Pharmacokinetic aspects of retinal drug delivery del Amo, Eva M.; Rimpelä, Anna-Kaisa; Heikkinen, Emma ...
Progress in retinal and eye research,
March 2017, 2017-Mar, 2017-03-00, 20170301, Letnik:
57
Journal Article
Recenzirano
Odprti dostop
Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, ...intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.
IMPORTANCE: Major postoperative complications and delirium contribute independently to adverse outcomes and high resource use in patients who undergo major surgery; however, their interrelationship ...is not well examined. OBJECTIVE: To evaluate the association of major postoperative complications and delirium, alone and combined, with adverse outcomes after surgery. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study in 2 large academic medical centers of 566 patients who were 70 years or older without recognized dementia or a history of delirium and underwent elective major orthopedic, vascular, or abdominal surgical procedures with a minimum 3-day hospitalization between June 18, 2010, and August 8, 2013. Data analysis took place from December 13, 2013, through May 1, 2015. MAIN OUTCOMES AND MEASURES: Major postoperative complications, defined as life-altering or life-threatening events (Accordion Severity grade 2 or higher), were identified by expert-panel adjudication. Delirium was measured daily with the Confusion Assessment Method and a validated medical record review method. The following 4 subgroups were analyzed: (1) no complications or delirium; (2) complications only; (3) delirium only; and (4) complications and delirium. Adverse outcomes included a length of stay (LOS) of more than 5 days, institutional discharge, and rehospitalization within 30 days of discharge. RESULTS: In the 566 participants, the mean (SD) age was 76.7 (5.2) years, 236 (41.7%) were male, and 523 (92.4%) were white. Forty-seven patients (8.3%) developed major complications and 135 (23.9%) developed delirium. Compared with no complications or delirium as the reference group, major complications only contributed to prolonged LOS only (relative risk RR, 2.8; 95% CI, 1.9-4.0); by contrast, delirium only significantly increased all adverse outcomes, including prolonged LOS (RR, 1.9; 95% CI, 1.4-2.7), institutional discharge (RR, 1.5; 95% CI, 1.3-1.7), and 30-day readmission (RR, 2.3; 95% CI, 1.4-3.7). The subgroup with complications and delirium had the highest rates of all adverse outcomes, including prolonged LOS (RR, 3.4; 95% CI, 2.3-4.8), institutional discharge (RR, 1.8; 95% CI, 1.4-2.5), and 30-day readmission (RR, 3.0; 95% CI, 1.3-6.8). Delirium exerted the highest attributable risk at the population level (5.8%; 95% CI, 4.7-6.8) compared with all other adverse events (prolonged LOS, institutional discharge, or readmission). CONCLUSIONS AND RELEVANCE: Major postoperative complications and delirium are separately associated with adverse events and demonstrate a combined effect. Delirium occurs more frequently and has a greater effect at the population level than other major complications.
Abstract Introduction As the relationship between delirium and long-term cognitive decline has not been well-explored, we evaluated this association in a prospective study. Methods SAGES is an ...ongoing study involving 560 adults age 70 years or more without dementia scheduled for major surgery. Delirium was assessed daily in the postoperative period using the Confusion Assessment Method. General Cognitive Performance (GCP) and the Informant Questionnaire for Cognitive Decline in the Elderly were assessed preoperatively then repeatedly out to 36 months. Results On average, patients with postoperative delirium had significantly lower preoperative cognitive performance, greater immediate (1 month) impairment, equivalent recovery at 2 months, and significantly greater long-term cognitive decline relative to the nondelirium group. Proxy reports corroborated the clinical significance of the long-term cognitive decline in delirious patients. Discussion Cognitive decline after surgery is biphasic and accelerated among persons with delirium. The pace of long-term decline is similar to that seen with mild cognitive impairment.
