Clinical Impact of the Implementation Strategies Used to Apply the 2013 Pain, Agitation/Sedation, Delirium or 2018 Pain, Agitation/Sedation, Delirium, Immobility, Sleep Disruption Guideline Recommendations: A Systematic Review and Meta-Analysis.

OBJECTIVES: To summarize the effectiveness of implementation strategies for ICU execution of recommendations from the 2013 Pain, Agitation/Sedation, Delirium (PAD) or 2018 PAD, Immobility, Sleep Disruption (PADIS) guidelines. DATA SOURCES: PubMed, CINAHL, Scopus, and Web of Science were searched from January 2012 to August 2023. The protocol was registered with PROSPERO (CRD42020175268). STUDY SELECTION: Articles were included if: 1) design was randomized or cohort, 2) adult population evaluated, 3) employed recommendations from greater than or equal to two PAD/PADIS domains, and 4) evaluated greater than or equal to 1 of the following outcome(s): short-term mortality, delirium occurrence, mechanical ventilation (MV) duration, or ICU length of stay (LOS). DATA EXTRACTION: Two authors independently reviewed articles for eligibility, number of PAD/PADIS domains, quality according to National Heart, Lung, and Blood Institute assessment tools, implementation strategy use (including Assess, prevent, and manage pain; Both SAT and SBT; Choice of analgesia and sedation; Delirium: assess, prevent, and manage; Early mobility and exercise; Family engagement and empowerment [ABCDEF] bundle) by Cochrane Effective Practice and Organization of Care (EPOC) category, and clinical outcomes. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation. DATA SYNTHESIS: Among the 25 of 243 (10.3%) full-text articles included ( n = 23,215 patients), risk of bias was high in 13 (52%). Most studies were cohort ( n = 22, 88%). A median of 5 (interquartile range [IQR] 4-7) EPOC strategies were used to implement recommendations from two (IQR 2-3) PAD/PADIS domains. Cohort and randomized studies were pooled separately. In the cohort studies, use of EPOC strategies was not associated with a change in mortality (risk ratio [RR] 1.01; 95% CI, 0.9-1.12), or delirium (RR 0.92; 95% CI, 0.82-1.03), but was associated with a reduction in MV duration (weighted mean difference [WMD] -0.84 d; 95% CI, -1.25 to -0.43) and ICU LOS (WMD -0.77 d; 95% CI, -1.51 to 0.04). For randomized studies, EPOC strategy use was associated with reduced mortality and MV duration but not delirium or ICU LOS. CONCLUSIONS: Using multiple implementation strategies to adopt PAD/PADIS guideline recommendations may reduce mortality, duration of MV, and ICU LOS. Further prospective, controlled studies are needed to identify the most effective strategies to implement PAD/PADIS recommendations.

Comparison of Methicillin-Resistant Staphylococcus aureus Nasal Screening Predictive Value in the Intensive Care Unit and General Ward.

BACKGROUND: The clinical utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening appears promising for antimicrobial stewardship programs. However, a paucity of data remains on the diagnostic performance of culture-based MRSA screen in the intensive care unit (ICU) for pneumonia and bacteremia. OBJECTIVE: The objective of this study was to compare the predictive value of culture-based MRSA nasal screening for pneumonia and bacteremia in ICU and general ward patients. METHODS: This multicenter, retrospective study was conducted over a 23-month period. Adult patients with MRSA nasal screening ≤48 hours of collecting a respiratory and/or blood culture with concurrent initiation of anti-MRSA therapy were included. The primary endpoint was to compare the negative predictive value (NPV) associated with culture-based MRSA nasal screening between ICU and general ward patients with suspected pneumonia. RESULTS: A total of 5106 patients representing the ICU (n = 2515) and general ward (n = 2591) were evaluated. The NPV of the MRSA nares for suspected pneumonia was not significantly different between ICU and general ward patient populations (98.3% and 97.6%, respectively; P = 0.41). The MRSA nares screening tool also had a high NPV for suspected bacteremia in ICU (99.8%) and general ward groups (99.7%) (P = 0.56). The overall positive MRSA nares rates in the ICU and general ward patient populations were 9.1% and 8.2%, respectively (P = 0.283). Moreover, MRSA-positive respiratory and blood cultures among ICU patients were 5.8% and 0.8%, respectively. CONCLUSION AND RELEVANCE: Our findings support the routine use of MRSA nasal screening using the culture-based method in ICU patients with pneumonia. Further research on the clinical performance for MRSA bacteremia in the ICU is warranted.

