The Impact of Augmented Renal Clearance on Vancomycin Pharmacokinetics and Pharmacodynamics in Critically Ill Patients.

Augmented renal clearance (ARC), defined as a creatinine clearance (CrCl) > 130 mL/min/1.73 m2, is observed in 30-65% of critically ill patients. When following standard dosage guidelines, patients with ARC often experience subtherapeutic vancomycin levels, resulting in treatment failure due to accelerated drug elimination. This review aims to explore ARC's impact on vancomycin pharmacokinetics and pharmacodynamics (PK/PD) indices in ARC patients, seeking to identify an accurate dose adjustment method for this patient population. In September 2023, a comprehensive literature search was conducted on the MEDLINE and EMBASE databases to include all available studies providing information on the impact of ARC on vancomycin therapy in critically ill adults. Articles that studied the pediatric population and those with insufficient PK data were excluded. A total of 21 articles met the inclusion criteria. The findings revealed a positive correlation between CrCl and vancomycin clearance, indicating low serum concentrations. Therefore, upward dosing adjustments are necessary to improve treatment success. Younger age consistently emerged as a major contributor to ARC and vancomycin PK/PD alterations. This study summarizes the PK/PD alterations, current dosage recommendations and proposes preliminary recommendations on possible dosing approaches to decrease the risk of subtherapeutic exposure in this patient population.

Acyclovir dosing in herpes encephalitis: A scoping review.

BACKGROUND: Herpes encephalitis, a rare yet potentially fatal viral infection, is treated exclusively with acyclovir, the sole antiviral medication used for this condition. Acyclovir recommended dose is 10 mg/kg/dose intravenous every 8 hours; however, it is unclear what body weight should be utilized in obese patients. Using the ideal body weight may result in subtherapeutic ineffective concentrations, while utilizing the actual body weight might result in acyclovir induced adverse effects, either nephrotoxicity or neurotoxicity or both. OBJECTIVE: The objective of this scoping review is to explore existing evidence regarding acyclovir dosing for obese patients afflicted with herpes encephalitis. METHODS: MEDLINE, EMBASE, Scopus, Web of Science, and CINAHL databases were searched on 26 May 2023, with no language restrictions. Two independent reviewers utilized the Covidence software to carry out the screening and selection of the articles. A total of 22 articles were included in the current review. RESULTS: The prevalence of acyclovir-associated nephrotoxicity ranged from 13% to 21%, while the prevalence of neurotoxicity was not clearly defined. However, there is lack of evidence regarding what may arise from subtherapeutic concentrations. An approach has been suggested to help clinicians to give the most appropriate acyclovir dose to herpes encephalitis patients. Patients with normal kidney function could receive the normal doses based on actual weight if normal weight and based on adjusted body weight if obese. On the other hand, if the patients are experiencing augmented renal clearance, they could receive up to the maximum recommended doses. CONCLUSION: Overall, there is a lack of consistency on which body weight to use to calculate acyclovir dose in obese patients. So it is recommended that further studies compare the concentration of intravenous acyclovir between obese and nonobese patients and relating the resultant concentration with patient outcomes.

Metabolomic Analysis in Neurocritical Care Patients.

Metabolomics is the analytical study of metabolites in biological matrices using high-throughput profiling. Traditionally, the metabolome has been studied to identify various biomarkers for the diagnosis and pathophysiology of disease. Over the last decade, metabolomic research has grown to include the identification of prognostic markers, the development of novel treatment strategies, and the prediction of disease severity. In this review, we summarized the available evidence on the use of metabolome profiling in neurocritical care populations. Specifically, we focused on aneurysmal subarachnoid hemorrhage, traumatic brain injury, and intracranial hemorrhage to identify the gaps in the current literature and to provide direction for future studies. A primary literature search of the Medline and EMBASE databases was conducted. Upon removing duplicate studies, abstract screening and full-text screening were performed. We screened 648 studies and extracted data from 17 studies. Based on the current evidence, the utility of metabolomic profiling has been limited due to inconsistencies amongst studies and a lack of reproducible data. Studies identified various biomarkers for diagnosis, prognosis, and treatment modification. However, studies evaluated and identified different metabolites, resulting in an inability to compare the study results. Future research towards addressing the gaps in the current literature, including reproducing data on the use of specific metabolite panels, is needed.