IMPORTANCE: Intraoperative electroencephalogram (EEG) waveform suppression, often suggesting excessive general anesthesia, has been associated with postoperative delirium. OBJECTIVE: To assess ...whether EEG-guided anesthetic administration decreases the incidence of postoperative delirium. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 1232 adults aged 60 years and older undergoing major surgery and receiving general anesthesia at Barnes-Jewish Hospital in St Louis. Recruitment was from January 2015 to May 2018, with follow-up until July 2018. INTERVENTIONS: Patients were randomized 1:1 (stratified by cardiac vs noncardiac surgery and positive vs negative recent fall history) to receive EEG-guided anesthetic administration (n = 614) or usual anesthetic care (n = 618). MAIN OUTCOMES AND MEASURES: The primary outcome was incident delirium during postoperative days 1 through 5. Intraoperative measures included anesthetic concentration, EEG suppression, and hypotension. Adverse events included undesirable intraoperative movement, intraoperative awareness with recall, postoperative nausea and vomiting, medical complications, and death. RESULTS: Of the 1232 randomized patients (median age, 69 years range, 60 to 95; 563 women 45.7%), 1213 (98.5%) were assessed for the primary outcome. Delirium during postoperative days 1 to 5 occurred in 157 of 604 patients (26.0%) in the guided group and 140 of 609 patients (23.0%) in the usual care group (difference, 3.0% 95% CI, −2.0% to 8.0%; P = .22). Median end-tidal volatile anesthetic concentration was significantly lower in the guided group than the usual care group (0.69 vs 0.80 minimum alveolar concentration; difference, −0.11 95% CI, −0.13 to −0.10), and median cumulative time with EEG suppression was significantly less (7 vs 13 minutes; difference, −6.0 95% CI, −9.9 to −2.1). There was no significant difference between groups in the median cumulative time with mean arterial pressure below 60 mm Hg (7 vs 7 minutes; difference, 0.0 95% CI, −1.7 to 1.7). Undesirable movement occurred in 137 patients (22.3%) in the guided and 95 (15.4%) in the usual care group. No patients reported intraoperative awareness. Postoperative nausea and vomiting was reported in 48 patients (7.8%) in the guided and 55 patients (8.9%) in the usual care group. Serious adverse events were reported in 124 patients (20.2%) in the guided and 130 (21.0%) in the usual care group. Within 30 days of surgery, 4 patients (0.65%) in the guided group and 19 (3.07%) in the usual care group died. CONCLUSIONS AND RELEVANCE: Among older adults undergoing major surgery, EEG-guided anesthetic administration, compared with usual care, did not decrease the incidence of postoperative delirium. This finding does not support the use of EEG-guided anesthetic administration for this indication. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02241655
Objective
To examine the association of the plasma neuroaxonal injury markers neurofilament light (NfL), total tau, glial fibrillary acid protein, and ubiquitin carboxyl‐terminal hydrolase L1 with ...delirium, delirium severity, and cognitive performance.
Methods
Delirium case–no delirium control (n = 108) pairs were matched by age, sex, surgery type, cognition, and vascular comorbidities. Biomarkers were measured in plasma collected preoperatively (PREOP), and 2 days (POD2) and 30 days postoperatively (PO1MO) using Simoa technology (Quanterix, Lexington, MA). The Confusion Assessment Method (CAM) and CAM‐S (Severity) were used to measure delirium and delirium severity, respectively. Cognitive function was measured with General Cognitive Performance (GCP) scores.
Results
Delirium cases had higher NfL on POD2 and PO1MO (median matched pair difference = 16.2pg/ml and 13.6pg/ml, respectively; p < 0.05). Patients with PREOP and POD2 NfL in the highest quartile (Q4) had increased risk for incident delirium (adjusted odds ratio OR = 3.7 95% confidence interval (CI) = 1.1–12.6 and 4.6 95% CI = 1.2–18.2, respectively) and experienced more severe delirium, with sum CAM‐S scores 7.8 points (95% CI = 1.6–14.0) and 9.3 points higher (95% CI = 3.2–15.5). At PO1MO, delirium cases had continued high NfL (adjusted OR = 9.7, 95% CI = 2.3–41.4), and those with Q4 NfL values showed a −2.3 point decline in GCP score (−2.3 points, 95% CI = −4.7 to −0.9).
Interpretation
Patients with the highest PREOP or POD2 NfL levels were more likely to develop delirium. Elevated NfL at PO1MO was associated with delirium and greater cognitive decline. These findings suggest NfL may be useful as a predictive biomarker for delirium risk and long‐term cognitive decline, and once confirmed would provide pathophysiological evidence for neuroaxonal injury following delirium. ANN NEUROL 2020;88:984–994
IMPORTANCE: Delirium is a common, serious, and potentially preventable problem for older adults, associated with adverse outcomes. Coupled with its preventable nature, these adverse sequelae make ...delirium a significant public health concern; understanding its economic costs is important for policy makers and health care leaders to prioritize care. OBJECTIVE: To evaluate current 1-year health care costs attributable to postoperative delirium in older patients undergoing elective surgery. