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Edward T Van Matre,1 Deb S Sherman,2 Tyree H Kiser1,21Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 2Department of Pharmacy, University of Colorado Hospital, Aurora, CO, USAAbstract: Intracerebral hemorrhage (ICH) is a neurologic injury resulting in significant morbidity and mortality. Statins play a significant role in primary and secondary prevention of cardiovascular and cerebrovascular ischemic events. Despite clear benefits of statins in ischemic stroke, post hoc analyses of some studies suggest there may be a link between statin therapy and development of ICH. Direct pharmacologic effects of decreased serum levels of total cholesterol and low-density lipoproteins in conjunction with pleiotropic effects are thought to be linked to this possible increase in ICH risk. In the face of the potential of statins to increase the risk of ICH, recent evidence suggests that statins may also have beneficial effects on patient outcomes when continued or initiated following an ICH. This discordance in findings and the overall lack of well-designed prospective clinical trials increase the complexity of clinical decision making when utilizing statin therapy in patients with, or at risk for, ICH. This review evaluates the pharmacologic effects of statin therapy and describes how these effects translate to both risks and benefits in ICH. The current literature regarding the effects of statin therapy on clinical outcomes in ICH is evaluated to help guide clinicians with decisions regarding initiation, continuation, or discontinuation of statin therapy in patients with ICH.Keywords: intracerebral hemorrhage, statin pharmacology, intracranial hemorrhage, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, pleiotropic effects

PURPOSE: The stability of extemporaneously prepared phenylephrine hydrochloride injection stored in polypropylene syringes was studied. METHODS: Dilution of phenylephrine hydrochloride to a nominal concentration of 100 mug/mL was performed under aseptic conditions by adding 100 mg of phenylephrine hydrochloride (total of 10 mL from two 5-mL 10-mg/mL vials) to 1000 mL of 0.9% sodium chloride injection. The resulting solution was drawn into 10-mL polypropylene syringes and sealed with syringe caps. The syringes were then frozen (-20 degrees C), refrigerated (3-5 degrees C), or kept at room temperature (23-25 degrees C). Four samples of each preparation were analyzed on days 0, 7, 15, 21, and 30. Physical stability was assessed by visual examination. The pH of each syringe was also measured at each time point. Sterility of the samples was not assessed. Chemical stability of phenylephrine hydrochloride was evaluated using high-performance liquid chromatography. To demonstrate the stability-indicating nature of the assay, forced degradation of phenylephrine was conducted. Samples were considered stable if there was less than 10% degradation of the initial concentration. RESULTS: Phenylephrine hydrochloride diluted to 100 mug/mL with 0.9% sodium chloride injection was physically stable throughout the study. No precipitation was observed. Minimal to no degradation was observed over the 30-day study period. CONCLUSION: Phenylephrine hydrochloride diluted to a concentration of 100 mug/mL in 0.9% sodium chloride injection was stable for at least 30 days when stored in polypropylene syringes at -20 degrees C, 3-5 degrees C, and 23-25 degrees C. [ABSTRACT FROM AUTHOR]

Objective: In addition to indications for proton pump inhibitors (PPIs) outside the intensive-care unit (ICU), these medications are frequently used to manage nonvariceal upper gastrointestinal (GI) hemorrhage and to prevent stress-related mucosal bleeding in ICU patients. In September 2004, the P&T committee at the University of Colorado Health Sciences Center substituted three PPIs for one less expensive, preferred PPI product; all dosage forms were included. Our goal was to determine whether switching these PPIs to the least expensive agent would alter their usage and associated costs in the ICU (48 beds) and in non-ICU sites (325 beds).Methods: We conducted analyses of hospital databases before the formulary switch of January 1, 2004, to June 30, 2004, and after the formulary switch of January 1, 2005, to June 30, 2005, to compare the usage and associated drug costs of PPIs and histamine-2 receptor antagonists (H2RAs) in non-ICU and ICU sites.Results: Case-mix indices and length of stay data were similar before and after the switch. The total number of intravenous (IV) and enteral PPI doses charged before and after the switch increased from 1,544 to 4,143 units and from 11,865 units to 17,201 units, respectively. When we adjusted for patient-days, usage patterns of PPIs in non-ICU sites were similar before and after the switch (0.253 and 0.220 units per patient-day, respectively). In contrast, the use of PPIs in the ICU increased after the formulary switch (from 0.942 to 2.056 units per patient-day) as a result of the increased use of both IV PPIs (0.571 to 1.205 units per patient-day) and enteral PPIs (0.371 to 0.852 units per patient-day). Compared with non-ICU usage, the likelihood of PPI use in the ICU was 2.51 times higher after the switch (95% confidence interval [CI], 2.05-3.07; P < .0001).In the ICU, the concomitant use of IV H2RAs decreased from 2.550 to 1.869 units per patient-day. Compared with non-ICU usage, the likelihood of H2RA use in the ICUs was 0.49 times lower (95% CI, 0.39-0.61; P < .0001).Despite increased PPI usage, the cost of acid-suppressant therapy per patient-day in the hospital was similar before and after the switch ($0.65 and $0.59, respectively).In the ICU, the cost of acid-suppressant therapy per patient-day was reduced from $9.66 to $7.80. Compared with non-ICU sites, the cost of acid-suppressant therapy was reduced by 0.72-fold in the ICU after the switch (95% CI, 0.52-1.00, P = .04).Conclusion: Substituting a less expensive PPI did not alter usage outside the ICU, but it was associated with increased usage in the ICU. Conversely, the use of IV H2RAs decreased in the ICU. Despite substantially more PPI use after the formulary switch, the cost of acid-suppressant therapy was unchanged overall; it was lower in the ICU, probably as a result of the acquisition drug cost savings associated with the switch. [ABSTRACT FROM AUTHOR]

