Management of noncytotoxic extravasation injuries: A focused update on medications, treatment strategies, and peripheral administration of vasopressors and hypertonic saline.

Extravasation is the leakage of intravenous solutions into surrounding tissues, which can be influenced by drug properties, infusion techniques, and patient-related risk factors. Although peripheral administration of vesicants may increase the risk of extravasation injuries, the time and resources required for central venous catheter placement may delay administration of time-sensitive therapies. Recent literature gathered from the growing use of peripheral vasopressors and hypertonic sodium suggests low risk of harm for initiating these emergent therapies peripherally, which may prevent delays and improve patient outcomes. Physiochemical causes of tissue injury include vasoconstriction, pH-mediated, osmolar-mediated, and cytotoxic mechanisms of extravasation injuries. Acidic agents, such as promethazine, amiodarone, and vancomycin, may cause edema, sloughing, and necrosis secondary to cellular desiccation. Alternatively, basic agents, such as phenytoin and acyclovir, may be more caustic due to deeper tissue penetration of the dissociated hydroxide ions. Osmotically active agents cause cellular damage as a result of osmotic shifts across cellular membranes in addition to agent-specific toxicities, such as calcium-induced vasoconstriction and calcifications or arginine-induced leakage of potassium causing apoptosis. A new category has been proposed to identify absorption-refractory mechanisms of injury in which agents such as propofol and lipids may persist in the extravasated space and cause necrosis or compartment syndrome. Pharmacological antidotes may be useful in select extravasations but requires prompt recognition and frequently complex administration strategies. Historically, intradermal phentolamine has been the preferred agent for vasopressor extravasations, but frequent supply shortages have led to the emergence of terbutaline, a ß2 -agonist, as an acceptable alternative treatment option. For hyperosmolar and pH-related mechanisms of injuries, hyaluronidase is most commonly used to facilitate absorption and dispersion of injected agents. However, extravasation management is largely supportive and requires a protocolized multidisciplinary approach for early detection, treatment, and timely surgical referral when required to minimize adverse events.

Association between Substance Misuse and Outcomes in Critically III Patients with Pneumonia.

Rationale: In patients with pneumonia requiring intensive care unit (ICU) admission, alcohol misuse is associated with increased mortality, but the relationship between other commonly misused substances and mortality is unknown. Objectives: We sought to establish whether alcohol misuse, cannabis misuse, opioid misuse, stimulant misuse, or misuse of more than one of these substances was associated with differences in mortality among ICU patients with pneumonia. Methods: This was a retrospective cohort study of hospitals participating in the Premier Healthcare Database between 2010 and 2017. Patients were included if they had a primary or secondary diagnosis of pneumonia and received antibiotics or antivirals within 1 day of admission. Substance misuse related to alcohol, cannabis, stimulants, and opioids, or more than one substance, were identified from the International Classification of Diseases (Ninth and Tenth Editions). The associations between substance misuse and in-hospital mortality were the primary outcomes of interest. Secondary outcomes included the measured associations between substance misuse disorders and mechanical ventilation, as well as vasopressor and continuous paralytic administration. Analyses were conducted with multivariable mixed-effects logistic regression modeling adjusting for age, comorbidities, and hospital characteristics. Results: A total of 167,095 ICU patients met inclusion criteria for pneumonia. Misuse of alcohol was present in 5.0%, cannabis misuse in 0.6%, opioid misuse in 1.5%, stimulant misuse in 0.6%, and misuse of more than one substance in 1.2%. No evidence of substance misuse was found in 91.1% of patients. In unadjusted analyses, alcohol misuse was associated with increased in-hospital mortality (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.06-1.19), whereas opioid misuse was associated with decreased in-hospital mortality (OR, 0.46; 95% CI, 0.39-0.53) compared with no substance misuse. These findings persisted in adjusted analyses. Although cannabis, stimulant, and more than one substance misuse (a majority of which were alcohol in combination with another substance) were associated with lower odds for in-hospital mortality in unadjusted analyses, these relationships were not consistently present after adjustment. Conclusions: In this study of ICU patients hospitalized with severe pneumonia, substance misuse subtypes were associated with different effects on mortality. Although administrative data can provide epidemiologic insight regarding substance misuse and pneumonia outcomes, biases inherent to these data should be considered when interpreting results.