Clinical Pharmacist-Led Impact on Inappropriate Albumin Utilization and Associated Costs in General Ward Patients.

BACKGROUND: Inappropriate albumin use in clinical practice remains problematic. Health-systems face continued challenges in promoting cost-appropriate use. OBJECTIVE: To evaluate the clinical and economic impact of a clinical pharmacist-led intervention strategy targeting inappropriate albumin use in general ward patients. METHODS: A retrospective cohort study evaluated all adult (≥18 years) general ward patients administered ≥1 dose of albumin at a university medical center over a 2-year period. The intervention consisted of a clinical pharmacist-led strategy intervening on all albumin orders not in accordance with institutional guidelines. The primary end point was to compare inappropriate albumin utilization before and after implementation. Secondary end points compared the rates of inappropriate albumin use adjusted for hospital admission and patient-days as well as associated costs by appropriateness between study periods. RESULTS: A total of 4420 patients were screened, with 1971 (44.6%) patients meeting inclusion criteria. The clinical pharmacist strategy significantly reduced inappropriate albumin (grams) utilization by 86.0% (P < 0.001). A 7-fold reduction of inappropriate albumin administered adjusted for the number of patient admissions was found from the preimplementation period following clinical pharmacist intervention strategy implementation (415.3 ± 83.2 vs 57.5 ± 34.2 g per 100 general ward hospital admissions, respectively; P < 0.001). Also, the adjusted inappropriate albumin rate was reduced from 62.2 ± 12.3 to 8.6 ± 5.2 g per 100 patient-days in the preimplementation and postimplementation periods, respectively (P < 0.001). Annual cost savings were $421 455 overall, with $341 930 resulting from mitigation of inappropriate use. CONCLUSION AND RELEVANCE: Clinical pharmacist-led interventions significantly reduced inappropriate albumin use and costs in hospitalized patients.

Comparison of Fixed-Dose Inhaled Epoprostenol and Inhaled Nitric Oxide for Acute Respiratory Distress Syndrome in Critically Ill Adults.

PURPOSE: Several reports have demonstrated similar effects on oxygenation between inhaled epoprostenol (iEPO) compared to inhaled nitric oxide (iNO) for acute respiratory distress syndrome (ARDS). Previous studies directly comparing oxygenation and clinical outcomes between iEPO and iNO exclusively in an adult ARDS patient population utilized a weight-based dosing strategy. The purpose of this study was to compare the clinical and economic impact between iNO and fixed-dosed iEPO for ARDS in adult intensive care unit (ICU) patients. METHODS: This retrospective cohort study was conducted at a major academic medical center between January 1, 2014, and October 31, 2018. Patients ≥18 years of age with moderate-to-severe ARDS were included. The primary end point was to compare the mean change in partial arterial oxygen pressure to fraction of inspired oxygen (Pao 2: Fio 2) at 4 hours from baseline between iEPO and iNO. Other secondary aims were total acquisition drug costs, in-hospital mortality, ICU and hospital length of stay, and duration of mechanical ventilation. RESULTS: A total of 239 patients were included with 139 (58.2%) and 100 (41.8%) in the iEPO and iNO groups, respectively. The mean change in Pao 2: Fio 2 at 4 hours from baseline in the iEPO and iNO groups were 31.4 ± 54.6 and 32.4 ± 42.7 mm Hg, respectively (P = .88). The responder rate at 4 hours was similar between iEPO and iNO groups (64.7% and 66.0%, respectively, P = .84). Clinical outcomes including mortality, overall hospital and ICU length of stay, and mechanical ventilation duration were similar between iEPO and iNO groups. Estimated annual cost-savings realized with iEPO was USD1 074 433. CONCLUSION: Fixed-dose iEPO was comparable to iNO in patients with moderate-to-severe ARDS for oxygenation and ventilation parameters as well as clinical outcomes. Significant cost-savings were realized with iEPO use.

Dexmedetomidine for Facilitating Mechanical Ventilation Extubation in Difficult-to-Wean ICU Patients: Systematic Review and Meta-Analysis of Clinical Trials.

