Daily Anesthesiology Research Analysis
A pragmatic multicentre RCT (OPTPRESS) shows that targeting higher mean arterial pressure (80–85 mmHg) in older adults with septic shock increases 90-day mortality versus standard targets (65–70 mmHg). A large individual patient data re-analysis across 29 postoperative analgesic RCTs supports a 50% pain reduction as a robust, patient-centered threshold for meaningful relief. Pediatric PK/PD modeling in Anesthesiology refines remimazolam dosing for procedural sedation, indicating higher per‑kg do
Summary
A pragmatic multicentre RCT (OPTPRESS) shows that targeting higher mean arterial pressure (80–85 mmHg) in older adults with septic shock increases 90-day mortality versus standard targets (65–70 mmHg). A large individual patient data re-analysis across 29 postoperative analgesic RCTs supports a 50% pain reduction as a robust, patient-centered threshold for meaningful relief. Pediatric PK/PD modeling in Anesthesiology refines remimazolam dosing for procedural sedation, indicating higher per‑kg doses without a capped maximum may improve sedation success.
Research Themes
- Hemodynamic targets in septic shock and their outcome impact
- Patient-centered efficacy thresholds for postoperative analgesia
- Precision dosing of novel sedatives in pediatric anesthesia
Selected Articles
1. Efficacy of targeting high mean arterial pressure for older patients with septic shock (OPTPRESS): a multicentre, pragmatic, open-label, randomised controlled trial.
In older ICU patients with septic shock, targeting MAP 80–85 mmHg increased 90-day mortality by an absolute 10.7% compared with 65–70 mmHg, and reduced renal replacement therapy–free days. No subgroup, including those with chronic hypertension, benefited from higher targets.
Impact: This RCT directly challenges prior assumptions about higher MAP targets, providing definitive evidence of harm in a large, pragmatic, multicentre setting. It has immediate implications for vasopressor titration in septic shock among older adults.
Clinical Implications: For older patients with septic shock, maintain MAP targets at 65–70 mmHg rather than 80–85 mmHg. Avoid escalation to high MAP targets even in patients with chronic hypertension; reconsider protocols and decision support to prevent overtitration of vasopressors.
Key Findings
- High MAP target (80–85 mmHg) increased 90-day all-cause mortality versus 65–70 mmHg (39.3% vs 28.6%; absolute risk difference 10.7%, 95% CI 2.6–18.9).
- Renal replacement therapy–free days at 28 days were fewer in the high-target group, indicating worse kidney-related outcomes.
- No subgroup, including patients with known chronic hypertension, derived clinical benefit from higher MAP targets.
Methodological Strengths
- Pragmatic, multicentre randomized controlled design with clinically meaningful endpoints (90-day mortality).
- Preplanned interim analysis and early stopping for harm enhance ethical conduct and patient safety.
Limitations
- Open-label design may introduce performance bias, although mortality is a hard endpoint.
- Conducted in one country; external generalizability to other healthcare systems may require validation.
Future Directions: Evaluate mechanisms underpinning harm at higher MAP (e.g., microcirculatory effects, organ-specific injury) and assess individualized targets incorporating frailty or vascular pathology. Validate findings in diverse health systems.