Restrictive resuscitation in patients with sepsis and mortality: A systematic review and meta-analysis with trial sequential analysis.

STUDY OBJECTIVE: Although fluid resuscitation is recommended by the Society of Critical Care Medicine Surviving Sepsis Campaign Guidelines, risks of volume overload persist.The objective of this systematic review is to assess the effects of a restrictive fluid resuscitation approach in the septic patient both during and after the initial resuscitation period (30 ml/kg). DESIGN: A systematic review and meta-analysis with trial sequential analysis (TSA) of randomized controlled trials was conducted. Two blinded reviewers independently assessed and included studies that evaluated adult patients with sepsis involving a comparator group with an effective restrictive fluid resuscitation approach. The primary outcome was mortality. Secondary outcomes included rates of acute kidney injury (AKI), renal replacement therapy (RRT), ventilator days, intensive care unit (ICU) and hospital length of stay (LOS), duration of vasopressor therapy, and limb (or digital) ischemia. SETTING: PubMed and Medline databases were queried for the search. PATIENTS: A total of eight trials in 2375 patients were included. INTERVENTION: Effective restrictive fluid resuscitation compared with standard of care. MEASUREMENTS AND MAIN RESULTS: The risk of bias was high in six studies and low in two studies, and all studies implemented fluid restriction after a 30-ml/kg infusion of fluids. Fluid restriction did not significantly reduce mortality in all studies compared to usual care (37% vs. 40% with usual care; risk ratio [RR] 0.90, 95% confidence interval [CI] 0.76-1.06, p = 0.23, I2  = 24%) or by TSA findings. There were no significant differences in rates of AKI or RRT (5 studies), LOS in ICU (4 studies) or hospital (3 studies), duration of vasopressor therapy (6 studies), or incidence of limb or digital ischemia (3 studies). However, fluid restriction significantly reduced ventilator days as evaluated in seven studies (mean difference - 1.25 days, 95% CI -1.92 to -0.58 days, p = 0.0003, I2  = 90%). CONCLUSION: This study demonstrated that a restrictive resuscitation strategy in sepsis resulted in no difference in mortality but may reduce ventilator days. Larger randomized trials are required to determine the optimal management of fluids in patients with sepsis.

Correlation Between and Nursing Satisfaction With CIWA-Ar, mMINDS, and SEWS Scoring Tools for the Assessment of Severe Alcohol Withdrawal Syndrome in ICU Patients.

BACKGROUND: Management of alcohol withdrawal syndrome (AWS) requires bedside assessments of symptom severity to guide therapies. Commonly used assessment tools are the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar), the modified Minnesota Detoxification Scale (mMINDS) and the Severity of Ethanol Withdrawal Scale (SEWS). OBJECTIVE: To determine strength of correlation between the CIWA-Ar, mMINDS, and SEWS for bedside assessment of severe AWS and to survey nurses regarding ease of use of each tool. METHODS: A single-center prospective correlation study of the three assessment tools performed by bedside nurses on patients with AWS followed by a questionnaire assessing ease of use of each tool (1 being the easiest and 9 being the hardest). RESULTS: A total of 66 correlation assessments were performed by 49 nurses in 21 patients with AWS. Bedside CIWA-Ar, mMINDS, and SEWS were 14 ± 8.3, 13.9 ± 6.5, and 10.1 ± 4.5, respectively. The Pearson correlation coefficients were 0.814 (95% CI, 0.714-0.881) between CIWA-Ar and mMINDS; 0.722 (95% CI, 0.585-0.820) between CIWA-Ar and SEWS; and 0.658 (95% CI, 0.498-0.775) between SEWS and mMINDS. Nurse ratings for ease of use were 4 ± 2.3 for CIWA-Ar, 2.9 ± 2 for mMINDS (p=0.0044 vs. CIWA-Ar), and 4.8 ± 2.1 for SEWS (p=0.036 vs. CIWA-Ar, p<0.0001 vs. mMINDS). Forty-six (69.7%) respondents preferred mMINDS versus 14 (21.2%) and 6 (9.1%) respondents favored CIWA-Ar and SEWS, respectively. CONCLUSION: Correlations between the three scoring tools in severe AWS are robust. Only mMINDS was considered easy to use by nurses. It was the preferred tool.