BACKGROUND: Agitation and delirium are common in mechanically ventilated adult intensive care unit (ICU) patients and may contribute to delayed extubation times. Difficult-to-wean ICU patients have been associated with an increased risk of longer ICU length of stays and mortality. The purpose of this systematic review and meta-analysis is to evaluate the evidence of dexmedetomidine facilitating successful mechanical ventilation extubation in difficult-to-wean ICU patients and clinical outcomes. METHODS: A literature search was conducted using MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Global Health, Cochrane Central Register of Controlled Trials, Clinical Trial Registries, and the Health Technology Assessment Database from inception to December 5, 2019. Randomized controlled trials evaluating dexmedetomidine with the intended purpose to facilitate mechanical ventilation liberation in adult ICU patients (≥18 years) experiencing extubation failure were included. The primary outcome of time to extubation was evaluated using the weighted mean difference (WMD), with a random effects model. Secondary analyses included hospital and ICU length of stay, in-hospital mortality, hypotension, and bradycardia. RESULTS: A total of 6 trials (n = 306 patients) were included. Dexmedetomidine significantly reduced the time to extubation (WMD: -11.61 hours, 95% CI: -16.5 to -6.7, P = .005) and ICU length of stay (WMD: -3.04 days; 95% CI: -4.66 to -1.43). Hypotension risk was increased with dexmedetomidine (risk ratio [RR]: 1.62, 95% CI: 1.05-2.51), but there was no difference in bradycardia risk (RR: 3.98, 95% CI: 0.70-22.78). No differences were observed in mortality rates (RR: 1.30, 95% CI: 0.45-3.75) or hospital length of stay (WMD: -2.67 days; 95% CI: -7.73 to 2.39). CONCLUSIONS: Dexmedetomidine was associated with a significant reduction in the time to extubation and shorter ICU stay in difficult-to-wean ICU patients. Although hypotension risk was increased with dexmedetomidine, no differences in other clinical outcomes were observed.

Clinical Pharmacist-Led Impact on Inappropriate Albumin Use and Costs in the Critically Ill.

Background:Optimal albumin use in the intensive care unit (ICU) remains challenging with inappropriate use approaching 50%. No published reports have described clinical pharmacist impact aimed at mitigating inappropriate albumin use in the ICU. Objective: To evaluate the clinical and economic impact of a clinical pharmacist-led intervention strategy targeting inappropriate albumin in the ICU. Methods: A retrospective cohort study evaluated all adult (≥18 years) ICU patients administered albumin at an academic medical center over a 2-year period. Institutional guidelines were developed with clinical pharmacists targeting inappropriate albumin use. The primary end point was to compare inappropriate use of albumin administered before and after pharmacist intervention implementation. Secondary analyses compared the overall albumin use between study periods. In-hospital mortality, length of stay, and albumin-related costs between study periods were also compared. Results: A total of 4419 patients were identified, with 2448 (55.4%) critically ill patients included. The pharmacist-led strategy resulted in a 50.9% reduction of inappropriate albumin use (P < 0.001). The rate of inappropriate albumin use was 44.3 ± 10.5 and 5.5 ± 2.9 g per patient-day in the preimplementation and postimplementation periods, respectively (P < 0.001). Costs associated with overall and inappropriate albumin use in the ICU decreased by 34.8% and 87.1%, respectively. Total annual cost-savings was $355 393 in the ICUs. No differences in clinical outcomes were found. Conclusion and Relevance: Clinical pharmacist-led interventions reduced overall and inappropriate albumin use and costs without negatively affecting clinical outcomes.

Adverse Hemodynamic Events Associated With Concomitant Dexmedetomidine and Propofol for Sedation in Mechanically Ventilated ICU Patients.