Prevalence of Drug-Drug Interactions in Primary Care Prescriptions in Egypt: A Cross-Sectional Retrospective Study.

In clinical practice, drug-drug interactions (DDIs) pose significant risks to a large number of patients. Consequently, healthcare providers are required to diligently identify, monitor, and effectively handle these interactions in order to enhance patient outcomes. In Egypt, DDIs are poorly addressed, with no reports for DDIs in primary care. In our cross-sectional, retrospective, observational study, we collected a total of five thousand, eight hundred and twenty prescriptions across eight major governorates in Egypt. Prescriptions were collected over a span of 15 months between 1 June 2021 and 30 September 2022. These prescriptions were analyzed for potential DDIs using the Lexicomp® drug interactions tool. The prevalence of DDIs was found to be 18%, with 22% of the prescriptions having two or more potential DDIs. Moreover, we found 1447 DDIs of categories C (monitoring therapy recommended), D (therapy modification suggested), and X (avoid combination). The most commonly interacting drugs in our study were diclofenac, aspirin, and clopidogrel, while non-steroidal anti-inflammatory drugs (NSAIDs) were the most reported therapeutic class implicated in pharmacologic DDIs. Pharmacodynamic agonistic activity was the most common mechanism of interaction. Therefore, it is crucial to conduct screenings, detect early signs, and closely monitor drug-drug interactions (DDIs) to enhance patients' overall health outcomes, medication responses, and safety. In this regard, the clinical pharmacist assumes a vital role in implementing these preventive measures.

Comparison of nimodipine formulations and administration techniques via enteral feeding tubes in patients with aneurysmal subarachnoid hemorrhage: A multicenter retrospective cohort study.

BACKGROUND: Nimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH) and current guidelines suggest that patients with aSAH receive nimodipine for 21 days. Patients with no difficulty swallowing will swallow the whole capsules or tablets; otherwise, nimodipine liquid must be drawn from capsules, tablets need to be crushed, or the commercially available liquid product be used to facilitate administration through an enteral feeding tube (FT). It is not clear whether these techniques are equivalent. The goal of the study was to determine if different nimodipine formulations and administration techniques were associated with the safety and effectiveness of nimodipine in aSAH. METHODS: This was a retrospective multicenter observational cohort study conducted in 21 hospitals across North America. Patients admitted with aSAH and received nimodipine by FT for ≥3 days were included. Patient demographics, disease severity, nimodipine administration, and study outcomes were collected. Safety end points included the prevalence of diarrhea and nimodipine dose reduction or discontinuation secondary to blood pressure reduction. Predictors of the study outcomes were analyzed using regression modeling. RESULTS: A total of 727 patients were included. Administration of nimodipine liquid product was independently associated with higher prevalence of diarrhea compared to other administration techniques/formulations (Odds ratio [OR] 2.28, 95% confidence interval [CI] 1.41-3.67, p-value = 0.001, OR 2.76, 95% CI 1.37-5.55, p-value = 0.005, for old and new commercially available formulations, respectively). Bedside withdrawal of liquid from nimodipine capsules prior to administration was significantly associated with higher prevalence of nimodipine dose reduction or discontinuation secondary to hypotension (OR 2.82, 95% CI 1.57-5.06, p-value = 0.001). Tablet crushing and bedside withdrawal of liquid from capsules prior to administration were associated with increased odds of delayed cerebral ischemia (OR 6.66, 95% CI 3.48-12.74, p-value <0.0001 and OR 3.92, 95% CI 2.05-7.52, p-value <0.0001, respectively). CONCLUSIONS: Our findings suggest that enteral nimodipine formulations and administration techniques might not be equivalent. This could be attributed to excipient differences, inconsistency and inaccuracy in medication administration, and altered nimodipine bioavailability. Further studies are needed.

Drug-disease interaction: Clinical consequences of inflammation on drugs action and disposition.