PURPOSE: The reliability and accuracy of practitioner-calculated Acute Physiology and Chronic Health Evaluation (APACHE) II scores for determining the appropriateness of drotrecogin alfa (activated) in critically ill patients were evaluated. METHODS: Three adjudicated clinical cases of sepsis were developed using composites of real patient scenarios. The patients' APACHE II scores were independently assessed by randomly selected critical care practitioners (physicians and nonphysicians). Each case contained at least one reason to consider withholding drotrecogin alfa (activated), but none had a definitive contraindication to drotrecogin alfa (activated). Intraobserver and interobserver variabilities were assessed using kappa correlation. Accuracy was assessed by comparing median scores to the adjudicated scores and evaluating correctly classified APACHE II scores. RESULTS: A total of 21 (42%) physicians and 14 (56%) nonphysicians completed all assessments. Intraobserver and interobserver variabilities were 0.16 and 0.49 for the total APACHE II score, respectively. Median calculated APACHE II scores significantly differed for case 1 (p = 0.003) and case 3 (p < 0.0001). The percentage of error in calculating the total APACHE II score approached 85%. The main reasons for administering drotrecogin alfa (activated) were an APACHE II score of >or=25 and multiple organ failures. The main reason for therapy was a high bleeding risk or an APACHE II score of <25. CONCLUSION: Weak intraobserver agreement, modest interobserver reliability, a high error rate, and low accuracy limited the clinical application of the APACHE II score by untrained practitioners, indicating that the APACHE II score should not be the only determinant for the use of drotrecogin alfa (activated). [ABSTRACT FROM AUTHOR]