PURPOSE: Nonbenzodiazepines are preferred for continuous sedation in mechanically ventilated intensive care unit (ICU) patients. Although dexmedetomidine and propofol have blood pressure lowering properties, limited data exist about the hemodynamic effects of concomitant administration. The purpose of this study was to compare the adverse hemodynamic event rate with concomitant dexmedetomidine and propofol compared to either agent alone in mechanically ventilated ICU patients. METHODS: This retrospective cohort study was conducted at a university medical center. Adult ICU patients (≥18 years) admitted between October 20, 2015, and January 25, 2018, and administered concurrent dexmedetomidine and propofol or either agent alone for ≥24 hours were included. Mean arterial pressure, heart rate, and sedative dosing requirements were assessed from initiation to 72 hours after initiation. The primary end point was comparing the incidence of hypotension among study groups. Secondary aims compared the incidence of tachycardia and bradycardia as well as clinical outcomes. RESULTS: Overall, 276 patients were included among combination (n = 93), dexmedetomidine (n = 91), and propofol (n = 92) groups. The incidence of hypotension was significantly higher in patients administered concomitant dexmedetomidine and propofol (62.4%) compared to those administered dexmedetomidine (23.1%) or propofol (23.9%) alone (P < .0001). Adjunctive dexmedetomidine with propofol was also associated with higher rates of clinically relevant hypotension requiring treatment (P = .048). The tachycardia incidence in the concomitant, dexmedetomidine, and propofol groups were 30.1%, 28.6%, and 14.1%, respectively (P = 02). Only 1.4% (n = 4) of all study patients developed bradycardia. Concomitant therapy was an independent risk factor of hypotension compared to either dexmedetomidine (odds ratio [OR]: 6.7, 95% confidence interval [CI]: 2.61-17.3, P < .0001) or propofol (OR: 2.89, 95% CI: 1.24-6.74, P = .014) monotherapy. Patients experiencing hypotension were associated with worse clinical outcomes. CONCLUSION: Concomitant dexmedetomidine and propofol use in mechanically ventilated patients increased the risk of hypotensive events. Adjunctive dexmedetomidine with propofol administration in the critically ill warrants caution.

The SUP-ICU Trial: Does It Confirm or Condemn the Practice of Stress Ulcer Prophylaxis?

Purpose: Stress ulcer prophylaxis (SUP) is routinely administered to critically ill patients for the prevention of stress ulcer-induced, clinically important bleeding (CIB). Recently, the value of SUP has been questioned due to the perceived decline in CIB and the potential for infectious complications secondary to acid suppressive therapy. The SUP-ICU trial is a large, randomized controlled trial comparing intravenous pantoprazole with placebo for the indication of SUP. It is hoped that this trial would answer many of the questions pertaining to the overall value of SUP. This article will provide an in-depth assessment of the SUP-ICU trial in the context of the overall body of literature in this area. Furthermore, applications for clinical practice and recommendations on the provision of SUP are provided. Summary: The SUP-ICU trial revealed no difference in the primary outcome of 90-day mortality with pantoprazole but lower rates of CIB were noted (which was a secondary outcome). Overall, these data provide important insight into the value of SUP along with other questions related to the provision of SUP such as the relationship between CIB and mortality, infectious complications, and enteral nutrition. Conclusions: The SUP-ICU trial is a landmark trial describing the value of SUP in a modern-day setting of intensive care unit (ICU) practice. The provision of SUP should be continued in high-risk patients. Future studies are ongoing that will add further insight to this routine practice.

Hyperoncotic Albumin Reduces Net Fluid Loss Associated With Hemodialysis.

Purpose: The purpose of this study was to compare the volume of fluid removal associated with and without 25% albumin administration in conjunction with hemodialysis. Methods: This retrospective, cohort study was conducted at a large academic medical center over a 6-month period to compare the net fluid amount removed (mL) during hemodialysis between patients administered 25% albumin and those without albumin. Results: A total of 238 patients consisting of 973 unique hemodialysis sessions were evaluated. The mean overall net fluid removed by hemodialysis in the 25% albumin and no albumin groups were 1242 mL and 1899 mL, P < .001, respectively. No albumin group had significantly higher mean fluid losses compared with 25% albumin for a total dose of either 25 g (P = .001) or 50 g (P = .001). There were no significant differences in mean fluid loss between the no albumin group and patients receiving 75 g or 100 g of albumin. Post hoc analysis failed to demonstrate a dose-dependent response in those patients receiving 25% albumin and no albumin. Conclusion: Hyperoncotic albumin administered during hemodialysis sessions reduced net fluid loss associated with hemodialysis. The findings of this study do not support the routine use of 25% albumin to improve fluid removal during dialysis.

Clinical Practice Guideline: Safe Medication Use in the ICU.