PURPOSE: We examined the effect of a high-target mean arterial pressure (MAP) on septic shock in a previously underrepresented region. METHODS: A multicentre, pragmatic, open-label, randomised controlled trial was conducted in 29 hospitals in Japan, where the prevalence of chronic hypertension among older individuals is 66.9%. Patients who were diagnosed with septic shock, aged ≥ 65 years, and admitted to an intensive care unit were randomised 1:1 to the high (target MAP = 80-85 mmHg) or control (target MAP = 65-70 mmHg) groups from 1 July 2021 to 12 December 2023. The target MAP was maintained for 72 h or until vasopressors were no longer required. The primary outcome was the 90-day all-cause mortality. Secondary outcomes included organ support-free days and adverse events. RESULTS: The trial was terminated early on the basis of the interim analysis results, suggesting the harm of the high-target strategy. Of the 518 patients, 258 were in the high-target group, and 260 were in the control group. By 90 days after randomisation, 101 patients (39.3%) in the high-target group and 74 (28.6%) in the control group had died from any cause (risk difference = 10.7; 95% confidence interval, 2.6-18.9). Renal replacement therapy-free days at 28 days were shorter in the high-target group. No clinical benefits for any outcome were observed in any subpopulation, including those with known chronic hypertension. CONCLUSION: Among older patients with septic shock, high-target MAP significantly increased mortality compared with standard care. TRIAL REGISTRATION: UMIN Clinical Trials Registry; UMIN000041775; 13 September 2020.
2. Minimum clinically important differences in acute pain: a patient-level re-analysis of randomized controlled analgesic trials submitted to the US Food and Drug Administration.
Using individual patient data from 29 double-blind RCTs (n=9,047), meaningful pain relief aligned with a 50% reduction in pain intensity across multiple surgical pain models. This threshold was consistent regardless of baseline pain severity, demographics, drug class, or route, supporting a standardized, patient-centric efficacy endpoint.
Impact: This analysis offers a robust, generalizable MCID for acute postoperative pain, enabling consistent trial design, regulatory assessment, and clinical interpretation of analgesic efficacy.
Clinical Implications: Adopt a 50% pain reduction as a primary or key secondary endpoint in acute postoperative analgesic trials and use it in clinical practice to interpret meaningful relief for patients.
Key Findings
- Across 29 double-blind, placebo-controlled trials (n=9,047), a 50% reduction in pain intensity best corresponded to patient-reported meaningful relief.
- The percent reduction at meaningful relief was stable across baseline pain severities and did not differ by age, sex, drug, or administration route.
- ROC analysis supported 50% reduction as a consistent, clinically meaningful threshold across dental, bunionectomy, orthopedic, and soft tissue models.
Methodological Strengths
- Individual patient data re-analysis of double-blind RCTs with standardized definitions via the double-stopwatch technique.
- Large sample size across multiple surgical pain models enhances generalizability.
Limitations
- Secondary analysis of trials; heterogeneity in trial designs and populations may persist.
- Meaningful relief is anchored to stopwatch-based reporting, which may not capture all patient-centered outcomes.
Future Directions: Prospectively validate the 50% threshold in contemporary analgesic trials and integrate composite recovery measures (e.g., QoR) to complement pain reduction metrics.
The lack of established minimum clinically important differences in acute pain has made it challenging to interpret efficacy in analgesic trials. We performed a patient-level re-analysis of double-blind, placebo-controlled trials submitted to the US Food and Drug Administration to estimate minimum clinically important differences in acute postoperative pain. Trials were categorized by acute surgical pain model: dental extraction, bunionectomy, orthopedic surgery, and soft tissue surgery. Pain intensity was assessed using the 0 to 10 numeric rating scale (NRS) or 0 to 100 visual analog scale, with visual analog scale scores converted to NRS for analysis. To avoid misclassification from arbitrary thresholds on global impression of change or pain relief scales, meaningful pain relief was determined using the double-stopwatch technique, where patients actively indicated the times they experienced perceptible and meaningful relief. Across 29 trials, 9047 patients with moderate-to-severe baseline pain were included. Patients with severe baseline pain (NRS ≥7) reported meaningful relief at a higher absolute NRS and required larger absolute reductions in pain intensity than those with moderate baseline pain (NRS 4-<7). However, the percent reduction in pain at meaningful relief remained stable across baseline pain levels, suggesting patients assess meaningful relief in relative rather than absolute terms. No appreciable differences in the changes in pain at meaningful relief were observed by age, sex, drug, or route of administration. Receiver operating characteristic curve analysis identified a 50% reduction in pain intensity as a consistent and clinically meaningful threshold across surgical pain models, supporting its use as a standardized patient-centric metric for evaluating analgesic efficacy.