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 497 patients from the Successful Aging after Elective Surgery (SAGES) study, an ongoing cohort study of older adults undergoing major elective surgery. Patients were enrolled from June 18, 2010, to August 8, 2013. Eligible patients were 70 years or older, English-speaking, able to communicate verbally, and scheduled to undergo major surgery at 1 of 2 Harvard-affiliated hospitals with an anticipated length of stay of at least 3 days. Eligible surgical procedures included total hip or knee replacement; lumbar, cervical, or sacral laminectomy; lower extremity arterial bypass surgery; open abdominal aortic aneurysm repair; and open or laparoscopic colectomy. Data were analyzed from October 15, 2019, to September 15, 2020. EXPOSURES: Major elective surgery and hospitalization. MAIN OUTCOMES AND MEASURES: Cumulative and period-specific costs (index hospitalization, 30-day, 90-day, and 1-year follow-up) were examined using Medicare claims and extensive clinical data. Total inflation-adjusted health care costs were determined using data from Medicare administrative claims files for the 2010 to 2014 period. Delirium was rated using the Confusion Assessment Method. We also examined whether increasing delirium severity was associated with higher cumulative and period-specific costs. Delirium severity was measured with the Confusion Assessment Method–Severity long form. Regression models were used to determine costs associated with delirium after adjusting for patient demographic and clinical characteristics. RESULTS: Of the 566 patients who were eligible for the study, a total of 497 patients (mean SD age, 76.8 5.1 years; 281 women 57%; 461 White participants 93%) were enrolled after exclusion criteria were applied. During the index hospitalization, 122 patients (25%) developed postoperative delirium, whereas 375 (75%) did not. Patients with delirium had significantly higher unadjusted health care costs than patients without delirium (mean SD cost, $146 358 $140 469 vs $94 609 $80 648). After adjusting for relevant confounders, the cumulative health care costs attributable to delirium were $44 291 (95% CI, $34 554-$56 673) per patient per year, with the majority of costs coming from the first 90 days: index hospitalization ($20 327), subsequent rehospitalizations ($27 797), and postacute rehabilitation stays ($2803). Health care costs increased directly and significantly with level of delirium severity (none-mild, $83 534; moderate, $99 756; severe, $140 008), suggesting an exposure-response relationship. The adjusted mean cumulative costs attributable to severe delirium were $56 474 (95% CI, $40 927-$77 440) per patient per year. Extrapolating nationally, the health care costs attributable to postoperative delirium were estimated at $32.9 billion (95% CI, $25.7 billion-$42.2 billion) per year. CONCLUSIONS AND RELEVANCE: These findings suggest that the economic outcomes of delirium and severe delirium after elective surgery are substantial, rivaling costs associated with cardiovascular disease and diabetes. These results highlight the need for policy imperatives to address delirium as a large-scale public health issue.
Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs), recorded using electroencephalography (EEG), reflect a combination of TMS-induced cortical activity and multi-sensory responses to ...TMS. The auditory evoked potential (AEP) is a high-amplitude sensory potential-evoked by the "click" sound produced by every TMS pulse-that can dominate the TEP and obscure observation of other neural components. The AEP is peripherally evoked and therefore should not be stimulation site specific. We address the problem of disentangling the peripherally evoked AEP of the TEP from components evoked by cortical stimulation and ask whether removal of AEP enables more accurate isolation of TEP. We hypothesized that isolation of the AEP using Independent Components Analysis (ICA) would reveal features that are stimulation site specific and unique individual features. In order to improve the effectiveness of ICA for removal of AEP from the TEP, and thus more clearly separate the transcranial-evoked and non-specific TMS-modulated potentials, we merged sham and active TMS datasets representing multiple stimulation conditions, removed the resulting AEP component, and evaluated performance across different sham protocols and clinical populations using reduction in Global and Local Mean Field Power (GMFP/LMFP) and cosine similarity analysis. We show that removing AEPs significantly reduced GMFP and LMFP in the post-stimulation TEP (14 to 400 ms), driven by time windows consistent with the N100 and P200 temporal characteristics of AEPs. Cosine similarity analysis supports that removing AEPs reduces TEP similarity between subjects and reduces TEP similarity between stimulation conditions. Similarity is reduced most in a mid-latency window consistent with the N100 time-course, but nevertheless remains high in this time window. Residual TEP in this window has a time-course and topography unique from AEPs, which follow-up exploratory analyses suggest could be a modulation in the alpha band that is not stimulation site specific but is unique to individual subject. We show, using two datasets and two implementations of sham, evidence in cortical topography, TEP time-course, GMFP/LMFP and cosine similarity analyses that this procedure is effective and conservative in removing the AEP from TEP, and may thus better isolate TMS-evoked activity. We show TEP remaining in early, mid and late latencies. The early response is site and subject specific. Later response may be consistent with TMS-modulated alpha activity that is not site specific but is unique to the individual. TEP remaining after removal of AEP is unique and can provide insight into TMS-evoked potentials and other modulated oscillatory dynamics.
Postoperative delirium is frequent in older adults and is associated with postoperative neurocognitive disorder (PND). Studies evaluating perioperative medication use and delirium have generally ...evaluated medications in aggregate and been poorly controlled; the association between perioperative medication use and PND remains unclear. We sought to evaluate the association between medication use and postoperative delirium and PND in older adults undergoing major elective surgery.