OBJECTIVE: To provide ICU clinicians with evidence-based guidance on safe medication use practices for the critically ill. DATA SOURCES: PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, Scopus, and ISI Web of Science for relevant material to December 2015. STUDY SELECTION: Based on three key components: 1) environment and patients, 2) the medication use process, and 3) the patient safety surveillance system. The committee collectively developed Population, Intervention, Comparator, Outcome questions and quality of evidence statements pertaining to medication errors and adverse drug events addressing the key components. A total of 34 Population, Intervention, Comparator, Outcome questions, five quality of evidence statements, and one commentary on disclosure was developed. DATA EXTRACTION: Subcommittee members were assigned selected Population, Intervention, Comparator, Outcome questions or quality of evidence statements. Subcommittee members completed their Grading of Recommendations Assessment, Development, and Evaluation of the question with his/her quality of evidence assessment and proposed strength of recommendation, then the draft was reviewed by the relevant subcommittee. The subcommittee collectively reviewed the evidence profiles for each question they developed. After the draft was discussed and approved by the entire committee, then the document was circulated among all members for voting on the quality of evidence and strength of recommendation. DATA SYNTHESIS: The committee followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation system to determine quality of evidence and strength of recommendations. CONCLUSIONS: This guideline evaluates the ICU environment as a risk for medication-related events and the environmental changes that are possible to improve safe medication use. Prevention strategies for medication-related events are reviewed by medication use process node (prescribing, distribution, administration, monitoring). Detailed considerations to an active surveillance system that includes reporting, identification, and evaluation are discussed. Also, highlighted is the need for future research for safe medication practices that is specific to critically ill patients.

Characterization of Guideline Evidence for Off-label Medication Use in the Intensive Care Unit.

BACKGROUND: Non-Food and Drug Administration (FDA) or off-label medication prescribing occurs commonly in the intensive care unit (ICU). Off-label medication use creates a concern for untoward adverse effects; however, this worry may be alleviated by supportive literature. OBJECTIVE: To evaluate the evidence behind off-label medication use by determining the presence of guideline support and compare graded recommendations to an online tertiary resource, DRUGDEX. METHODS: Off-label medication use was identified prospectively over 3 months in medical ICUs in 3 academic medical centers. Literature searches were conducted in PubMed and the national guideline clearinghouse website to determine the presence of guideline support. DRUGDEX was also searched for strength-of-evidence ratings to serve as a comparator. RESULTS: A total of 287 off-label medication indication searches resulted in 44% (126/287) without identified evidence; 253 guidelines were identified for 56% (161/287) of indications. Of the published guidelines, 89% (226/253) supported the off-label indication. In the DRUGDEX comparison, 67% (97/144) of guideline gradings disagree with DRUGDEX, whereas 33% (47/144) of the gradings matched the online database. CONCLUSION: Because more than half of off-label medication use has the benefit of supportive guidelines recommendations and a majority of gradings are inconsistent with DRUGDEX, clinicians should consider utilizing guidelines to inform off-label medication use in the ICU. Still, there is a considerable amount of off-label medication use in the ICU that lacks supporting evidence, and use remains concerning because it may lead to inappropriate treatment and adverse events.

Stress Ulcer Prophylaxis.

OBJECTIVES: Stress ulcer prophylaxis is commonly administered to critically ill patients for the prevention of clinically important stress-related mucosal bleeding from the upper gastrointestinal tract. Despite widespread incorporation of stress ulcer prophylaxis into practice around the world, questions are emerging about its indications and impact. This clinically focused article will review current controversies related to stress ulcer prophylaxis for critically ill adult patients, including bleeding frequency, risk factors, comparative efficacy, adverse effect profile, and overall cost-effectiveness of the available stress ulcer prophylaxis regimens. DATA SOURCES: A MEDLINE search was conducted from inception through August 2015. STUDY SELECTION: Selected publications describing stress ulcer prophylaxis in adult patients were retrieved (original research, systematic reviews, and practice guidelines); their bibliographies were also reviewed to identify additional pertinent publications. DATA EXTRACTION: Data from relevant publications were abstracted and summarized. DATA SYNTHESIS: The existing evidence is organized to describe the patients most likely to benefit from stress ulcer prophylaxis, review the comparative efficacy of proton pump inhibitors and histamine 2 receptor antagonists, the adverse effects of stress ulcer prophylaxis, and overall cost-effectiveness. CONCLUSIONS: Many stress ulcer prophylaxis recommendations are based on older studies at risk of bias, which may not be applicable to modern practice. Stress ulcer prophylaxis should be limited to patients considered to be at high risk for clinically important bleeding. When evaluating only the trials at low risk for bias, the evidence does not clearly support lower bleeding rates with proton pump inhibitors over histamine 2 receptor antagonists; however, proton pump inhibitors appear to be the dominant drug class used worldwide today. The current rate of upper gastrointestinal bleeding and the relative adverse effects of acid suppression on infectious risk may drive not only the effectiveness, but also the cost-effectiveness of stress ulcer prophylaxis today. Research is currently underway to better address these issues.