Associated Mortality Risk of Proton Pump Inhibitor Therapy for the Prevention of Stress Ulceration in Intensive Care Unit Patients: A Systematic Review and Meta-analysis.

GOALS: The aim was to systematically evaluate risks and benefits of proton pump inhibitor (PPI) use for stress ulcer prophylaxis in the critically ill patient. BACKGROUND: Whether PPIs increase mortality in the critically ill patient remains controversial. STUDY: Systematic review and meta-analysis of randomized controlled trials (RCTs) and cohort studies with trial sequential analysis, Bayesian sensitivity analysis, and fragility index analysis. RESULTS: A total of 31 studies in 78,009 critically ill adults receiving PPIs versus any comparator were included. PPI use was associated with an increased mortality risk in all studies [19.6% PPI vs. 17.5% comparator; RR: 1.10; 95% confidence interval (CI): 1.02-1.20; P =0.01], in the subgroup of RCTs (19.4% vs. 18.7%; RR: 1.05; 95% CI: 1.0-1.09, P =0.04), but not cohort studies (19.9% vs. 16.7%; RR: 1.12; 95% CI: 0.98-1.28, P =0.09). Results were maintained with a Bayesian sensitivity analysis (RR: 1.13; 95% credible interval: 1.035-1.227) and a fragility index analysis, but not sequential analysis ( P =0.16). RCTs with a higher baseline severity of illness revealed the greatest mortality risk with PPI use (32.1% PPI vs. 29.4% comparator; RR: 1.09; 95% CI: 1.04-1.14; P <0.001). PPI use reduced clinically important bleeding in RCTs (1.4% PPI vs. 2.1% comparator; RR: 0.67; 95% CI: 0.5-0.9; P =0.009) but increased bleeding in cohort studies (2.7% PPI vs. 1.2% comparator; RR: 2.05; 95% CI: 1.2-3.52; P =0.009). PPI use was not associated with a lower incidence of clinically important bleeding when compared with histamine-2 receptor antagonists (1.3% vs. 1.9%; RR: 0.59; 95% CI: 0.28-1.25, P =0.09). CONCLUSIONS: This meta-analysis demonstrated an association between PPI use and an increased risk of mortality.

Extracorporeal Membrane Oxygenation for Refractory Asthma Exacerbations With Respiratory Failure.

BACKGROUND: Asthma exacerbations with respiratory failure (AERF) are associated with hospital mortality of 7% to 15%. Extracorporeal membrane oxygenation (ECMO) has been used as a salvage therapy for refractory AERF, but controlled studies showing its association with mortality have not been performed. RESEARCH QUESTION: Is treatment with ECMO associated with lower mortality in refractory AERF compared with standard care? STUDY DESIGN AND METHODS: This is a retrospective, epidemiologic, observational cohort study using a national, administrative data set from 2010 to 2020 that includes 25% of US hospitalizations. People were included if they were admitted to an ECMO-capable hospital with an asthma exacerbation, and were treated with short-acting bronchodilators, systemic corticosteroids, and invasive ventilation. People were excluded for age < 18 years, no ICU stay, nonasthma chronic lung disease, COVID-19, or multiple admissions. The main exposure was ECMO vs No ECMO. The primary outcome was hospital mortality. Key secondary outcomes were ICU length of stay (LOS), hospital LOS, time receiving invasive ventilation, and total hospital costs. RESULTS: The study analyzed 13,714 patients with AERF, including 127 with ECMO and 13,587 with No ECMO. ECMO was associated with reduced mortality in the covariate-adjusted (OR, 0.33; 95% CI, 0.17-0.64; P = .001), propensity score-adjusted (OR, 0.36; 95% CI, 0.16-0.81; P = .01), and propensity score-matched models (OR, 0.48; 95% CI, 0.24-0.98; P = .04) vs No ECMO. Sensitivity analyses showed that mortality reduction related to ECMO ranged from OR 0.34 to 0.61. ECMO was also associated with increased hospital costs in all three models (P < .0001 for all) vs No ECMO, but not with decreased ICU LOS, hospital LOS, or time receiving invasive ventilation. INTERPRETATION: ECMO was associated with lower mortality and higher hospital costs, suggesting that it may be an important salvage therapy for refractory AERF following confirmatory clinical trials.