Background: Midazolam (MZ) is commonly used in critically ill neurosurgical patients. Neuro-penetration of MZ and its metabolite, 1-hydroxy-midazolam (1-OH-MZ), is not well characterized., Objective: This study evaluated correlations between serum and cerebrospinal fluid (CSF) concentrations of MZ and 1-OH-MZ and assessed implications on patient sedation., Methods: Adults in the neurosurgical intensive care unit (ICU) with external ventricular drains receiving MZ via continuous infusion were prospectively studied. Serum and CSF samples were obtained 12-24 h and 72-96 h after initiation, and concentrations were determined in duplicate by high-performance liquid chromatography with tandem mass spectrometry. Bivariate correlation analyses used Pearson coefficient., Results: A total of 31 serum and CSF samples were obtained from 18 subjects. At sampling, mean MZ infusion rate was 3.9 ± 4.4 mg/h, and previous 12-h cumulative dose was 51.4 ± 78.2 mg. Mean concentrations of MZ and 1-OH-MZ in serum and CSF were similar between timepoints. Similarly, ratios of 1-OH-MZ to MZ in serum and CSF remained stable over time. Serum MZ (126.2 ± 89.3 ng/mL) showed moderate correlation (r 2 = 0.68, P < 0.001) with serum 1-OH-MZ (17.7 ± 17.6 ng/mL) but not CSF MZ (3.9 ± 2.5 ng/mL; r 2 = 0.24, P = 0.005) or CSF 1-OH-MZ (2.5 ± 0.6 ng/mL; r 2 = 0.47, P = 0.30). CSF MZ did not correlate with CSF 1-OH-MZ (r 2 = 0.003, P < 0.001). Mean serum ratio of 1-OH-MZ to MZ (0.14 ± 0.2 ng/mL) did not correlate with CSF ratio (1.06 ± 0.83 ng/mL; r 2 = 0.06, P = 0.19). Concentrations and ratios were unrelated to MZ infusion rate or 12-h cumulative dose. Sedation was weakly correlated with CSF 1-OH-MZ, but not with serum MZ, serum 1-OH-MZ, or CSF MZ., Conclusion and Relevance: Continuous infusions of MZ result in measurable concentrations of MZ and 1-OH-MZ in CSF; however, CSF concentrations of MZ and 1-OH-MZ poorly represent serum concentrations or dosages. Accumulation of MZ and 1-OH-MZ in serum or CSF over time was not evident. Concentrations of MZ and 1-OH-MZ do not predict sedation levels, reinforcing that pharmacodynamic assessments are warranted., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To describe U.S. practice regarding administration of sedation and analgesia to patients on noninvasive ventilation (NIV) for acute respiratory failure (ARF) and to determine the association of this practice with odds of intubation or death., Design: A retrospective multicenter cohort study., Setting: A total of 1017 hospitals contributed data between January 2010 and September 2020 to the Premier Healthcare Database, a nationally representative healthcare database in the United States., Patients: Adult (≥ 18 yr) patients admitted to U.S. hospitals requiring NIV for ARF., Interventions: None., Measurements and Main Results: We identified 433,357 patients on NIV of whom (26.7% [95% CI] 26.3%-27.0%) received sedation or analgesia. A total of 50,589 patients (11.7%) received opioids only, 40,646 (9.4%) received benzodiazepines only, 20,146 (4.6%) received opioids and benzodiazepines, 1.573 (0.4%) received dexmedetomidine only, and 2,639 (0.6%) received dexmedetomidine in addition to opioid and/or benzodiazepine. Of 433,357 patients receiving NIV, 50,413 (11.6%; 95% CI, 11.5-11.7%) patients underwent invasive mechanical ventilation on hospital days 2-5 or died on hospital days 2-30. Intubation was used in 32,301 patients (7.4%; 95% CI, 7.3-7.6%). Further, death occurred in 24,140 (5.6%; 95% CI, 5.5-5.7%). In multivariable analysis adjusting for relevant covariates, receipt of any medication studied was associated with increased odds of intubation or death. In inverse probability weighting, receipt of any study medication was also associated with increased odds of intubation or death (average treatment effect odds ratio 1.38; 95% CI, 1.35-1.40)., Conclusions: The use of sedation and analgesia during NIV is common. Medication exposure was associated with increased odds of intubation or death. Further investigation is needed to confirm this finding and determine whether any subpopulations are especially harmed by this practice., Competing Interests: This article was supported by an Institutional National Research Service Award (T32) funded by the National Institute of Health, National Heart, Lung, and Blood Institute (T32 HL007085). Dr. Ho disclosed government work. Dr. Sottile’s institution received funding from the National Heart, Lung, and Blood Institute; he received support for article research from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

BACKGROUND Peritonitis is a complication associated with peritoneal dialysis (PD), which carries a significant morbidity and mortality risk. Empiric therapy must include coverage of gram-positive organisms; vancomycin is a recommended treatment option, particularly when MRSA infection is a risk. Vancomycin is cumbersome for patients, requiring therapeutic drug monitoring and re-administration by a healthcare provider. Dalbavancin, administered as a one-time intravenous dose, is a convenient potential treatment option for PD patients to cover gram-positive organisms without the need for routine drug monitoring. CASE REPORT We present 2 patients effectively treated with dalbavancin for infectious peritonitis. The first patient, a 73-year-old woman with end-stage renal disease (ESRD) on PD, presented to the hospital with fever, elevated white blood cells (WBCs), and cloudy peritoneal fluid with elevated nucleated cell counts (88% neutrophils). This patient was given 1 dose of 1500 mg IV dalbavancin. Within 3 days, her fever resolved, WBCs returned to normal, and peritoneal fluid results improved. The second patient was a 36-year-old woman presenting to an outpatient clinic with abdominal pain and cloudy peritoneal fluid with elevated nucleated cell counts (53% neutrophils) treated with dalbavancin 1500 mg IV once. Within 4 days, this patient's pain had resolved, and peritoneal fluid results returned to baseline. No adverse effects were noted for either patient. CONCLUSIONS These cases illustrate the potential of dalbavancin as a convenient option for patients with PD-associated peritonitis. Both patients demonstrated rapid and complete response to a single dose of dalbavancin without complications. Further prospective studies are needed to establish dalbavancin as an option for peritonitis.

