Variation in Nimodipine Exposure and its Effect on Outcomes in Patients with Aneurysmal Subarachnoid Hemorrhage
Notice bibliographique
Résumé
Aneurysmal Subarachnoid Hemorrhage (SAH) is a life-threatening neurological emergency caused by a ruptured brain aneurysm leading to extravasation of blood into the subarachnoid space. SAH accounts for 5-10% of all strokes, affecting relatively younger age compared to ischemic strokes, leading to premature loss of productive life years. Neurological and medical complications are common following SAH and contribute significantly to patient outcomes. Delayed cerebral ischemia (DCI) and vasospasm are the main challenges that contribute to post SAH unfavorable patient outcomes. The Only Health Canada and FDA approved drug to prevent these two complications is nimodipine, a calcium channel blocker. Guidelines recommend that all patients with SAH to receive a fixed dose of oral nimodipine for 21 days. However, review of literature pertaining to nimodipine pharmacokinetics demonstrated extensive pharmacokinetic variability among different group of patients. Furthermore, limited evidence suggested lower exposure of the drug following enteral feeding administration compared to oral dosing. It is not clear if all patients are getting the full benefit of nimodipine. Therefore, our research aimed first to investigate retrospectively the impact of administering nimodipine via enteral feeding tubes on outcomes in patients with SAH. Second, we aimed to develop and validate an enantioselective assay for nimodipine to be utilized in our pilot study. Third, we aimed to conduct a prospective pilot study aimed to preliminarily determine potential factors that might have an influence on nimodipine exposure and to investigate whether there is a trend of possible association between nimodipine exposure and patient outcomes (vasospasm, DCI, and modified Rankin Scale (mRS) at 90 days post SAH admission). For the first objective, a retrospective chart review study was carried out that involved reviewing 85 charts for patients admitted to the University of Alberta Hospital. Following adjustment for disease severity, nimodipine administration through feeding tubes was associated with vasospasm in the first 7 days of patient admission where patients receiving nimodipine via enteral feeding tubes had increased odds of vasospasm compared to those administered it as whole tablets (OR 8.9, 95% CI 1.1-73.1, p value 0.042). When analyzed over the 21-day period, nimodipine administration by feeding tube was associated with increased odds of DCI compared to whole tablets (OR 38.1, 95% CI 1.4-1067.9, p value 0.032). For the enantioselective assay development, we presented an LC-MS/MS method for quantifying nimodipine enantiomers in human plasma using a small sample volume (0.3 ml) and a single liquid-liquid extraction step. The peak area ratios were linear over the tested concentration ranges (1.5-75 ng/ml) with r2 > 0.99. The intraday and interday CV and percent error were within ±14% while that of the interday was within ±13% making this analytical method feasible for research purposes and pharmacokinetic studies. For our third objective, we were able to recruit 7 patients admitted to the University of Alberta Hospital. Blood samples were collected following a single nimodipine 60 mg dose at steady state. Plasma nimodipine enantiomers concentrations were quantified using the LC-MS/MS method that we validated. Area under the concentration-time curve (AUC0-4h) was calculated. Factors that could influence plasma nimodipine concentrations were assessed in different patient categories. Both discharge outcomes and 3-months mRS were collected. Patients who took nimodipine through feeding tubes and those with high grade disease had a trend for lower systemic exposure. On the other hand, older patients had higher nimodipine exposure compared to younger ones. With regards to outcomes, the median AUC0-4h values for both nimodipine enantiomers were lower in the 2 patients who had developed vasospasm. There was also a trend for a lower (+)-R nimodipine exposure for patients who had modified Rankin Scale of 3 (worse outcome) than those who had an mRS of 1 (better outcome). In conclusion, the retrospective chart review findings suggested that nimodipine administration via enteral feeding tubes may be associated with vasospasm and DCI in subarachnoid hemorrhage patients possibly secondary to reduced exposure. In addition, we hope the findings of our retrospective and the pilot studies to lay the foundation of a larger prospective observational study to investigate the association between nimodipine exposure and patient outcomes, a step towards nimodipine individualization in SAH patients.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,005 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».