- Replicates most CDC conversion factors and adds 7 opioids and 6 formulations absent from CDC 2022 table.
- Implements four standardized time-window calculation methods and allows inclusion/exclusion of buprenorphine.
Methodological Strengths
- PRISMA-compliant systematic evidence evaluation with modified GRADE ratings.
- Publicly accessible calculator and companion website enabling consistent implementation across studies.
Limitations
- Underlying evidence base for some conversion factors is limited or heterogeneous, relying on pharmacokinetic extrapolation.
- Clinical validation in prospective cohorts and sensitivity to differing clinical contexts remains to be established.
Future Directions: Prospective validation of conversion accuracy across clinical contexts (acute perioperative, chronic pain, opioid-tolerant patients) and integration with EHR and research networks to automate standardized exposure capture.
We developed the National Institutes of Health helping to end addiction long-term initiative morphine milligram equivalent (MME) calculator to standardize MME calculations across pain research studies, addressing a critical barrier to effective research synthesis and meta-analysis. The tool provides evidence-based mapping factors for 29 opioids through a research electronic data capture-based calculator and companion Web site ( research-mme.wakehealth.edu ). Development involved systematic evidence evaluation of literature from 1949 to March 2024, following PRISMA guidelines. From an initial screening of over 170,050 articles, we identified 24 studies providing evidence for conversion factors. The calculator incorporates 4 standardized time-window calculation methods aligned with current research approaches and includes traditional full agonists, partial agonists, and mixed-mechanism agents. Using modified GRADE methodology, we evaluated evidence quality for each conversion factor, documenting levels from high-quality randomized controlled trials to pharmacokinetic extrapolation. Our tool replicates most existing Centers for Disease Control and Prevention (CDC) conversion factors while expanding coverage to 7 additional opioids and 6 formulations not included in the 2022 CDC conversion table. The calculator features options to analyze results with or without buprenorphine, accommodating its emerging role in pain research. This standardized framework enables researchers to map opioid doses using consistent, evidence-based ratios and harmonize data collection across research networks. While the tool represents a significant advance in standardizing MME calculations for research, limitations in the underlying evidence base highlight the need for continued validation through clinical research.
2. Remimazolam for procedural sedation: A systematic review with meta-analyses and trial sequential analyses.
Across 63 RCTs, remimazolam achieved similar procedural sedation success to active comparators but reduced respiratory and cardiovascular complications, particularly versus propofol. Evidence certainty is very low to low due to high risk of bias across included trials.
Impact: This synthesis informs agent selection for procedural sedation by balancing success against cardio-respiratory safety, a core perioperative concern.
Clinical Implications: Remimazolam may be preferred when minimizing respiratory or cardiovascular complications is paramount, while recognizing that overall sedation success is comparable to alternatives and that local protocols should account for low-certainty evidence.
Key Findings
- Sedation success with remimazolam is similar to active comparators overall (RR ~1.04).
- Remimazolam reduces respiratory (RR 0.47) and cardiovascular (RR 0.46) complications versus active comparators, notably compared with propofol.
- Subgroup analyses suggest higher success versus midazolam, with similar risk profiles versus midazolam.
- All included trials had high risk of bias; GRADE certainty is very low to low.
Methodological Strengths
- Comprehensive database search with meta-analysis, trial sequential analysis, and GRADE assessment.
- Subgroup comparisons against key agents (propofol, midazolam) to contextualize safety and efficacy.
Limitations
- High risk of bias across included RCTs limits certainty; heterogeneity in procedures and dosing regimens.
- Potential publication bias and industry sponsorship were not fully resolved.
Future Directions: Head-to-head, CONSORT-compliant RCTs against propofol with standardized adverse event definitions and patient-centered outcomes (eg, recovery profile) are needed.
BACKGROUND: Midazolam and propofol are frequently used for procedural sedation. Remimazolam may provide a more controllable sedation with fewer adverse effects. OBJECTIVE: To assess the sedation success rate and respiratory and cardiovascular complications of remimazolam versus placebo and other sedatives in adults undergoing procedural sedation. DESIGN: A systematic review of randomised controlled trials (RCTs) with meta-analyses, trial sequential analyses (TSA), and GRADE evaluations of the certainty of evidence. DATA SOURCES: We searched Medline, Embase, CENTRAL, BIOSIS, CINAHL, and Web of Science Core Collection from their inception to 22 June 2024. ELIGIBILITY CRITERIA: RCTs allocating participants undergoing procedural sedation to remimazolam versus placebo or any active comparator. RESULTS: We included 63 trials randomising 13 953 participants. All included trial results were judged to be at high risk of bias. The sedation success rate was similar with remimazolam versus active comparators, relative risk (RR) 1.04, [97.5% confidence interval (CI), 0.96 to 1.14; TSA-adjusted CI, 0.95 to 1.18], P = 0.26, GRADE: very low. Subgroup analyses indicated that remimazolam versus midazolam increased sedation success rate, while the risks were similar with remimazolam versus comparators. Remimazolam versus active comparators decreased the risk of respiratory complications, RR 0.47, (97.5% CI, 0.36 to 0.61; TSA-adjusted CI, 0.35 to 0.61), P < 0.01; and cardiovascular complications, RR 0.46, (97.5% CI, 0.37 to 0.56; TSA-adjusted CI, 0.38 to 0.57), P < 0.01. Subgroup analyses indicated that remimazolam versus propofol reduced respiratory and cardiovascular complications, while the risks were similar versus midazolam. CONCLUSION: Remimazolam seems to provide a similar sedation success rate as other active comparators (propofol, ciprofol, midazolam, dexmedetomidine, etomidate), although subgroup analyses indicated that remimazolam increased sedation success rate compared to midazolam. Remimazolam compared to propofol may decrease the risk of respiratory and cardiovascular complications. The certainty of the evidence was very low to low, and firm conclusions could not be drawn.