Introduction: Aminoglycoside antibiotics such as gentamicin are bactericidal and effective against gram negative organisms and act synergistically against gram positive organisms, including S taphylococcus aureus . However, they have serious adverse effects such as nephrotoxicity and ototoxicity. Gentamicin ototoxicity may occur after a single dose and results in decreased vestibular function, which is frequently debilitating and often permanent., Objective: To emphasize the risk of gentamicin ototoxicity and suggest alternative antibiotics in penicillin-allergic patients undergoing surgery., Case Summary: We present a case of a woman with preexisting Meniere's Disease who received gentamicin 400 mg perioperatively for a sigmoidectomy due to a penicillin allergy listed in the patient's medical record. The patient developed severe ototoxicity preventing her from working or driving. Physical examination was remarkable for a broad-based gait requiring assistance to walk and bilateral corrective saccades. Vestibular testing revealed high-grade bilateral vestibular loss associated with all semicircular canals, a considerable decline compared to her function 3 years prior., Discussion: Gentamicin is indicated for surgical prophylaxis when a patient has a true allergy to penicillins and cannot receive cephalosporins, though alternatives exist. True allergies include IgE-mediated illness (anaphylaxis, bronchospasm, or urticaria 30-60 minutes after administration) or exfoliative reactions (Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis). The authors encourage more prudent use of gentamicin, especially in patients susceptible for debilitating otologic insults, and offer recommendations for alternative agents prior to using gentamicin., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: There was no external funding specific to this work. Author Tyree H. Kiser reports support by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535. Contents are the authors’ sole responsibility and do not necessarily represent official NIH views. Dr. Kiser is a member of the JACCP editorial board.

Background. Vasopressin is frequently utilized for a variety of shock states in critically ill patients. Short stability (≤24 hours) after intravenous admixture with current manufacturer labeling requires just in time preparation and may lead to delays in therapy and increased medication waste. We aimed to evaluate vasopressin stability in 0.9% sodium chloride stored in polyvinyl chloride bags and polypropylene syringes for up to 90 days. Additionally, we evaluated the impact of extended stability on the time to administration and cost savings from reduced medical waste at an academic medical center. Methods. Dilutions of vasopressin to concentrations of 0.4 and 1.0 unit/mL were performed under aseptic conditions. The bags and syringes were stored at room temperature (23°C-25°C) or under refrigeration (3°C-5°C). Three samples of each preparation and storage environment were analyzed on days 0, 2, 14, 30, 45, 60, and 90. Physical stability was performed by visual examination. The pH was assessed at each point and upon final degradation evaluation. Sterility of the samples was not assessed. Chemical stability of vasopressin was evaluated using liquid chromatography with tandem mass spectrometry. Samples were considered stable if there was <10% degradation of the initial concentration. Results. Vasopressin diluted to 0.4 and 1.0 unit/mL with 0.9% sodium chloride injection was physically stable throughout the study. No precipitation was observed. At days 2, 14, 30, 45, 60, and 90 all bags and syringes diluted to 0.4 units/mL had <10% degradation. Vasopressin diluted to 1 unit/mL and stored under refrigeration had <10% degradation at all measured days, but when stored under room temperature was found to have >10% degradation at day 30. Implementation of a batching process resulted in reduced waste ($185 300) and improved time to administration (26 vs 4 minutes). Conclusion. Vasopressin diluted to a concentration of 0.4 units/mL with 0.9% sodium chloride injection is stable for 90 days at room temperature and under refrigeration. When diluted to 1.0 unit/mL with 0.9% sodium chloride injection it is stable for 90 days under refrigeration. Use of extended stability and sterility testing to batch prepare infusions may lead to improved time to administration and cost savings from reduced medication waste., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

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 β 2 -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., (© 2023 Pharmacotherapy Publications, Inc.)

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.

Purpose: Evaluate the stability of isoproterenol hydrochloride injection in 0.9% sodium chloride in polyvinyl chloride bags for up to 90 days. Methods: Dilutions of isoproterenol hydrochloride injection to a concentration of 4 μg/mL were performed under aseptic conditions. The bags were stored in amber ultraviolet light blocking bags at room temperature (23°C-25°C) or under refrigeration (3°C-5°C). Three samples of each preparation and storage environment were analyzed on days 0, 2, 14, 30, 45, 60, and 90. Physical stability was performed by visual examination. The pH was assessed at baseline, each analysis day, and upon final degradation evaluation. Sterility of the samples was not assessed. Chemical stability of isoproterenol hydrochloride was evaluated using liquid chromatography with tandem mass spectrometry. Samples were considered stable if there was <10% degradation of the initial concentration. Results: Isoproterenol hydrochloride diluted to 4 μg/mL with 0.9% sodium chloride injection was physically stable throughout the study. No precipitation was observed. At days 2, 14, 30, 45, 60, and 90 all bags diluted to 4 μg/mL had <10% degradation when stored under refrigeration (3°C-5°C) or stored at room temperature (23°C-25°C). Conclusion: Isoproterenol hydrochloride diluted to a concentration of 4 μg/mL with 0.9% sodium chloride for injection in ultraviolet light blocking bags was stable for 90 days at room temperature and under refrigeration., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

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.

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., (Copyright © 2022. Published by Elsevier Inc.)

