Interventions to address potentially inappropriate prescriptions and over-the-counter medication use among adults 65 years and older in primary care settings: protocol for a systematic review.

PURPOSE: To inform recommendations by the Canadian Task Force on Preventive Health Care on potentially inappropriate prescribing and over-the-counter (OTC) medication use among adults aged 65 years and older in primary care settings. This protocol outlines the planned scope and methods for a systematic review of the benefits and harms and acceptability of interventions to reduce potentially inappropriate prescriptions and OTC medication use. METHODS: De novo systematic reviews will be conducted to synthesize the available evidence on (a) the benefits and harms of interventions to reduce potentially inappropriate prescriptions and OTC medications compared to no intervention, usual care, or non- or minimally active intervention among adults aged 65 years and older and (b) the acceptability of these interventions or attributes among patients. Outcomes of interest for the benefits and harms review are all-cause mortality, hospitalization, non-serious adverse drug reactions, quality of life, emergency department visits, injurious falls, medical visits, and the number of medications (and number of pills). Outcomes for the acceptability review are the preference for and relative importance of different interventions or their attributes. For the benefits and harms review, we will search MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for randomized controlled trials. For the acceptability review, we will search MEDLINE, Embase, PsycInfo, Cochrane Central Register of Controlled Trials, and the NHS Economic Evaluation Database for experimental and observational studies with a comparator. Websites of relevant organizations, other grey literature sources, and reference lists of included studies and reviews will be searched. Title and abstract screening will be completed by two independent reviewers using the liberal accelerated approach. Full-text review, data extraction, risk of bias assessments, and GRADE (Grading of Recommendations Assessment, Development and Evaluation) will be completed independently by two reviewers, with any disagreements resolved by consensus or by consulting with a third reviewer. The GRADE approach will be used to assess the certainty of the evidence for outcomes. DISCUSSION: The results of this systematic review will be used by the Canadian Task Force on Preventive Health Care to inform their recommendation on potentially inappropriate prescribing and OTC medication use among adults aged 65 years and older. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (KQ1: CRD42022302313; KQ2: CRD42022302324); Open Science Framework ( https://osf.io/urj4b/ ).

Delirium and Associated Length of Stay and Costs in Critically Ill Patients.

PURPOSE: Delirium frequently affects critically ill patients in the intensive care unit (ICU). The purpose of this study is to evaluate the impact of delirium on ICU and hospital length of stay (LOS) and perform a cost analysis. MATERIALS AND METHODS: Prospective studies and randomized controlled trials of patients in the ICU with delirium published between January 1, 2015, and December 31, 2020, were evaluated. Outcome variables including ICU and hospital LOS were obtained, and ICU and hospital costs were derived from the respective LOS. RESULTS: Forty-one studies met inclusion criteria. The mean difference of ICU LOS between patients with and without delirium was significant at 4.77 days (p < 0.001); for hospital LOS, this was significant at 6.67 days (p < 0.001). Cost data were extractable for 27 studies in which both ICU and hospital LOS were available. The mean difference of ICU costs between patients with and without delirium was significant at $3,921 (p < 0.001); for hospital costs, the mean difference was $5,936 (p < 0.001). CONCLUSION: ICU and hospital LOS and associated costs were significantly higher for patients with delirium, compared to those without delirium. Further research is necessary to elucidate other determinants of increased costs and cost-reducing strategies for critically ill patients with delirium. This can provide insight into the required resources for the prevention of delirium, which may contribute to decreasing healthcare expenditure while optimizing the quality of care.

It Takes a Village : Contending With Drug Shortages During Disasters.

Critical drug shortages have been widely documented during the coronavirus disease 2019 (COVID-19) pandemic, particularly for IV sedatives used to facilitate mechanical ventilation. Surges in volume of patients requiring mechanical ventilation coupled with prolonged ventilator days and the high sedative dosing requirements observed quickly led to the depletion of "just-in-time" inventories typically maintained by institutions. This manuscript describes drug shortages in the context of global, manufacturing, regional and institutional perspectives in times of a worldwide crisis such as a pandemic. We describe etiologic factors that lead to drug shortages including issues related to supply (eg, manufacturing difficulties, supply chain breakdowns) and variables that influence demand (eg, volatile prescribing practices, anecdotal or low-level data, hoarding). In addition, we describe methods to mitigate drug shortages as well as conservation strategies for sedatives, analgesics and neuromuscular blockers that could readily be applied at the bedside. The COVID-19 pandemic has accentuated the need for a coordinated, multi-pronged approach to optimize medication availability as individual or unilateral efforts are unlikely to be successful.

Vancomycin Population Pharmacokinetics in Critically Ill Adults During Sustained Low-Efficiency Dialysis.