Predicting the Success of International Pharmacists in a Distance-Based US Doctor of Pharmacy (PharmD) Program: Results from a 5-Year Cohort.

Background: To establish the predictors of success in an international-trained PharmD (ITPD) program between admission criteria and academic performance. Methods: The primary outcome of this study was the correlation of admission criteria with didactic and experiential grade point averages (GPA) for the first 5 years. Candidates meeting the minimum criteria completed a competency exam or the US-Foreign Pharmacy Graduate Equivalency Exam (US-FPGEE). Tests of English language proficiency (TOEFL(R) and ACTFL's Oral Proficiency Interview) plus interview with faculty, students, and alumni were also required. Scores were correlated with both didactic and experiential GPAs. Results: The 23 students admitted to the ITPD program had a cumulative GPA of 3.72. There was a significant correlation between total admissions score and the median pharmacy and healthcare course category GPA (ρ 0.53), but not other categories. The composite TOEFL did not predict any performance but TOEFL writing and speaking did correlate with advanced pharmacy practice experience (APPE) performance. The OPI scores were associated with higher GPAs overall, in advanced integrated clinical sciences, and APPEs. The admission interview scores consistently and significantly correlated with preceptor-rated APPE GPA, practitioner skills, and professionalism (ρ > 0.5; p < 0.05). Performance in early courses significantly predicted the performance in advanced courses and experiential performance (ρ 0.48−0.61). Conclusion: The correlations between early and late course performance demonstrated the cohesiveness of this program. Further study is needed between the predictors of success using non-cognitive admission criteria.

Correlation of antimicrobial fraction unbound and sieving coefficient in critically ill patients on continuous renal replacement therapy: a systematic review.

BACKGROUND: Fraction unbound has been used as a surrogate for antimicrobial sieving coefficient (SC) to predict extracorporeal clearance in critically ill patients on continuous renal replacement therapy (CRRT), but this is based largely on expert opinion. OBJECTIVES: To examine relationships between package insert-derived fraction unbound (Fu-P), study-specific fraction unbound (Fu-S), and SC in critically ill patients receiving CRRT. METHODS: English-language studies containing patient-specific in vivo pharmacokinetic parameters for antimicrobials in critically ill patients requiring CRRT were included. The primary outcome included correlations between Fu-S, Fu-P, and SC. Secondary outcomes included correlations across protein binding quartiles, serum albumin, and predicted in-hospital mortality, and identification of predictors for SC through multivariable analysis. RESULTS: Eighty-nine studies including 32 antimicrobials were included for analysis. SC was moderately correlated to Fu-S (R2 = 0.55, P < 0.001) and Fu-P (R2 = 0.41, P < 0.001). SC was best correlated to Fu-S in first (<69%) and fourth (>92%) quartiles of fraction unbound and above median albumin concentrations of 24.5 g/L (R2 = 0.71, P = 0.07). Conversely, correlation was weaker in patients with mortality estimates greater than the median of 55% (R2 = 0.06, P = 0.84). SC and Fu-P were also best correlated in the first quartile of antimicrobial fraction unbound (R2 = 0.66, P < 0.001). Increasing Fu-P, flow rate, membrane surface area, and serum albumin, and decreasing physiologic charge significantly predicted increasing SC. CONCLUSIONS: Fu-S and Fu-P were both reasonably correlated to SC. Caution should be taken when using Fu-S to calculate extracorporeal clearance in antimicrobials with 69%-92% fraction unbound or with >55% estimated in-hospital patient mortality. Fu-P may serve as a rudimentary surrogate for SC when Fu-S is unavailable.

Association Between Vasopressin Rebranding and Utilization in Patients With Septic Shock.