Despite evolving evidence, the use of direct oral anticoagulants (DOACs) in patients with extremes of body weight remains controversial. This study aimed to measure the impact of DOACs compared to warfarin on safety and efficacy outcomes in extreme body weight patients. This multi-center, health system, retrospective study examined the outcomes of patients with all body weights and extreme body weights prescribed a DOAC (rivaroxaban, apixaban, dabigatran, edoxaban) or warfarin for atrial fibrillation or venous thromboembolism over a 9-year period. The primary outcome was a composite of thromboembolism, symptomatic recurrent VTE, or severe bleeding; analyzed by pre-determined BMI cutoffs. A total of 19,697 patients were included in the study: 11,604 in the DOAC group and in the 8093 in the warfarin group. 295 patients were underweight and 9108 patients were pre-obese to obese class 3. After adjusting for potential confounders, warfarin patients had higher odds of experiencing the composite outcome compared to DOAC patients (OR 1.337, 95% CI 1.212-1.475). Additionally, obese patients were 24.6% more likely to experience the outcome compared to normal BMI patients. Adjusted modeling showed that warfarin patients experienced higher bleed rates compared to DOAC patients (OR 1.432, 95% CI 1.266-1.620). Obese patients were less likely to be diagnosed with a bleed (OR 0.749, 95% CI 0.658-0.854), and underweight patients were more likely to be diagnosed with a bleed (OR 1.522, 95% CI 1.095-2.115) compared to normal BMI patients. In conclusion, DOACs for atrial fibrillation or VTE in patients with extreme body weights appear safe and effective when compared to warfarin., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., Competing Interests: Dr. Bauer reports he is a consultant for Wolters Kluwer. Dr. Reynolds has a research contract with Bristol, Myers, and Squibb administered through the University of Colorado and serves as the Deputy Editor at Circulation: Cardiovascular Quality and Outcomes Journal. Dr. Kiser’s institution received funding from seed grant funding from the Department of Clinical Pharmacy at the University of Colorado Skaggs School of Pharmacy, and the Colorado Clinical and Translational Science Award grant UL1 TR002535 from the National Center for Advancing Translational Sciences/National Institutes of Health. Dr. Ho’s institution received funding from Bristol-Myers Squibb through the University of Colorado; he received funding from Circulation: Cardiovascular Quality and Outcomes (Deputy Editor); he received research grants from Veterans Affairs and the National Heart, Lung, and Blood Institute and the University of Colorado School of Medicine; and he disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Introduction: There is minimal literature to support the appropriate dosing for the initiation of IV regular insulin therapy in DKA patients. A 0.1 unit/kg bolus followed by 0.1 units/kg/hour or 0.14 units/kg/hour is commonly utilized and recommended in guidelines., Objective: We sought to assess clinical and safety outcomes associated with various insulin infusion starting doses in patients diagnosed with DKA in the emergency department in an effort to help guide prescribing., Methods: A retrospective cohort study was conducted within an academic emergency department and included patients who received continuous infusion regular insulin with an ICD-10 code for DKA between January 2016 and January 2019. A predictive regression model was applied to test if predefined lab values influenced the starting insulin infusion rates. Clinical and safety outcomes were evaluated by starting insulin infusion rate. Data was analyzed based on starting insulin infusion rates., Results: 347 patients met inclusion criteria with 92 (26.5%) patients receiving <0.07 units/kg/hr, 123 (35.4%) patients receiving 0.07 to 0.099 units/kg/hr, 123 (35.4%) patients receiving 0.10 to 0.139 units/kg/hr, and 9 (2.6%) patients receiving ≥0.14 units/kg/hr. After adjusting for baseline labs, glucose was the only significant predictor of the initial infusion rate (p < 0.001). For every 100 mg/dL increase in the baseline glucose value, the initial infusion rate increased by 0.005 units/kg/hr. There was no difference between insulin starting infusion rates and length of stay, rates of hypoglycemia, hypokalemia, or dysrhythmias., Conclusion: Glucose levels significantly influenced the insulin starting infusion rate, with no identified differences in adverse effects or clinical outcomes., Competing Interests: Conflicts of Interest The authors report no conflicts of interest related to this work.