Correlation of Free and Total Phenytoin Serum Concentrations in Critically Ill Patients.

BACKGROUND: Phenytoin is a common medication for seizure treatment and prophylaxis in the intensive care unit (ICU). The clinical utility of the Sheiner-Tozer equation for adjusting total phenytoin levels for hypoalbuminemia remains controversial. OBJECTIVE: The purpose of this study was to evaluate the correlation of this formula in predicting phenytoin serum concentrations. METHODS: A retrospective cohort study was conducted in the adult ICU between January 1, 2010, and June 21, 2013. Patients meeting the following study criteria were included: age ≥18 years, admission to the ICU, simultaneously drawn total and free serum phenytoin concentrations with albumin ≤48 hours of phenytoin draws. Study end points were the correlation as well as the level of agreement in the interpretation of the free and adjusted phenytoin concentrations using the Sheiner-Tozer formula in critically ill patients with hypoalbuminemia. RESULTS: A total of 238 patients were analyzed. Mean adjusted total phenytoin and free levels were 16.1 ± 8.1 and 1.5 ± 0.8 µg/mL, respectively (r = 0.817; P < 0.001). Absolute agreement with level interpretation between adjusted total phenytoin and free levels was 77% (κ = 0.633; P < 0.001). Adjusted phenytoin serum concentrations more frequently overestimated the free level. CONCLUSIONS: There is a significant correlation between free and adjusted total phenytoin levels using the Sheiner-Tozer equation in critically ill patients. However, disagreement was noted with interpretation, primarily because of the adjusted concentration overestimating the free level. This imprecision may lead to inaccurate decision making regarding the management of phenytoin in this patient population. Thus, free phenytoin levels should be utilized.

Drug Class Combination-Associated Acute Kidney Injury.

OBJECTIVE: To evaluate the quality of available evidence of drug class combinations and their association with the development of acute kidney injury (AKI). DATA SOURCES: A search of MEDLINE and Embase databases was completed using the following terms: "risk factor AND (acute kidney injury or acute kidney failure) AND (drug or medication)." STUDY SELECTION AND DATA EXTRACTION: Inclusion criteria were the following: English language, full-text availability, and at least 1 drug-combination. Each citation was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria. The literature was evaluated using the quality of evidence component of GRADE. No standardized definition of AKI was applied throughout.. DATA SYNTHESIS: Out of 2139 total citations, 151 were assessed for full-text review, with 121 citations (6%) meeting inclusion criteria, producing76 unique drug class combinations. Overall, 56 combinations (73.7%) were considered very low quality; 12 (15.8%) were considered low quality. There were 8 (10.5%) of moderate quality, and no combination was considered high quality. 58 (76%) combinations that had a single citation,with a mean of 1.6 citations per drug class combination. The combination of nonsteroidal anti-inflammatory drugs (NSAIDs) and diuretics was reported in 10 citations, the largest number of citations. CONCLUSIONS: Our study demonstrates a lack of well-designed studies addressing drug class combination-associated AKI. The combination of NSAIDs and diuretics with or without additional renin-angiotensin aldosterone agents had the strongest level of evidence. Despite limitations, the information included in this review may result in additional scrutiny about combining certain individual nephrotoxic drugs.

A Multicenter Evaluation of Off-Label Medication Use and Associated Adverse Drug Reactions in Adult Medical ICUs.