OBJECTIVES: Vasopressin is suggested as an adjunct to norepinephrine in patients with septic shock. However, after vasopressin was rebranded in November 2014, its cost exponentially increased. Utilization patterns of vasopressin after its rebranding are unclear. The objective of this study was to determine if there is an association between the rebranding of vasopressin in November 2014 and its utilization in vasopressor-dependent patients with severe sepsis or septic shock. DESIGN: Retrospective, multicenter, database study between January 2010 and March 2017. SETTING: Premier Healthcare Database hospitals. PATIENTS: Adult patients admitted to an ICU with severe sepsis or septic shock, who received at least one vasoactive agent for two or more calendar days were included. INTERVENTIONS: The proportion of patients who received vasopressin and vasopressin cost was assessed before and after rebranding, and evaluated with segmented regression. MEASUREMENTS AND MAIN RESULTS: Among 294,733 patients (mean age, 66 ± 15 yr), 27.8% received vasopressin, and ICU mortality was 26.5%. The proportion of patients receiving vasopressin was higher after rebranding (31.2% postrebranding vs 25.8% prerebranding). Before vasopressin rebranding, the quarterly proportion of patients who received vasopressin had an increasing slope (prerebranding slope 0.41% [95% CI, 0.35-0.46%]), with no difference in slope detected after vasopressin rebranding (postrebranding slope, 0.47% [95% CI, 0.29-0.64%]). After vasopressin rebranding, mean vasopressin cost per patient was higher ($527 ± 1,130 vs $77 ± 160), and the quarterly slope of vasopressin cost was higher (change in slope $77.18 [95% CI, $75.73-78.61]). Total vasopressin billed cost postrebranding continually increased by ~$294,276 per quarter from less than $500,000 in Q4 2014 to over $3,000,000 in Q1 2017. CONCLUSIONS: After vasopressin rebranding, utilization continued to increase quarterly despite a significant increase in vasopressin cost. Vasopressin appeared to have price inelastic demand in septic shock.

Retrospective Comparison of Andexanet Alfa and 4-Factor Prothrombin Complex for Reversal of Factor Xa-Inhibitor Related Bleeding.

The aim of this retrospective study was to compare andexanet alfa and 4-factor prothrombin complex (4F-PCC) for reversal of factor Xa (FXa)-inhibitor bleeding. Patients that received andexanet alfa for reversal were included. An equivalent number of patients administered 4F-PCC for FXa-inhibitor bleeding were randomly selected as historical controls. The primary outcome was effective hemostasis achievement within 12 h, defined using ANNEXA-4 criteria. Thromboembolic events and mortality within 30 days were also evaluated. A total of 32 patients were included. Baseline characteristics were not statistically different between andexanet alfa (n = 16) and 4F-PCC (n = 16). Intracranial bleeding was the primary reversal indication in 43.8% versus 62.5% of patients, respectively. Effective hemostasis was reached in 75.0% of andexanet alfa patients compared to 62.5% of 4F-PCC patients (P = .70). Thromboembolic events occurred in 4 (25.0%) patients and 3 (18.8%) patients, respectively (P = .99). Mortality incidence was 12.5% and 31.3%, respectively (P = .39). Andexanet alfa and 4F-PCC attained hemostasis in a majority of patients. A high, but a similar rate of thromboembolic events was seen with both treatments. Prospective studies are needed to elucidate comparative risks and benefits of the 2 agents.

An overview of current and emerging antifungal pharmacotherapy for invasive fungal infections.

Introduction: Invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality despite significant advancements in currently available therapy. With a flush pipeline of investigational antifungals, the clinician must identify appropriate roles of currently available therapies, potential advantages of emerging antifungals, and shortcomings in the evolving clinical evidence.Areas covered: Standard and developing treatment approaches for IFIs with currently available antifungals are summarized with a focus on invasive candidiasis and invasive aspergillosis. Emerging investigational antifungals are discussed in depth, including mechanisms of action, fungal activity, clinical evidence, and ongoing research. An opinion on the impact and potential role of therapy for emerging antifungals of interest is also provided.Expert opinion: Despite advances and clinical studies optimizing antifungal use, current therapies fall short in preventing IFI morbidity and mortality. Further optimization of currently available antifungals may improve outcomes; however, novel agents are required for historically difficult-to-treat infections, transitions to oral treatment, minimizing adverse drug effects, decreasing drug interactions, and ultimately improving patient quality of life. Emerging antifungals may positively revolutionize the treatment of IFIs.

Educational Methods and Technological Innovations for Introductory Experiential Learning Given the Contact-Related Limitations Imposed by the SARS-CoV2/COVID-19 Pandemic.