BACKGROUND: Sustained low-efficiency dialysis (SLED) is a hybrid form of dialysis that is increasingly used in critically ill patients with kidney injury and hemodynamic instability. Antimicrobial dosing for patients receiving SLED is informed by pharmacokinetic studies that describe the drug clearance. Studies available to assist in the dosing of vancomycin in the context of SLED are lacking. OBJECTIVE: The objective of this prospective observational study was to describe the population pharmacokinetics of vancomycin in critically ill patients receiving SLED, and use simulation studies to propose dosing strategies. METHODS: Serial serum samples were obtained from 31 critically ill patients prescribed vancomycin while receiving SLED. Vancomycin concentrations were quantified in plasma using a validated liquid chromatography mass spectrometry/mass spectrometry method. A population pharmacokinetic model was developed, and Monte Carlo simulation was used to determine the probability of target attainment at different doses. RESULTS: From a total of 335 serum samples from 31 patients receiving 52 sessions of SLED therapy, a two-compartment linear model with zero-order input was developed. The mean (standard deviation) clearance of vancomycin on and off SLED was 5.97 (4.04) and 2.40 (1.46) L/h, respectively. Using pharmacodynamic targets for efficacy (area under the concentration-time curve from time zero to 24 h [AUC24]/minimum inhibitory concentration [MIC] ≥ 400) and safety (AUC24 ≥ 700), a loading dose of 2400 mg followed by daily doses of 1600 mg is recommended. Subsequent dosing should be informed by therapeutic drug monitoring of vancomycin levels. CONCLUSIONS: In critically ill patients receiving SLED, vancomycin clearance is highly variable with a narrow therapeutic window. Empiric dosing is proposed but subsequent dosing should be guided by drug levels.

Incidence, causes, and consequences of preventable adverse drug events: protocol for an overview of reviews.

BACKGROUND: Medication errors represent a noteworthy source of harm to patients. In recent years, several systematic reviews have assessed the frequency and causes of these events, as well as other factors such as commonly associated drugs, their incidence in different specialties, and their consequences to patients. Despite this past literature, there remains a need to study discrepancies between these reviews and establish the current state of the evidence. The planned review will bring together, compare, and contract existing evidence related to the occurrence of medication errors in acute and continuing/long-term care settings. METHODS: A systematic review of reviews will be performed. A literature search designed by an experienced information specialist will be carried out in Medline, Embase, and the Cochrane Library. We will seek systematic reviews and meta-analyses of primary research studies that evaluate one or more of the following aspects of the occurrence of preventable adverse drug events in hospitals and long-term care centers: the incidence of preventable adverse drug events, either overall or within subgroups of interest related to setting; drug or patient characteristics; cited consequences of these events to patients, including death, emergency room visits, or other outcomes; and established causes of the preventable adverse drug events. Two researchers will independently screen all abstracts and full texts for study selection and subsequently perform data extraction from all included studies. Quality of the reviews will be assessed using the assessing the methodological quality of systematic reviews (AMSTAR) tool. Where objectives from two or more reviews overlap, we will employ the Jadad framework to assess the causes of any noted discrepancies between reviews. An overall summary of results will be performed using tabular and graphical approaches and will be supplemented by narrative description. DISCUSSION: This overview will help synthesize the broad degree of information available on this important topic. This review is being performed by members of the Drug Safety and Effectiveness Network along with collaboration from Health Canada, and its findings will be published in a peer-reviewed journal. The results may also inform future research in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016043220.

Epidemiology and management of atrial fibrillation in medical and noncardiac surgical adult intensive care unit patients.

PURPOSE: The aim of the study was to describe the epidemiology and management of atrial fibrillation (AF) in noncardiac surgery critically ill patients in a retrospective, observational study at 3 mixed medical-surgical, university-affiliated intensive care units (ICUs). METHODS: Consecutive patients admitted during a 1-year period with any documentation of AF during ICU stay were identified. Demographic data, risk factors, interventions, and outcomes were collected from the medical record. RESULTS: A total of 3081 patients were admitted during the 1-year study period in which 348 consecutive patients (10.5%) had documented AF. Atrial fibrillation was of new onset in 139 patients (4.5%) and preexisting in 186 patients (6.0%). Hemodynamic instability developed in 37% and 10% of patients with new-onset AF and patients with preexisting AF, respectively. Most (73%) patients with new-onset AF had at least 1 modifiable risk factor. Pharmacologic rhythm conversion was attempted in 76% and 26% of patients with new-onset AF and patients with preexisting AF, respectively. Although initially successful in 87% of new-onset cases, 42% reverted back to AF. Electrical conversion was successful in 7 (27%) of 26 and 0 (0%) of 5 of patients with new-onset AF and patients with preexisting AF, respectively. In total, 18% and 62% of patients with new-onset AF and patients with preexisting AF, respectively, who survived to ICU discharge left the ICU in AF. CONCLUSIONS: Atrial fibrillation is common but transient in most ICU patients. Electrical cardioversion is often unsuccessful, and pharmacologic rhythm conversion is often only transiently effective. Modifiable risk factors are common among these patients. Future studies are needed to address the management of AF in the ICU.

