Inhaled milrinone in cardiac surgical patients: pharmacokinetic and pharmacodynamic exploration
Bibliographic record
Abstract
Abstract Mean arterial pressure to mean pulmonary arterial pressure ratio (mAP/mPAP) has been identified as a strong predictor of perioperative complications in cardiac surgery. We therefore investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationship of inhaled milrinone in these patients using this ratio (R) as a PD marker. Following approval by the ethics and research committee and informed consent, we performed the following experiment. Before initiation of cardiopulmonary bypass in 28 pulmonary hypertensive patients scheduled for cardiac surgery, milrinone (5 mg) was nebulized, plasma concentrations measured (up to 10 h) and compartmental PK analysis carried out. Baseline (R 0 ) and peak (R max ) ratios as well as magnitude of peak response (∆ Rmax-R0 ) were measured. During inhalation, individual area under effect-time (AUEC) and plasma concentration–time (AUC) curves were correlated. Potential relationships between PD markers and difficult separation from bypass (DSB) were explored. In this study, we observed that milrinone peak concentrations (41–189 ng ml −1 ) and Δ Rmax-R0 (− 0.12–1.5) were obtained at the end of inhalation (10–30 min). Mean PK parameters agreed with intravenous milrinone published data after correction for the estimated inhaled dose. Paired comparisons yielded a statistically significant increase between R 0 and R max (mean difference, 0.58: 95% CI 0.43–0.73; P < 0.001). Individual AUEC correlated with AUC (r = 0.3890, r 2 = 0.1513; P = 0.045); significance increased after exclusion of non-responders (r = 4787, r 2 = 0.2292; P = 0.024). Individual AUEC correlated with ∆R max-R0 (r = 5973, r 2 = 0.3568; P = 0.001). Both ∆R max-R0 ( P = 0.009) and CPB duration ( P < 0.001) were identified as predictors of DSB. In conclusion, both magnitude of peak response of the mAP/mPAP ratio and CPB duration were associated with DSB.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".