Inflammation is a culprit in many conditions affecting millions of people worldwide. A plethora of studies has revealed that inflammation and inflammatory mediators such as cytokines and chemokines are associated with altered expression and activity of various proteins such as those involved in drug metabolism, specifically cytochrome P450 enzymes (CYPs). Emphasis of most available reports is on the inflammation-induced downregulation of CYPs, subsequently an increase in their substrate concentrations, and the link between the condition and the inflammatory mediators such as interleukin-6 and tumor necrosis factor alpha. However, reports also suggest that inflammation influences expression and/or activity of other proteins such as those involved in the drug-receptor interaction. These multifaced involvements render the clinical consequence of the inflammation unexpected. Such changes are shown in many inflammatory conditions including rheumatoid arthritis, Crohn's disease, acute respiratory illnesses as well as natural processes such as aging, among others. For example, some commonly used cardiovascular drugs lose their efficacy when patients get afflicted with inflammatory conditions such as rheumatoid arthritis and Crohn's disease. Interestingly, this is despite increased concentration subsequent to reduced clearance. The observation is attributed to a simultaneous reduction in the expression of target receptor proteins such as the calcium and potassium channel and ß-adrenergic receptor as well as the metabolic enzymes. This narrative review summarizes the current understanding and clinical implications of the inflammatory effects on both CYPs and drug-receptor target proteins.

Simple HPLC-UV Method for Piperacillin/Tazobactam Assay in Human Plasma.

BACKGROUND: Piperacillin (Pip)/tazobactam (Taz) is a broad-spectrum antimicrobial agent that has been commonly used in the intensive care unit for severe and life-threatening infections. Recent evidence suggests that therapeutic drug monitoring (TDM) for Pip could be beneficial in clinical practice to facilitate dose optimization and increase the odds of treatment success. The aim was to develop and validate a sensitive and simple high-performance liquid chromatography (HPLC) method for the simultaneous quantification of Pip and Taz in human plasma. METHODS: Samples (0.3 mL) were deproteinized with acetonitrile. The supernatant was evaporated and then reconstituted and injected into the HPLC. The chromatographic analysis was carried out by using the C18 column and gradient elution with the acetonitrile:water mobile phase mixture with 0.1% trifluoracetic acid at a flow rate of 0.8 mL/min using a UV detector at 218 nm. RESULTS: The method had acceptable linearity (r2 > 0.99) over the concentration ranges of 0.5-400 µg/mL and 1-100 µg/mL for Pip and Taz, respectively. The method demonstrated acceptable inter- and intra-day precision and accuracy within ±20% with adequate stability results. CONCLUSION: The developed method is sensitive and simple and utilizes simple sample preparation and elution steps, making it suitable and practical for Pip/Taz TDM.

Nimodipine systemic exposure and outcomes following aneurysmal subarachnoid hemorrhage: a pilot prospective observational study (ASH-1 study).

Background: Nimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH). Guidelines recommend that all patients should receive a fixed-dose nimodipine for 21 days. However, studies reported variability of nimodipine concentrations in aSAH. It is not clear if reduced systemic exposure contributes to worsening outcomes. The aim of this study was to compare nimodipine systemic exposure in those who experienced poor outcomes to those who experienced favorable outcomes. Methods: This was a pilot prospective observational study in 30 adult patients admitted to the University of Alberta Hospital with aSAH. Data were collected from the electronic health records following enrollment. Blood samples were collected around one nimodipine 60 mg dose at a steady state, and nimodipine [total, (+)-R and (-)-S enantiomers] plasma concentrations were determined. The poor outcome was defined as a modified Rankin Scale (mRS) score at 90 days of 3-6, while the favorable outcome was an mRS score of 0-2. The correlation between nimodipine concentrations and percent changes in mean arterial pressure (MAP) before and after nimodipine administration was also determined. Furthermore, covariates potentially associated with nimodipine exposure were explored. Results: In total, 20 (69%) participants had favorable outcomes and 9 (31%) had poor outcomes. Following the exclusion of those with delayed presentation (>96 h from aSAH onset), among those presented with the World Federation of Neurological Surgeons (WFNS) grade 3-5, nimodipine median (interquartile range) area under the concentration time curve (AUC0-3h) in those with favorable outcomes were 4-fold higher than in those with poor outcomes [136 (52-192) vs. 33 (23-39) ng.h/mL, respectively, value of p = 0.2]. On the other hand, among those presented with WFNS grade 1-2, nimodipine AUC0-3h in those with favorable outcomes were significantly lower than in those with poor outcomes [30 (28-36) vs. 172 (117-308) ng.h/mL, respectively, value of p = 0.03)]. (+)-R-nimodipine AUC0-3h in those who did not develop vasospasm were 4-fold significantly higher than those who had vasospasm (value of p = 0.047). (-)-S-nimodipine was significantly correlated with percentage MAP reduction. Similar results were obtained when the whole cohort was analyzed. Conclusion: The study was the first to investigate the potential association between nimodipine exposure following oral dosing and outcomes. In addition, it suggests differential effects of nimodipine enantiomers, shedding light on the potential utility of nimodipine enantiomers. Larger studies are needed.