3. Pharmacokinetics and Pharmacodynamics of Remimazolam for Procedural Sedation in Children and Adolescents.
Population PK/PD modeling in 31 children/adolescents found remimazolam clearance of 0.70 L·min−1·70 kg−1 and an exposure–response relationship modified by concomitant fentanyl. Simulations suggest higher per‑kg dosing and removing maximum caps are needed to reliably achieve adequate sedation (UMSS ≥3) in 88–97% of patients.
Impact: Provides foundational pediatric PK/PD data for a modern ultra–short-acting benzodiazepine and recommends practical dosing modifications that could enable consistent procedural sedation.
Clinical Implications: When using remimazolam for pediatric procedural sedation, consider higher weight-based dosing and avoid strict maximum dose caps; account for fentanyl coadministration lowering EC50. Implementation awaits regulatory approval and prospective validation.
Key Findings
- Estimated remimazolam elimination clearance: 0.70 L·min−1·70 kg−1; pediatric PK differs from adults after size correction.
- EC50 for UMSS ≥3 was 777 ng/mL without fentanyl, decreasing to 655, 533, and 287 ng/mL at fentanyl concentrations of 1, 2, and 4 ng/mL, respectively.
- Simulations indicate current dosing leaves 9.2–22.0% under-sedated; optimized higher per‑kg dosing without caps achieves UMSS ≥3 in 88–97%.
Methodological Strengths
- Prospective stratified design with rich PK sampling and integrated PK/PD modeling.
- Use of validated sedation scale (UMSS) and simulation-based dosing optimization.
Limitations
- Small single-study sample (n=31) limits precision and generalizability.
- Not powered for clinical outcomes; dosing recommendations require prospective validation and regulatory review.
Future Directions: Prospective randomized comparisons against standard sedatives (e.g., propofol), validation of model-informed dosing across age/weight ranges, and safety/PK in younger children.
BACKGROUND: Remimazolam is not approved for use in pediatric patients. The pharmacokinetics of remimazolam have been reported to be similar to those of adult patients after scaling for body size. This article reports on the pharmacokinetics and pharmacodynamics of pediatric patients aged 6 to 18 yr and a subsequent model-based optimization of the used dosing regimen. METHODS: Thirty-one patients were included in the trial and stratified across four treatment arms: bolus administration, infusion, bolus plus fentanyl, or infusion plus fentanyl. The University of Michigan (Ann Arbor, Michigan) Sedation Scale (UMSS) was used to assess the depth of sedation. Blood samples were drawn to measure the concentrations of remimazolam and its metabolite CNS7054. Population pharmacokinetic pharmacodynamic modeling was performed in NONMEM (GloboMax LLC, USA). RESULTS: A population pharmacokinetic model was developed for remimazolam and CNS7054. The elimination clearance of remimazolam was 0.70 l · min -1 · 70 kg -1 . A proportional odds model combined with a simplified Minto model described the observed UMSS well. The EC50 of remimazolam for a UMSS score of 3 or greater was 777 ng · ml -1 in the absence of fentanyl, and decreased to 655, 533, and 287 ng/ml for concomitant fentanyl steady state concentrations of 1, 2, or 4 ng · ml -1 , respectively. Simulations confirmed that the studied dosing regimen resulted in 9.2 to 22.0% of patients not reaching a UMSS score of 3 or greater at the end of the induction. Model-based optimization resulted in higher per-kilogram dosages and the removal of the maximum allowable dose. Simulations indicated that the percentage of patients achieving a UMSS score of 3 or greater can be expected to be high (88 to 97%). CONCLUSIONS: This study has shown that the pharmacokinetics of remimazolam are likely different between children 6 yr or older and adults (after correcting for size). In addition, the exposure-response relationship shows that to effectively use remimazolam for procedural sedation in children 6 yr or older, the dosing regimen should be modified to allow for higher remimazolam exposures.