BACKGROUND: Acute respiratory syndrome related coronavirus disease (COVID-19) has led to substantial changes in pharmacy curricula, including the ability to provide in-person introductory experiential practice experiences (IPPEs) to University of Colorado's International-Trained PharmD (ITPD) students. METHODS: The IPPE course for ITPD students was redesigned to offer remote educational activities in the health system setting and simulated practice and communication activities in the community setting. Students were evaluated via surveys regarding the perceived value of these changes, and changes in knowledge, skills and abilities before and after activities. RESULTS: A total of 6 students were enrolled in the revised IPPE course. Students agreed or strongly agreed that the overall distance-based IPPE experience, the remote health system activities, and the community activities were valuable. Students also strongly agreed that course design successfully met course outcomes and was relevant to pharmacy practice. In terms of knowledge, skills and abilities, numeric improvements were observed in remote health system activities and community-based simulated patient interactions, but results were not statistically significant. A high baseline level of knowledge led to minimal improvements in perceptions of improvement in community pharmacy skills regarding pharmacy simulation software. CONCLUSION: Implementation of distance-based IPPE activities may be an alternate educational modality.

Opioid Prescribing After Discharge in a Previously Mechanically Ventilated, Opioid-Naïve Cohort.

BACKGROUND: Opioids are utilized for pain management during and after mechanical ventilation in the intensive care unit (ICU). OBJECTIVE: The purpose of this study was to determine the percentage of potentially unnecessary opioid prescriptions on discharge in previously opioid-naïve patients. METHODS: This retrospective cohort study included mechanically ventilated, opioid-naïve ICU patients who received opioids. The primary outcome of this study was the discrepancy between the amounts of opioids prescribed at discharge versus those likely required based on actual 24-hour prehospital discharge opioid requirements. RESULTS: A total of 71 patients were included. Of these, 63.3% (n = 45) of discharge prescriptions were in alignment with 24-hour predischarge requirements, and 36.7% (n = 26) of discharge prescriptions were in excess of calculated predischarge requirements. At discharge, 57.7% (n = 41) of patients received a nonopioid analgesic. Multivariable linear regression revealed that cardiothoracic ICU admission was associated with an increased risk of inappropriate discharge opioid prescribing, whereas a shorter duration of inpatient oral opioid therapy decreased risk of inappropriate discharge prescribing. CONCLUSION AND RELEVANCE: Opioid prescribing for previously mechanically ventilated patients warrants improvement as a part of the discharge planning process. Application of these data may aid in the reduction of opioid overprescribing at discharge after an ICU stay.

Extrapolating Antifungal Animal Data to Humans - Is it reliable?

PURPOSE OF REVIEW: This article aimed to review animal models of antifungals and identifies human literature to assess if the extrapolation of results is reliable. RECENT FINDINGS: Animal studies have helped identify AUC/MIC targets for new drugs and formulations such as isavuconazole and delayed release posaconazole that have translated to successful outcomes in humans. Models have also been influential in the identification of possible combination therapies for the treatment of aspergillosis, such as voriconazole and echinocandins. However, challenges are endured with animal models when it comes to replicating the pharmacokinetics of humans which has been exemplified with the newest itraconazole formulation. Additionally, animal models have displayed a survival benefit with the use of iron chelators and amphotericin for mucormycosis which was not demonstrated in humans. SUMMARY: Animal models have been a staple in the development and optimization of antifungal agents. They afford the ability to investigate uncommon diseases, such as invasive fungal infections, that would otherwise take years and many resources to complete. Although there are many benefits of animal models there are also shortcomings. This is why the reliability of extrapolating data from animal models to humans is often scrutinized.

Predicting gene expression using morphological cell responses to nanotopography.

Cells respond in complex ways to their environment, making it challenging to predict a direct relationship between the two. A key problem is the lack of informative representations of parameters that translate directly into biological function. Here we present a platform to relate the effects of cell morphology to gene expression induced by nanotopography. This platform utilizes the 'morphome', a multivariate dataset of cell morphology parameters. We create a Bayesian linear regression model that uses the morphome to robustly predict changes in bone, cartilage, muscle and fibrous gene expression induced by nanotopography. Furthermore, through this model we effectively predict nanotopography-induced gene expression from a complex co-culture microenvironment. The information from the morphome uncovers previously unknown effects of nanotopography on altering cell-cell interaction and osteogenic gene expression at the single cell level. The predictive relationship between morphology and gene expression arising from cell-material interaction shows promise for exploration of new topographies.