Dalbavancin is a synthetic lipoglycopeptide that exerts its antimicrobial activity through two distinct modes of action, inhibition of cell wall synthesis and an anchoring mechanism. Compared with previous glycopeptide antibiotics, dalbavancin demonstrates improved antibacterial potency against Gram-positive organisms and a long half-life of approximately 1 week, which is longer in tissues (e.g., skin, bone) than plasma. These factors facilitated the development of single-dose or once-weekly dosing regimens to treat acute bacterial skin and skin structure infections (ABSSSI). Dalbavancin exhibits dose-proportional pharmacokinetics and is highly protein bound (93%). Despite being highly protein bound, it has a steady-state volume of distribution >10 L and distributes widely into the skin, bone, peritoneal space, and epithelial lining fluid, but not cerebrospinal fluid. Dalbavancin elimination occurs via a combination of renal (approximately 45%) and non-renal clearance, with dose adjustments recommended only in patients with a creatinine clearance <30 mL/min not receiving any form of dialysis. The established pharmacokinetic/pharmacodynamic index associated with bacterial kill is free area under the concentration-time curve over the minimum inhibitory concentration (fAUC/MIC), with a goal 24-h fAUC/MIC of at least 27.1 for Staphylococcus aureus infections. Recent data suggest usefulness in the treatment of infections beyond ABSSSI, with convenient dosing and redosing strategies for complicated infections requiring extended treatment durations. Additional studies are needed to confirm these preliminary findings., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Patients with COVID-19 are at higher risk of thrombosis due to the inflammatory nature of their disease. A higher-intensity approach to pharmacologic thromboprophylaxis may be warranted. The objective of this retrospective cohort study was to determine if a patient specific, targeted-intensity pharmacologic thromboprophylaxis protocol incorporating severity of illness, weight, and biomarkers decreased incidence of thrombosis in hospitalized patients with COVID-19. Included patients were hospitalized with COVID-19 and received thromboprophylaxis within 48 h of admission. Exclusion criteria included receipt of therapeutic anticoagulation prior to or within 24 h of admission, history of heparin-induced thrombocytopenia, extracorporeal membrane oxygenation, pregnancy, or incarceration. Per-protocol patients received thromboprophylaxis according to institutional protocol involving escalated doses of anticoagulants based upon severity of illness, total body weight, and biomarker thresholds. The primary outcome was thrombosis. Secondary outcomes included major bleeding, mortality, and identification of risk factors for thrombosis. Of 1189 patients screened, 803 were included in the final analysis. The median age was 54 (42-65) and 446 (55.5%) were male. Patients in the per-protocol group experienced significantly fewer thrombotic events (4.4% vs. 10.7%, p = 0.002), less major bleeding (3.1% vs. 9.6%, p < 0.001), and lower mortality (6.3% vs. 11.8%, p = 0.02) when compared to patients treated off-protocol. Significant predictors of thrombosis included mechanical ventilation and male sex. Post-hoc regression analysis identified mechanical ventilation, major bleeding, and D-dimer ≥ 1500 ng/mL FEU as significant predictors of mortality. A targeted pharmacologic thromboprophylaxis protocol incorporating severity of illness, body weight, and biomarkers appears effective and safe for preventing thrombosis in patients with COVID-19., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In recent years, vasopressin has been increasingly used as an early treatment of vasopressor-refractory septic shock. In this article, we describe 2 episodes of transient diabetes insipidus after vasopressin for the treatment of septic shock was discontinued, which adds to a modest number of case studies reporting the same phenomenon. With the anticipated continued use of vasopressin in intensive care units, it can be expected that this adverse effect will occur with some frequency. Awareness and early recognition of this phenomenon can lead to prompt diagnosis and treatment.

Background: The relative distribution of cefazolin into the cerebrospinal fluid (CSF) remains debated. Determining the distribution of cefazolin into the CSF in noninfected adults may allow for further treatment applications of cefazolin. This prospective pharmacokinetic study aimed to determine the pharmacokinetic parameters of cefazolin in serum and CSF from external ventricular drains (EVDs) in neurologically injured adults., Methods: Blood and CSF were collected, using a biologic waste protocol, for cefazolin quantification and trapezoidal rule-based pharmacokinetic analysis in a total of 15 critically ill adults receiving 2000 mg intravenously every 8 hours or the renal dose equivalent for EVD prophylaxis., Results: A median (range) of 3 (2-4) blood and 3 (2-5) CSF samples were collected for each patient. The most common admitting diagnosis was subarachnoid hemorrhage (66.7%). The median calculated cefazolin CSF C max and C min values (interquartile range [IQR]) were 2.97 (1.76-8.56) mg/L and 1.59 (0.77-2.17) mg/L, respectively. The median (IQR) CSF to serum area under the curve ratio was 6.7% (3.7%-10.6%), with time-matched estimates providing a similar estimate (8.4%). Of those receiving cefazolin every 8 hours, the median and minimum directly measured CSF cefazolin concentration ≥4 hours following administration were 1.87 and 0.78 mg/L, respectively., Conclusions: Cefazolin dosed for EVD prophylaxis achieved CSF concentrations suggesting viability as a therapeutic option for patients with meningitis or ventriculitis due to susceptible bacteria such as methicillin-susceptible Staphylococcus aureus . Further clinical trials are required to confirm a role in therapy for cefazolin. Population-based pharmacokinetic-pharmacodynamic modeling may suggest an optimal cefazolin regimen for the treatment of central nervous system infections., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Heart failure hospitalization is a hallmark of disease progression associated with increased morbidity and mortality. Benefits of multidisciplinary clinics have been established in the care of heart failure patients and can be particularly impactful post-hospital discharge., Objective: This study aimed to investigate the impact of a clinical pharmacist-integrated model of care within a Heart Failure Bridge Clinic (HFBC) at a large tertiary care referral center., Methods: In this single-center retrospective study, patients with left ventricular ejection fraction (LVEF) ≤40% discharged from Mission Hospital (Asheville, North Carolina) between August 2018 and July 2019 were screened. Patients in the HFBC arm had a clinic visit inclusive of a clinical pharmacist within 30 days of hospital discharge and were compared with a control group of patients with a usual care provider clinic visit. The HFBC provided clinical assessment, detailed heart failure education, and medication reconciliation and adjustment with an emphasis on optimization of Guideline Directed Medical Therapy (GDMT). Patients were followed for 90 days for the primary end point of hospitalization, emergency department (ED) visit, or death., Results: A total of 1463 patients (HFBC, n = 307; control, n = 1156) comprised our final cohort. After accounting for baseline variables, 90-day cumulative probability of hospitalization, ED visit, or death favored HFBC patients (26% vs 32%, P = .0275). Comprehensive review of medications prior to and after HFBC appointment demonstrated significant alterations to therapies (30% GDMT addition, 27% GDMT titration, 7.2% discontinuation of medications associated with worsening heart failure, and 28% loop diuretic adjustment)., Conclusion: Clinical pharmacist-integrated HFBC allows for focused medication review and optimization and is associated with a 19% relative risk reduction in hospitalization, ED visit, or death at 90 days., Competing Interests: CONFLICT OF INTEREST The authors declare no conflicts of interest.