Drug Dosing in Critically Ill Adult Patients with Augmented Renal Clearance.

Augmented renal clearance (ARC) is a phenomenon of enhanced renal function seen in critically ill patients. ARC alters the disposition of renally eliminated medications currently used in the intensive care unit, resulting in underdosing and potential therapy failure. Our review addresses the rising concern of inadequate dosing in patients with ARC by summarizing the currently available evidence. To our knowledge, this guide is the first to provide clinicians with dose recommendation insights for renally eliminated agents in adult critically ill patients with ARC. A comprehensive literature search using MEDLINE, Embase, Cochrane Library, CINAHL, Scopus, and ProQuest Dissertations and Theses Global was conducted until 3 November 2021. Screening and data extraction were conducted in two steps: title and abstract screening followed by full-text review. Full text review resulted in a total of 51 studies included in this review. The results demonstrated the need for higher-than-standard doses for meropenem, imipenem, and vancomycin and reduced dosing intervals for ceftriaxone in patients with ARC. The potential need for increased dosing frequency in patients with ARC was also found for both enoxaparin and levetiracetam. In conclusion, ARC has been shown to influence the probability of target attainment in several medications requiring dosing changes to mitigate the risk of therapeutic failure.

A Survey of Canadian Pharmacists' Knowledge and Comfort in the Management of Epilepsy and Antiepileptic Drugs.

Background: As antiepileptic drugs (AED) remain the mainstay of epilepsy management, pharmacists have the potential to play an integral role in the management. Objective: The goal of our study was to characterize Canadian pharmacists' knowledge and comfort in managing epilepsy and AED and identify areas of need for the development of support tools. Methods: An electronic survey was designed and distributed to Canadian pharmacists through professional organizations. The survey consisted of 4 sections, including demographics, knowledge, comfort, and needs assessment around epilepsy management. Results: A total of 605 complete responses were included. Nearly two-thirds of the participants were females (61.6%) and most reported more than 10 years of practice experience (61.6%). For comfort, a majority of the participants responded agree or strongly agree to the statement inquiring about the comfort in checking prescriptions, answering questions about drug interactions, and counseling on AED. Conversely, more than 50% of the participants selected disagree or strongly disagree when asked about their comfort regarding interpreting therapeutic drug monitoring and assisting patients withdraw from AED. For the knowledge section, the overall average score was 57.6% ± 19.1%. Hospital practice, recent graduation, and neurology experience were independent predictors of high scores. Many participants indicated a need for tools addressing newer AED and monitoring of therapy. Conclusion: Although Canadian pharmacists displayed knowledge and comfort in certain aspects of epilepsy management, some clear knowledge and comfort gaps are prevalent. These findings indicate a need for the development of epilepsy educational support tools.

The Efficacy of a Didactic and Case-Based Pharmacogenomics Education Program on Improving the Knowledge and Confidence of Alberta Pharmacists.