Fenoldopam versus nitroprusside for the treatment of hypertensive emergency.

BACKGROUND: While sodium nitroprusside remains first-line therapy for hypertensive emergency (HEM), fenoldopam is increasingly being used because of its benign safety profile and potential renal protective effects. OBJECTIVE: To compare the efficacy, safety, and cost of sodium nitroprusside versus fenoldopam for the treatment of HEM. METHODS: This study was a retrospective analysis of consecutive patients with HEM admitted to a university-affiliated, level 1 trauma center from 1999 to 2001 and treated with either nitroprusside (n = 21) or fenoldopam (n = 22) for >30 minutes. Time to reach mean arterial pressure (MAP) goal, change in MAP over time, time to initiation of oral antihypertensive therapy, change in renal function, incidence of cyanide toxicity, and cost of therapy were compared between groups. RESULTS: Demographic parameters were similar between groups, except renal failure, which was more prevalent in the fenoldopam group (10% vs 46%; p = 0.009). Neither the mean +/- SD pretreatment MAP (nitroprusside 168 +/- 19; fenoldopam 163 +/- 19; p = 0.45), time to reach MAP goal (3.6 [0.4-30] vs 4 [1-22] h; p = 0.51), nor infusion duration (18 [0.7-113] vs 18 [3-74] h; p = 0.45) differed between the patient groups. Time to initiation of oral antihypertensive therapy was similar between nitroprusside--(4.5 h [0.5-22] and fenoldopam--(6.5 h [1-100] treated patients; p = 0.65). Additional intravenous antihypertensives were administered to 16 patients in each group (p = 0.80). Change in creatinine clearance and incidence of tachycardia did not differ between groups. No symptoms of cyanide toxicity were detected. Cost of drug therapy was greater with fenoldopam (597.60 dollars, 199.20-6675.20 dollars); than nitroprusside (2.66 dollars, 1.68-3.48 dollars; p < 0.001). CONCLUSIONS: Treatment of HEM with fenoldopam appears to result in patient outcomes equivalent to those with nitroprusside but at a substantially higher cost. Further study is required to delineate the exact role of fenoldopam for treatment of HEM.

An evaluation of the cost effectiveness of drotrecogin alfa (activated) relative to the number of organ system failures.

BACKGROUND: While drotrecogin alfa (activated) was shown to decrease absolute 28-day mortality by 6.1% in patients with severe sepsis in the Recombinant Human Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study, no mortality benefit was observed in the subset of patients with only one organ system failure. Consequently, some institutions restrict drotrecogin alfa (activated) use to patients with severe sepsis with >/=2 organ system failures. OBJECTIVE: To measure the cost effectiveness of drotrecogin alfa (activated) for treatment of severe sepsis in relation to the number of organ system failures and determine the economic impact of restricting drotrecogin alfa (activated) use based on the number of organ system failures. PERSPECTIVE: Policy perspective specific to our 340-bed, level I trauma centre. METHODS: A Monte Carlo simulation analysis was conducted to evaluate a hypothetical cohort of 10 000 patients with severe sepsis in four scenarios restricting treatment with drotrecogin alfa (activated) to patients with >/=1, >/=2, >/=3 or >/=4 organ system failures. The primary outcomes of 28-day all-cause mortality and serious bleeding were obtained from the PROWESS study. Costs (year 2002 values) were obtained from institutional financial records and literature estimates. The incremental cost per life saved at 28 days with drotrecogin alfa (activated) plus best standard care versus best standard care alone (placebo) was calculated. The incidence of severe sepsis and number of drotrecogin alfa (activated) candidates were estimated through chart review, and projected annual institutional expenditures were derived according to these data. RESULTS: With increasing number of organ system failures, the proportion of lives saved with drotrecogin alfa (activated) increased, and consequently the ICER decreased. Restriction of drotrecogin alfa (activated) to patients with >/=4 organ system failures was the most cost-effective scenario (0.11 lives saved; 56727 US dollars per life saved). For the nine patients that would be treated annually by our institution under this policy, one life would be saved at a total additional cost of 56160 US dollars per year. Use of the drug in patients with >/=1 or >/=2 organ system failures would save the greatest number of lives per year (4-5); however, restricting drotrecogin alfa (activated) to patients with >/=2 organ system failures would be the cheaper alternative (total additional cost 356022 US dollars vs 462204 US dollars . CONCLUSION: While restriction of drotrecogin alfa (activated) use to patients with sepsis with >/=4 organ system failures is the most cost-effective alternative, restriction to those with >/=2 organ system failures is the preferred alternative for our institution according to the number of lives saved and available financial resources.