Medications are an important part of the management of patients with kidney disease. When used appropriately, pharmacotherapy can slow disease progression and reduce morbidity and mortality. Unfortunately, reduced kidney function can significantly alter the pharmacokinetics and pharmacodynamics of many medications, putting patients at risk for drug toxicity if modifications to therapy are not appropriately managed. Adding complexity to the appropriateness of medication and dosage selection is the difficulty in estimating kidney function and the discordance between the Cockcroft-Gault-derived dosing cut points in most medication package inserts and the estimations of glomerular filtration rate by newer and generally more accurate guideline-recommended equations. This installment of the AJKD Core Curriculum in Nephrology provides recent updates and practical considerations for designing optimal medication regimens. Given the prevalence of abnormal kidney function and its importance in medication selection and dose adjustment, additional focus and specific recommendations are provided for anticoagulant, anti-infective, analgesic, antidiabetic, and antihypertensive agents., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Left ventricular (LV) thrombus is a complication of acute endomyocardial injury and chronic ventricular wall hypokinesis, resulting in increased risk of thromboembolic complications. Observational studies support the general safety and efficacy of warfarin for this indication. Limited data exists regarding the use of direct oral anticoagulants (DOACs) for LV thrombus. This retrospective cohort study sought to compare the incidence of thromboembolic events, bleeding rates, and blood product administration in patients receiving a DOAC versus warfarin. A total of 949 patients met inclusion, 180 (19%) received a DOAC and 769 (81%) warfarin. For the primary endpoint of new onset thromboembolic stroke, no difference existed between treatments (DOAC: 7.8% vs warfarin: 11.7%, p = 0.13). When compared to warfarin, no difference existed in the composite of thromboembolic events (33% vs 30.6%, p = 0.53, respectively) or in GUSTO bleeding (10.9% vs 7.8%, p = 0.40, respectively). More patients on warfarin received blood products compared to those taking a DOAC (25.8% vs 13.9%, p < 0.001).DOACs may be an alternative to warfarin for the treatment of LV thrombus based on a retrospective assessment of thromboembolic events and GUSTO bleeding events within 90 days of diagnosis of LV thrombus. However, further prospective studies are warranted., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

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.