Background: Pharmacogenomics (PGx) is the study of how genetic variations for functional proteins, such as metabolizing enzymes and drug receptors, impact drug pharmacokinetics and pharmacodynamics. In theory, pharmacists are well suited to utilize PGx in tailoring medications to patient genetics when providing medication therapy management services. However, PGx education needs to reach pharmacists prior to implementation. The aim of this study is to develop and evaluate a PGx course for pharmacists. Methods: A PGx education program was created and offered synchronously (virtual) and asynchronously (self-study) to pharmacists in Alberta, Canada. Lectures were delivered by experts live (virtual) with a question-and-answer period for synchronous sessions. These sessions were recorded for asynchronous delivery. Six case studies were discussed in large and small groups ("breakout rooms") in synchronous sessions, and provided for self-study in the asynchronous subgroup. Topics included genetic and PGx concepts; therapeutic applications; ethical, legal, and social considerations; and practical implementation. Pre- and post-course surveys measured self-rated knowledge using a 5-point Likert Scale and tested objective knowledge with a graded quiz. Results: Thirty-six pharmacists completed the course and both surveys. Participants reported backgrounds in community (88.9%) and hospital (38.9%) practice. Prior education in PGx was reported by 44.4% from degree programs and 27.8% from continuing education. Overall responses to statements about confidence in PGx moved from a median of "Disagree" at baseline to "Agree" after receiving PGx education (2-point difference [1,2] on 5-point Likert Scale; p < 0.001), indicating an increase in self-assessed competency in PGx. Likewise, mean participant grades on the knowledge quiz improved (20.8±21.9% pre-course vs 70.2±19.1% post-course, p < 0.001). There was no difference in these results between synchronous and asynchronous groups. Conclusion: A didactic and case-based PGx education program was effective at increasing pharmacist knowledge and confidence in PGx in both synchronous and asynchronous environments. Knowledge gained can be utilized in delivery of patient-centered, personalized medication therapy management in the pharmacy setting.

Prevalence and Risk Factors of Augmented Renal Clearance: A Systematic Review and Meta-Analysis.

Kidney function assessment in the critically ill overlooks the possibility for hyperfunctioning kidneys, known as augmented renal clearance (ARC), which could contribute to therapeutic failures in the intensive care unit (ICU). The aim of this research is to conduct a systematic review and meta-analysis of prevalence and risk factors of ARC in the critically ill. MEDLINE, Embase, Cochrane Library, CINAHL, Scopus, ProQuest Dissertations and Theses Global databases were searched on 27 October 2020. We included studies conducted in critically ill adults who reported the prevalence and/or risk factors of ARC. We evaluated study quality using the Joanna Briggs Institute appraisal tool. Case reports, reviews, editorials and commentaries were excluded. We generated a random-effects meta-analytic model using the inverse variance method and visualized the pooled estimates using forest plots. Seventy studies were included. The pooled prevalence (95% CI) was 39% (34.9-43.3). Prevalence for neuro, trauma, mixed and sepsis ICUs were 74 (55-87), 58 (48-67), 36 (31-41) and 33 (21-48), respectively. Age, male sex and trauma were associated with ARC with pooled OR (95% CI) of 0.95 (0.93-0.96), 2.36 (1.28-4.36), 2.60 (1.21-5.58), respectively. Limitations included variations in ARC definition, inclusion and exclusion criteria and studies design. In conclusion, ARC is prevalent in critically ill patients, especially those in the neurocritical care and trauma ICU population. Young age, male sex and trauma are risk factors for ARC in those with apparently normal renal function. Further research on optimal dosing of drugs in the setting of ARC is warranted. (Prospero registration: CRD42021246417).

Applications for pharmacogenomics in pharmacy practice: A scoping review.

BACKGROUND: Pharmacogenomics (PGx) can provide valuable pharmacokinetic and pharmacodynamic information for the pharmacist's assessment of drug therapy, especially within medication therapy management (MTM) services. However, no review has comprehensively mapped the pharmacists' use of PGx in practice-based research. Doing so would allow future researchers, practitioners, and policy-makers to identify the ideal populations and settings for PGx implementation within the pharmacy. OBJECTIVE: The purpose of this review is to identify the evidence to date of PGx use in pharmacy practice. METHODS: A scoping review was conducted to find all studied non-oncologic pharmacy practices incorporating PGx testing. Search terms were applied to 5 databases and relevant journals. Characteristics of patients, pharmacy settings, genetic tests, and outcomes were summarized to determine models most likely to benefit patients. RESULTS: The search identified 43 studies on the use of PGx by pharmacists published between 2007 and 2020. CYP2C19 testing with antiplatelets was the most studied model, found in both community and institutional settings. It also was the most actionable test: approximately 30% of patients have polymorphisms indicating a need for alternative antiplatelets, and identifying these patients can reduce morbidity and mortality by more than 50%. As technology shifts, broader studies using multi-gene panel tests within MTM demonstrate an approximate 50% decrease in emergency visits and hospitalizations in elderly polypharmacy patients. Clinical benefit or drug-gene interactions are also found in other cardiovascular, psychiatric, analgesic, and gastrointestinal indications. No evaluations of actual costs or of pharmacist prescribing within pharmacy-based PGx have been performed. Facilitators towards successful PGx implementation included pharmacist education, collaboration with other healthcare providers, and the use of clinical decision software. CONCLUSIONS: Pharmacogenomic testing has demonstrated feasibility and improved medication outcomes in pharmacy practice, including in the community pharmacy. Further PGx research should be directed towards pharmacist prescribing, pharmacist education, and pharmacoeconomics.