OBJECTIVE: Prior research indicates that off-label use is common in the ICU; however, the safety of off-label use has not been assessed. The study objective was to determine the prevalence of adverse drug reactions associated with off-label use and evaluate off-label use as a risk factor for the development of adverse drug reactions in an adult ICU population. DESIGN: Multicenter, observational study SETTING: : Medical ICUs at three academic medical centers. PATIENTS: Adult patients (age ≥ 18 yr old) receiving medication therapy. INTERVENTIONS: All administered medications were evaluated for Food and Drug Administration-approved or off-label use. Patients were assessed daily for the development of an adverse drug reaction through active surveillance. Three adverse drug reaction assessment instruments were used to determine the probability of an adverse drug reaction resulting from drug therapy. Severity and harm of the adverse drug reaction were also assessed. Cox proportional hazard regression was used to identify a set of covariates that influenced the rate of adverse drug reactions. MEASUREMENTS AND MAIN RESULTS: Overall, 1,654 patient-days (327 patients) and 16,391 medications were evaluated, with 43% of medications being used off-label. One hundred and sixteen adverse drug reactions were categorized dichotomously (Food and Drug Administration or off-label), with 56% and 44% being associated with Food and Drug Administration-approved and off-label use, respectively. The number of adverse drug reactions for medications administered and the number of harmful and severe adverse drug reactions did not differ for medications used for Food and Drug Administration-approved or off-label use (0.74% vs 0.67%; p = 0.336; 33 vs 31 events, p = 0.567; 24 vs 24 events, p = 0.276). Age, sex, number of high-risk medications, number of off-label medications, and severity of illness score were included in the Cox proportional hazard regression. It was found that the rate of adverse drug reactions increases by 8% for every one additional off-label medication (hazard ratio = 1.08; 95% CI, 1.018-1.154). CONCLUSION: Although adverse drug reactions do not occur more frequently with off-label use, adverse drug reaction risk increases with each additional off-label medication used.

Interpatient variability in dexmedetomidine response: a survey of the literature.

Fifty-five thousand patients are cared for in the intensive care unit (ICU) daily with sedation utilized to reduce anxiety and agitation while optimizing comfort. The Society of Critical Care Medicine (SCCM) released updated guidelines for management of pain, agitation, and delirium in the ICU and recommended nonbenzodiazepines, such as dexmedetomidine and propofol, as first line sedation agents. Dexmedetomidine, an alpha-2 agonist, offers many benefits yet its use is mired by the inability to consistently achieve sedation goals. Three hypotheses including patient traits/characteristics, pharmacokinetics in critically ill patients, and clinically relevant genetic polymorphisms that could affect dexmedetomidine response are presented. Studies in patient traits have yielded conflicting results regarding the role of race yet suggest that dexmedetomidine may produce more consistent results in less critically ill patients and with home antidepressant use. Pharmacokinetics of critically ill patients are reported as similar to healthy individuals yet wide, unexplained interpatient variability in dexmedetomidine serum levels exist. Genetic polymorphisms in both metabolism and receptor response have been evaluated in few studies, and the results remain inconclusive. To fully understand the role of dexmedetomidine, it is vital to further evaluate what prompts such marked interpatient variability in critically ill patients.

A common data model for the standardization of intensive care unit medication features.

Objective: Common data models provide a standard means of describing data for artificial intelligence (AI) applications, but this process has never been undertaken for medications used in the intensive care unit (ICU). We sought to develop a common data model (CDM) for ICU medications to standardize the medication features needed to support future ICU AI efforts. Materials and Methods: A 9-member, multi-professional team of ICU clinicians and AI experts conducted a 5-round modified Delphi process employing conference calls, web-based communication, and electronic surveys to define the most important medication features for AI efforts. Candidate ICU medication features were generated through group discussion and then independently scored by each team member based on relevance to ICU clinical decision-making and feasibility for collection and coding. A key consideration was to ensure the final ontology both distinguished unique medications and met Findable, Accessible, Interoperable, and Reusable (FAIR) guiding principles. Results: Using a list of 889 ICU medications, the team initially generated 106 different medication features, and 71 were ranked as being core features for the CDM. Through this process, 106 medication features were assigned to 2 key feature domains: drug product-related (n = 43) and clinical practice-related (n = 63). Each feature included a standardized definition and suggested response values housed in the electronic data library. This CDM for ICU medications is available online. Conclusion: The CDM for ICU medications represents an important first step for the research community focused on exploring how AI can improve patient outcomes and will require ongoing engagement and refinement.