This is a secondary analysis of a prospective cohort study of adults ≥70 years without dementia undergoing major elective surgery. Patients were interviewed preoperatively to determine home medication use. Postoperatively, daily hospital use of 7 different medication classes listed in guidelines as risk factors for delirium was collected; administration before delirium was verified. While hospitalized, patients were assessed daily for delirium using the Confusion Assessment Method and a validated chart review method. Cognition was evaluated preoperatively and 1 month after surgery using a neurocognitive battery. The association between prehospital medication use and postoperative delirium was assessed using a generalized linear model with a log link function, controlling for age, sex, type of surgery, Charlson comorbidity index, and baseline cognition. The association between daily postoperative medication use (when class exposure ≥5%) and time to delirium was assessed using time-varying Cox models adjusted for age, sex, surgery type, Charlson comorbidity index, Acute Physiology and Chronic Health Evaluation (APACHE)-II score, and baseline cognition. Mediation analysis was utilized to evaluate the association between medication use, delirium, and cognitive change from baseline to 1 month.
Among 560 patients enrolled, 134 (24%) developed delirium during hospitalization. The multivariable analyses revealed no significant association between prehospital benzodiazepine (relative risk RR, 1.44; 95% confidence interval CI, 0.85-2.44), beta-blocker (RR, 1.38; 95% CI, 0.94-2.05), NSAID (RR, 1.12; 95% CI, 0.77-1.62), opioid (RR, 1.22; 95% CI, 0.82-1.82), or statin (RR, 1.34; 95% CI, 0.92-1.95) exposure and delirium. Postoperative hospital benzodiazepine use (adjusted hazard ratio aHR, 3.23; 95% CI, 2.10-4.99) was associated with greater delirium. Neither postoperative hospital antipsychotic (aHR, 1.48; 95% CI, 0.74-2.94) nor opioid (aHR, 0.82; 95% CI, 0.62-1.11) use before delirium was associated with delirium. Antipsychotic use (either presurgery or postsurgery) was associated with a 0.34 point (standard error, 0.16) decrease in general cognitive performance at 1 month through its effect on delirium (P = .03), despite no total effect being observed.
Administration of benzodiazepines to older adults hospitalized after major surgery is associated with increased postoperative delirium. Association between inhospital, postoperative medication use and cognition at 1 month, independent of delirium, was not detected.
Quantifying the severity of delirium is essential to advancing clinical care by improved understanding of delirium effect, prognosis, pathophysiology, and response to treatment.
To develop and ...validate a new delirium severity measure (CAM-S) based on the Confusion Assessment Method.
Validation analysis in 2 independent cohorts.
Three academic medical centers.
The first cohort included 300 patients aged 70 years or older scheduled for major surgery. The second included 919 medical patients aged 70 years or older.
A 4-item short form and a 10-item long form were developed. Association of the maximum CAM-S score during hospitalization with hospital and posthospital outcomes related to delirium was evaluated.
Representative results included adjusted mean length of stay, which increased across levels of short-form severity from 6.5 days (95% CI, 6.2 to 6.9 days) to 12.7 days (CI, 11.2 to 14.3 days) (P for trend < 0.001) and across levels of long-form severity from 5.6 days (CI, 5.1 to 6.1 days) to 11.9 days (CI, 10.8 to 12.9 days) (P for trend < 0.001). Representative results for the composite outcome of adjusted relative risk of death or nursing home residence at 90 days increased progressively across levels of short-form severity from 1.0 (referent) to 2.5 (CI, 1.9 to 3.3) (P for trend < 0.001) and across levels of long-form severity from 1.0 (referent) to 2.5 (CI, 1.6 to 3.7) (P for trend < 0.001).
Data on clinical outcomes were measured in an older data set limited to patients aged 70 years or older.
The CAM-S provides a new delirium severity measure with strong psychometric properties and strong associations with important clinical outcomes.
National Institute on Aging.
Solidarity experienced a revival during the COVID-19 pandemic and has been an important component of the political discourse in every economic-and therefore also the social-crisis that hit Europe in ...the last years. This contribution aims to assess the relevance that members of German governing parties at the Laender level attached to solidarity during the COVID-19 pandemic. By conducting a frame analysis, we identify calls to different types of solidarity, and brought these in relation to the explanatory power of situational aspects, economic interests and party-political positions. Empirical analysis displays that solidarity is an important, albeit not too frequently used frame, in crisis dialogue. High threat perception (but not actual threat) appears to foster claims to solidarity and other forms of communal behaviour, while the economic situation and party-political stances do not exhibit an equally strong effect. Nevertheless, aligned party-political positions on solidarity go along with a reduced understanding of the concept, which primarily serves as a justification for placing a burden on the caretakers of society. This traditional notion of solidarity is even more prominent amongst leftist party members, a fact raising questions concerning the distinctiveness of German party positions, as well as concerning social equality.
PDF