Feasibility of Using Oral Fluid for Therapeutic Drug Monitoring of Antiepileptic Drugs.

Therapeutic drug monitoring (TDM) of antiepileptic drugs (AED) using blood is well established but limited by its invasiveness, accessibility, cost, interpretation errors, and related disturbances in protein binding. TDM using oral fluid (OF) could overcome these limitations. This paper provides a summary of the current evidence for using OF as a matrix to perform TDM of AEDs, as well as practical considerations. A literature search of MEDLINE, EMBASE, and the Cochrane Library was conducted on April 9, 2018 (and then updated on May 20, 2020) using all AEDs as keywords along with "oral fluid," "saliva," "salivary," "seizure," "epilepsy," "antiepileptic," and "anticonvulsant." A total of 18 relevant articles were found and included in this review. There is evidence to suggest that AED TDM using OF is feasible and that reference ranges can be calculated for the following drugs: carbamazepine, ethosuximide, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, topiramate, and valproic acid. For all other AEDs, there is either a lack of evidence on the feasibility of TDM using OF or the evidence indicates that TDM using OF is not feasible. Practical considerations should include the timing and method of OF collection (stimulated or unstimulated) due to their probable impact on the reliability of AED TDM. Using OF may improve the acceptability and accessibility and reduce the cost of AED TDM. Clinical implementation requires standardized collection protocols, more rigorously defined OF reference ranges, and further studies to determine the relevance to clinically important outcomes.

Drug Dosing in Patients Undergoing Therapeutic Plasma Exchange.

Therapeutic plasma exchange (TPE) is an extracorporeal process in which a large volume of whole blood is taken from the patient's vein. Plasma is then separated from the other cellular components of the blood and discarded while the remaining blood components may then be returned to the patient. Replacement fluids such as albumin or fresh-frozen plasma may or may not be used. TPE has been used clinically for the removal of pathologic targets in the plasma in a variety of conditions, such as pathogenic antibodies in autoimmune disorders. TPE is becoming more common in the neurointensive care space as autoimmunity has been shown to play an etiological role in many acute neurological disorders. It is important to note that not only does TPE removes pathologic elements from the plasma, but may also remove drugs, which may be an intended or unintended consequence. The objective of the current review is to provide an up-to-date summary of the available evidence pertaining to drug removal via TPE and provide relevant clinical suggestions where applicable. This review also aims to provide an easy-to-follow clinical tool in order to determine the possibility of a drug removal via TPE given the procedure-specific and pharmacokinetic drug properties.

Enantioselective assay of nimodipine in human plasma using liquid chromatography-tandem mass spectrometry.

Nimodipine is a dihydropyridine calcium channel blocker that exhibits higher selectivity toward cerebral blood vessels compared with other members of the same class. It has been shown to improve outcomes and prevent delayed cerebral ischemia in the setting of aneurysmal subarachnoid hemorrhage, a life-threatening brain bleed. Nimodipine is a chiral compound and it is marketed as a racemic mixture of (+)-R and (-)-S enantiomers. (-)-S-Nimodipine is approximately twice as potent a vasorelaxant as the racemic mixture and is more rapidly eliminated than the (+)-R counterpart following oral dosing. Few analytical procedures have been reported to determine nimodipine enantiomers in biological samples; however, the reported methods were time-consuming, involved multistep extraction procedures and required large sample volumes. Herein, we present 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 CV and percentage error were within ±14% while the interday values were within ±13%, making this analytical method feasible for research purposes and pharmacokinetic studies.

Nimodipine Pharmacokinetic Variability in Various Patient Populations.