3. Neurodevelopmental Outcomes After Nitric Oxide During Cardiopulmonary Bypass for Open Heart Surgery: A Randomized Clinical Trial.
In a multicenter double-masked RCT of 1364 infants, nitric oxide at 20 ppm added to the CPB oxygenator did not improve 12‑month neurodevelopment (ASQ‑3) or HRQOL after open heart surgery. Risk factors for lower neurodevelopmental scores included prematurity, univentricular lesions, congenital syndromes, and longer ICU stay.
Impact: This high-quality negative trial informs perioperative perfusion strategies by discouraging routine NO use for neurodevelopmental benefit in infant CPB.
Clinical Implications: Routine NO administration into CPB oxygenators for neurodevelopmental benefit in infants is not supported; resources may be redirected to modifiable perioperative risk factors and alternative neuroprotection strategies.
Key Findings
- No difference in ASQ-3 total scores at 12 months between NO and standard CPB groups (adjusted mean difference −2.24; 95% CI −11.84 to 7.36).
- No differences in HRQOL or functional status.
- Prematurity, univentricular lesions, congenital syndromes, and longer ICU stay were independently associated with lower neurodevelopmental scores.
Methodological Strengths
- Multicenter, double-masked randomized design with preplanned 12‑month follow-up and trial registration.
- Adjusted multivariable analyses identified clinically relevant risk factors.
Limitations
- Loss to follow-up reduced analyzable sample; parent-reported ASQ-3 may be less sensitive than formal neurocognitive testing.
- Heterogeneity of surgical procedures and patient phenotypes may dilute subgroup effects; dose-response not tested.
Future Directions: Evaluate higher-dose NO or alternative anti-inflammatory/neuroprotective strategies in homogeneous, high-risk infant cohorts with standardized neurocognitive batteries.
IMPORTANCE: Children with congenital heart defects who undergo cardiopulmonary bypass (CPB) surgery are at risk for delayed or impaired neurodevelopmental outcomes. Nitric oxide (NO) added to the CPB oxygenator may reduce systemic inflammation due to CPB and improve recovery from surgery, including improved neurodevelopmental outcomes. OBJECTIVE: To investigate neurodevelopment, health-related quality of life (HRQOL), and factors associated with impaired neurodevelopment at 12 months post surgery in infants who received CPB with NO or standard CPB. DESIGN, SETTING, AND PARTICIPANTS: This double-masked randomized clinical trial was conducted in 6 centers in Australia, New Zealand, and the Netherlands between July 19, 2017, and April 28, 2021, with a preplanned prospective follow-up 12 months postrandomization completed on August 5, 2022. The cohort included 1364 infants younger than 2 years who underwent open heart surgery with CPB for congenital heart disease. INTERVENTIONS: The intervention group received NO 20 ppm into the CPB oxygenator. The control group received standard CPB. MAIN OUTCOMES AND MEASURES: The primary outcome was neurodevelopment, defined as the Ages and Stages Questionnaire, Third Edition (ASQ-3) total score. Secondary outcomes were HRQOL and functional status as measured by Pediatric Quality of Life Inventory and modified Pediatric Overall Performance Category scores, respectively. Sensitivity analyses modeled the outcome for patients lost to follow-up. RESULTS: Of 1318 infants alive 12 months after randomization, follow-up was performed in 927, with 462 patients in the NO group and 465 in the standard care group (median [IQR] age at follow-up, 16.6 [13.7-19.8] months; median [IQR] time since randomization, 12.7 [12.1-13.9] months; 516 male [55.7%]). There were no differences between the NO and standard care groups in ASQ-3 total score (mean [SD], 196.6 [75.4] vs 198.7 [73.8], respectively; adjusted mean difference, -2.24; 95% CI, -11.84 to 7.36). There were no differences in secondary outcomes. Prematurity (gestational age <37 weeks), univentricular lesions, congenital syndromes, and longer intensive care unit length of stay were associated with lower ASQ-3 total scores in adjusted multivariable analyses. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of infants with congenital heart disease, NO administered via the CPB oxygenator did not improve neurodevelopmental outcomes or HRQOL 12 months after open heart surgery. Further research should explore homogenous cohorts with higher surgical risk and higher-dose or alternative therapies. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12617000821392.