Establishing the Therapeutic Index of Fluid Resuscitation in the Septic Patient: A Narrative Review and Meta-Analysis.

This comprehensive review comparatively evaluates the safety and benefits of parenteral fluids used in resuscitation with a focus on sepsis. It also provides a random-effects meta-analysis of studies comparing restrictive resuscitation and usual care in sepsis with the primary outcome of mortality. In the septic patient, fluid therapy remains a complex interplay between fluid compartments in the body, the integrity of the endothelial barrier, and the inflammatory tone of the patient. Recent data have emerged describing the pharmacokinetics of fluid resuscitation that can be affected by the factors just listed, as well as mean arterial pressure, rate of infusion, volume of fluid infusate, nature of the fluid, and drug interactions. Fluid overload in sepsis has been associated with vasodilation, kidney injury, and increased mortality. Restrictive resuscitation after the initial septic insult is an emerging practice. Our search strategy of Medline databases revealed six randomized studies with 706 patients that examined restrictive resuscitation in sepsis. Results of this meta-analysis demonstrated no differences in mortality with restrictive resuscitation compared with usual care (30.6% vs 37.8%; risk ratio 0.83, 95% confidence interval 0.66-1.05, respectively) but was limited by the small number of studies and larger quantities of pre-randomization fluids. Another approach to address fluid overload is active (diuresis) de-resuscitation strategies that may shorten the need for mechanical ventilation and intensive care unit length of stay. Data suggest that colloids may confer mortality benefit over saline in the most severely ill septic patients. Compared with isotonic saline, balanced resuscitation fluids are associated with a lower incidence of acute kidney injury and mortality. The benefits of balanced resuscitation fluids are most evident when higher volumes of fluids are used for sepsis. Clinicians should consider these pharmacotherapeutic factors when selecting a fluid, its quantity, and rate of infusion.

Customizable, engineered substrates for rapid screening of cellular cues.

Biophysical cues robustly direct cell responses and are thus important tools for in vitro and translational biomedical applications. High throughput platforms exploring substrates with varying physical properties are therefore valuable. However, currently existing platforms are limited in throughput, the biomaterials used, the capability to segregate between different cues and the assessment of dynamic responses. Here we present a multiwell array (3 × 8) made of a substrate engineered to present topography or rigidity cues welded to a bottomless plate with a 96-well format. Both the patterns on the engineered substrate and the well plate format can be easily customized, permitting systematic and efficient screening of biophysical cues. To demonstrate the broad range of possible biophysical cues examinable, we designed and tested three multiwell arrays to influence cardiomyocyte, chondrocyte and osteoblast function. Using the multiwell array, we were able to measure different cell functionalities using analytical modalities such as live microscopy, qPCR and immunofluorescence. We observed that grooves (5 µm in size) induced less variation in contractile function of cardiomyocytes. Compared to unpatterned plastic, nanopillars with 127 nm height, 100 nm diameter and 300 nm pitch enhanced matrix deposition, chondrogenic gene expression and chondrogenic maintenance. High aspect ratio pillars with an elastic shear modulus of 16 kPa mimicking the matrix found in early stages of bone development improved osteogenic gene expression compared to stiff plastic. We envisage that our bespoke multiwell array will accelerate the discovery of relevant biophysical cues through improved throughput and variety.

Coagulation Factor Xa (Recombinant), Inactivated-Zhzo (Andexanet Alfa) Hemostatic Outcomes and Thrombotic Event Incidence at an Academic Medical Center.