AutoDensity: an automated method to measure mammographic breast density that predicts breast cancer risk and screening outcomes.

INTRODUCTION: While Cumulus - a semi-automated method for measuring breast density - is utilised extensively in research, it is labour-intensive and unsuitable for screening programmes that require an efficient and valid measure on which to base screening recommendations. We develop an automated method to measure breast density (AutoDensity) and compare it to Cumulus in terms of association with breast cancer risk and breast cancer screening outcomes. METHODS: AutoDensity automatically identifies the breast area in the mammogram and classifies breast density in a similar way to Cumulus, through a fast, stand-alone Windows or Linux program. Our sample comprised 985 women with screen-detected cancers, 367 women with interval cancers and 4,975 controls (women who did not have cancer), sampled from first and subsequent screening rounds of a film mammography screening programme. To test the validity of AutoDensity, we compared the effect estimates using AutoDensity with those using Cumulus from logistic regression models that tested the association between breast density and breast cancer risk, risk of small and large screen-detected cancers and interval cancers, and screening programme sensitivity (the proportion of cancers that are screen-detected). As a secondary analysis, we report on correlation between AutoDensity and Cumulus measures. RESULTS: AutoDensity performed similarly to Cumulus in all associations tested. For example, using AutoDensity, the odds ratios for women in the highest decile of breast density compared to women in the lowest quintile for invasive breast cancer, interval cancers, large and small screen-detected cancers were 3.2 (95% CI 2.5 to 4.1), 4.7 (95% CI 3.0 to 7.4), 6.4 (95% CI 3.7 to 11.1) and 2.2 (95% CI 1.6 to 3.0) respectively. For Cumulus the corresponding odds ratios were: 2.4 (95% CI 1.9 to 3.1), 4.1 (95% CI 2.6 to 6.3), 6.6 (95% CI 3.7 to 11.7) and 1.3 (95% CI 0.9 to 1.8). Correlation between Cumulus and AutoDensity measures was 0.63 (P < 0.001). CONCLUSIONS: Based on the similarity of the effect estimates for AutoDensity and Cumulus inmodels of breast density and breast cancer risk and screening outcomes, we conclude that AutoDensity is a valid automated method for measuring breast density from digitised film mammograms.

Conivaptan for treatment of hyponatremia in neurologic and neurosurgical adults.

OBJECTIVE: To review the literature evaluating the clinical safety and efficacy of conivaptan in the management of hyponatremia in a neurologic and neuro-surgical adult patient population. DATA SOURCES: A literature search was conducted using MEDLINE, EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials (1966-May 2013). Search limits were English, human, and adult using the terms vasopressin receptor antagonist, conivaptan, tolvaptan, lixivaptan, neurology, neurological disorder, neurosurgery, neurointensive care, and neurocritical care. STUDY SELECTION AND DATA EXTRACTION: All case reports, case series, and clinical trials investigating the use of conivaptan in neurosurgical patients were included. DATA SYNTHESIS: Seven reports were identified using conivaptan as monotherapy or adjunctive treatment for hyponatremia in a neurosurgical patient population. One study was a prospective, randomized, controlled trial, while 6 reports were case reports or case series. The prospective randomized trial found a significant increase in serum sodium concentration over baseline with a conivaptan 20-mg intravenous bolus dose followed by a 20-mg/day continuous infusion for 24 hours compared to "usual care" at 6 hours (7.0 ± 1.7 vs -0.6 ± 2.1 mEq/L, respectively; p = 0.008) and 36 hours (8.0 ± 5.6 vs -1.7 ± 2.1 mEq/L, respectively; p = 0.05) after treatment. One case series found that the mean serum sodium remained significantly increased from baseline up to 72 hours (5.12 ± 4.0 mEq/L; p < 0.001) after a single conivaptan 20-mg intravenous bolus dose. All reports demonstrated clinical effectiveness of conivaptan in significantly increasing serum sodium concentrations following administration compared to baseline. However, the clinical significance of this finding remains debatable since some of these patients remained hyponatremic. CONCLUSIONS: Overall, conivaptan is a promising and well-tolerated agent for the management of hyponatremia in neurologic and neurosurgical patients. However, its use should be limited to patients in whom conventional therapies fail or as adjunctive therapy.