Nimodipine has been shown to improve outcomes following aneurysmal subarachnoid hemorrhage. Guidelines recommend that all patients receive a fixed dose of oral nimodipine for 21 days. However, pharmacokinetic studies have suggested variability of nimodipine pharmacokinetics in subarachnoid hemorrhage and in other patient populations. The clinical relevance of such variability is unknown. Therefore, the objective of the present review is, first, to conduct a literature review and summarize nimodipine pharmacokinetic data and sources of variability in various patient groups. Second, to determine if there is any evidence reporting an association between nimodipine exposure and clinical outcomes in patients with subarachnoid hemorrhage. A systematic literature search was performed in MEDLINE and EMBASE. The following keywords were used: ("nimodipine" OR "nymalize" OR "nimotop") AND ("pharmacokinetic*", OR "PK"). The search results were limited to English language and human studies. A large interpatient variability in nimodipine pharmacokinetics has been reported. Patient-specific factors that had an influence on pharmacokinetic parameters are age, comorbidities, variabilities in metabolism due to genetic polymorphism and co-administered medications, as well as nimodipine administration technique. The association between nimodipine exposure and clinical outcomes remains unclear and data available are too scarce to reach a firm conclusion. Here, we present a narrative review with a systematic literature search discussing nimodipine pharmacokinetic variability in various patient populations. It is not clear if minimal or lack of systemic exposure to nimodipine denies its benefit and contributes to worsening outcomes in patients with subarachnoid hemorrhage. Further studies are needed to determine if such an association exists.

The Impact of Nimodipine Administration through Feeding Tube on Outcomes in Patients with Aneurysmal Subarachnoid Hemorrhage.

PURPOSE: Delayed cerebral ischemia (DCI) and vasospasm are the main challenges contributing to unfavorable outcomes following aneurysmal subarachnoid hemorrhage. Nimodipine has been shown to decrease the incidence of delayed cerebral ischemia and improve outcomes. In patients who are unable to swallow, nimodipine tablets are crushed and administered through enteral feeding tubes. However, it is not clear whether this may result in reduced clinical effectiveness. The aims of the study were to investigate the impact of nimodipine administration through enteral feeding tubes, in the first 7 days and over the 21-days period on patient outcomes. METHODS: A retrospective chart review of subarachnoid hemorrhage patients admitted at the University of Alberta Hospital, Edmonton, Alberta, Canada was carried out. Logistic regression modelling was utilized to identify predictors of vasospasm and delayed cerebral ischemia. Main outcome measures were angiographic evidence of moderate to severe vasospasm, development of delayed cerebral ischemia and hospital mortality. RESULTS: 85 patients were included. Following adjustment for disease severity, nimodipine administration technique 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). CONCLUSIONS: Our findings suggest that nimodipine administration via enteral feeding tubes may be associated with vasospasm and DCI in subarachnoid hemorrhage patients secondary to reduced exposure. Prospective studies are needed to confirm such association and alternate methods of administration should be explored to ensure patients are getting the benefits of nimodipine.

Systematic review of ketogenic diet use in adult patients with status epilepticus.

Status epilepticus (SE) is a medical emergency that is associated with a significant morbidity and mortality. Recently, there has been significant interest in the use of ketogenic diets (KD) in the management of SE. KD is a high-fat, low-carbohydrate, and adequate protein diet that has been shown to be a safe and effective adjuvant to present SE management in patients with refractory epilepsy. Many case reports and case series have demonstrated the potential safety and effectiveness of KD for the acute treatment of SE; however, quality studies remain scarce on this topic. The purpose of this systematic review is to summarize the available evidence for the safety and effectiveness of KD in adults with SE. A literature search was performed in MEDLINE, EMBASE, Cochrane Library, and CINAHL (September 14, 2018). The search was repeated on March 27, 2019, to include any studies published since the original search. Keywords related to KD and SE were used. Studies were selected based on the reported use of the KD in SE. The search resulted in a total of 954 records. After screening and full-text review, 17 articles were included in this review: four observational studies, 10 case reports, and 3 case series. Based on the observational studies, a total of 38 Patients with SE have been reported. KD was successful in achieving cessation of SE in 31 Patients (82%). The most common adverse effects reported were metabolic acidosis, hyperlipidemia, and hypoglycemia. The current limited evidence suggests that KD might be considered as an option for adult patients with SE. Although promising, the results need to be interpreted with caution due to the inherent bias, confounding and small sample size of the included studies. A randomized controlled trial is recommended to establish role of KD in the management of SE in adults.