Andexanet alfa is approved for the reversal of factor Xa inhibitors in patients with major bleeding events. We aimed to review the incidence of effective hemostasis with andexanet alfa in a real-world environment. This retrospective cohort included patients hospitalized for a major bleed that resulted in andexanet alfa administration. The primary outcome was effective hemostasis at 12 hours after andexanet alfa treatment. Thromboembolic events and mortality within 30 days were also assessed. Over a 14-month period, 13 patients received andexanet alfa with a mean age of 69 ± 10 years, 54% male, 69% exposed to apixaban (31% rivaroxaban), and had intracranial (46%) and nonintracranial (54%) bleeding sites. Effective hemostasis was observed in 10 (77%) patients. Four (31%) patients experienced 5 thromboembolic events with a median time to event of 6.5 days (range: 0.5-29). Four thrombotic events occurred during the period in which anticoagulation (prophylaxis or therapeutic) was not restarted. Mortality rate was 15%. Andexanet alfa was effective in obtaining hemostasis in a majority of patients. However, the incidence of thromboembolic events was high and may be attributed to a delay in restarting anticoagulation.

Assessment of Opioid Cross-reactivity and Provider Perceptions in Hospitalized Patients With Reported Opioid Allergies.

Background: The incidence of opioid allergy cross-reactivity in hospitalized patients with historical opioid allergies remains unknown. Objectives: The purpose of this study was to characterize the incidence of newly suspected IgE-mediated reactions (IMRs) based on clinical criteria among patients with a chart-documented opioid allergy and to assess clinician perceptions of opioid allergies. Methods: This retrospective cohort study was conducted in hospitalized adults with a historically documented opioid allergy who received a subsequent opioid. The primary outcome was the incidence of allergic cross-reactivity between clinical and chemical opioid classes in patients with historical IMRs (H-IMRs) identified by clinical criteria, ICD-9 diagnosis codes, or allergic reaction treatment. Secondary outcomes included the incidence of opioid intolerances incorrectly documented as allergies and a survey to clinicians to assess the impact of opiate warnings on prescribing practices. Results: A total of 499 patients with historical opioid allergies were included. H-IMR to an opioid of any class was not significantly associated with IMR cross-reactivity to the same or any other class, with cross-reactivity rates ranging from 0% to 6.7%. Of the historical chart-documented allergies, 249 reactions (50%) were determined to be intolerances. A total of 461 (92.5%) patients successfully tolerated readministration of opioids despite a chart-documented allergy, and 8 (1.6%) patients developed possible IMR (7 pruritus, 1 possible anaphylaxis). Survey results (n = 54) indicated that opiate allergy warnings were neutral or unlikely to change opiate prescribing. Conclusions: The risk of IMRs caused by opioids is low in patients with H-IMRs to opioids. Opioid allergy documentations may propagate alert fatigue and unwarranted prescribing changes.

Dry Beriberi Due to Thiamine Deficiency Associated with Peripheral Neuropathy and Wernicke's Encephalopathy Mimicking Guillain-Barré syndrome: A Case Report and Review of the Literature.

BACKGROUND Beriberi due to thiamine (vitamin B1) deficiency has two clinical presentations. Patients with dry beriberi present with neuropathy, and patients with wet beriberi present with heart failure, with or without neuropathy. Dry beriberi can mimic the most common form of Guillain-Barre syndrome (GBS), an acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Severe thiamine deficiency results in Wernicke's encephalopathy. This report of a case of dry beriberi and Wernicke's encephalopathy due to thiamine deficiency includes a review of the literature. CASE REPORT A 56-year old woman with a history of gallstone pancreatitis and protein-calorie malnutrition was treated six months previously with total parenteral nutrition (TPN). She initially presented at another hospital with paresthesia of the lower limbs, arms, and neck, and symptoms of encephalopathy. Initial diagnosis of GBS was made, based on magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) findings. Despite five days of intravenous immunoglobulin (IVIG) treatment, her encephalopathy worsened, requiring transfer to our hospital, where she required intubation and treatment with vasopressors. A repeat MRI of her brain showed changes consistent with Wernicke's encephalopathy. Following treatment with high-dose intravenous thiamine, her mental status improved within 48 hours, and by the third hospital day, she no longer required intubation. CONCLUSIONS Symptoms and signs of dry beriberi due to thiamine deficiency can mimic those of acute or chronic GBS. However, thiamine repletion leads to rapid clinical improvement and can prevent irreversible neurologic sequelae, including Korsakoff syndrome. Clinicians should consider thiamine deficiency in malnourished patients presenting with symptoms and signs of GBS.