BACKGROUND Immune checkpoint inhibitors (ICIs) are a novel class of antibodies, which have been increasingly utilized in cancer immunotherapies. Pembrolizumab is a humanized IgG4 monoclonal antibody, which acts against programmed cell death (PD)-1 receptors to help restore the body's T-cell and immune response. CASE REPORT In this case, we present a 51-year-old woman with a past medical history of lung adenocarcinoma and triple-positive breast cancer who was actively receiving therapy with pembrolizumab. Following her second chemotherapy cycle, she developed a severe case of diabetic ketoacidosis (DKA), with concern for new-onset autoimmune type 1 diabetes mellitus (T1DM), secondary to her recent ICI therapy. The patient was initiated on a high-dose insulin infusion for rapid glycemic control and was successfully transitioned to a subcutaneous regimen approximately 24 h after presentation. She additionally developed other autoimmune-related complications, including hepatoxicity, duodenitis, and a maculopapular rash, which all resolved upon discontinuation of the ICI treatment. Her laboratory test results were consistent with positive anti-glutamic acid decarboxylase (anti-GAD) antibodies and undetectable c-peptides, illustrating the uniqueness of an ICI potentially precipitating an autoimmune T1DM. CONCLUSIONS Immune-related adverse events from ICI therapy warrant further investigation to acknowledge the risk of potentially life-threatening adverse reactions, such as the development of DKA. Patients receiving ICI therapy should be educated on signs and symptoms of hyperglycemia, and routine measurements of blood glucose levels should be completed during each chemotherapy cycle. Future research in assessing potential biomarkers of beta cell dysfunction, such as anti-GAD antibodies and c-peptides, is of interest, particularly for patients receiving ICI therapies.

Complicated methicillin-resistant Staphylococcus aureus bloodstream infections (MRSA-BSIs), particularly those with delayed culture clearance, are associated with high mortality. Combination therapy with daptomycin and ceftaroline (DAP+CPT) represents a novel therapeutic approach to MRSA-BSI owing to synergistic bactericidal activity. This study aimed to compare DAP+CPT with historical standard of care (SoC) for treatment of complicated MRSA-BSI. This single-centre retrospective cohort study included patients with complicated MRSA-BSI at University of Colorado Hospital. Patients receiving DAP+CPT for ≥48 h between November 2013 and March 2020 or SoC with vancomycin or DAP ± gentamicin and/or rifampicin from November 2011 to December 2013 were compared. The primary outcome was clinical failure defined as a composite of MRSA-related mortality and recurrent infection at 60 days. A total of 60 patients received DAP+CPT (n = 30) or SoC (n = 30). Median age was 56 years and median Pitt bacteremia score was 3. Common infectious sites were endovascular (63%) and musculoskeletal (40%). DAP+CPT was associated with a numerically lower incidence of clinical failure compared with SoC (20% vs. 43%; P = 0.052). Multivariable analysis controlling for immunocompromised status (OR, 6.90, 95% CI 1.08-44.15), Charlson comorbidity index (OR, 1.12, 95% CI 0.90-1.39) and source control (OR, 0.35, 95% CI 0.08-1.46) associated DAP+CPT with 77% lower odds of clinical failure (OR, 0.23, 95% CI 0.06-0.89). In patients with complicated MRSA-BSI with delayed clearance, DAP+CPT trended towards lower rates of clinical failure than SoC and was significantly associated with decreased clinical failure after adjustment for baseline differences., (Copyright © 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

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.

Rationale: Noninvasive ventilation decreases the need for invasive mechanical ventilation and mortality among patients with chronic obstructive pulmonary disease but has not been well studied in asthma. Objectives: To assess the association between noninvasive ventilation and subsequent need for invasive mechanical ventilation and in-hospital mortality among patients admitted with asthma exacerbation to the ICU. Methods: We performed a retrospective cohort study using administrative data collected during 2010-2017 from 682 hospitals in the United States. Outcomes included receipt of invasive mechanical ventilation and in-hospital mortality. Generalized estimating equations, propensity-matched models, and marginal structural models were used to assess the association between noninvasive ventilation and outcomes. Measurements and Main Results: The study population included 53,654 participants with asthma exacerbation. During the study period, 13,540 patients received noninvasive ventilation (25.2%; 95% confidence interval [CI], 24.9-25.6%), 14,498 underwent invasive mechanical ventilation (27.0%; 95% CI, 26.7-27.4%), and 1,291 died (2.4%; 95% CI, 2.3-2.5%). Among those receiving noninvasive ventilation, 3,013 patients (22.3%; 95% CI, 21.6-23.0%) required invasive mechanical ventilation after first receiving noninvasive ventilation, 136 of whom died (4.5%; 95% CI, 3.8-5.3%). Across all models, the use of noninvasive ventilation was associated with a lower odds of receiving invasive mechanical ventilation (adjusted generalized estimating equation odds ratio, 0.36; 95% CI, 0.32-0.40) and in-hospital mortality (odds ratio, 0.48; 95% CI 0.40-0.58). Those who received noninvasive ventilation before invasive mechanical ventilation were more likely to have comorbid pneumonia and severe sepsis. Conclusions: Noninvasive ventilation use during asthma exacerbation was associated with improved outcomes but should be used cautiously with acute comorbid conditions.

Objective: To compare methylene blue with hydroxocobalamin as a rescue therapy for vasoplegic syndrome., Design: Retrospective cohort., Setting: Academic medical center., Participants: Patients undergoing cardiothoracic surgery treated for vasoplegic syndrome., Interventions: Thirty-five patients were treated with methylene blue (n = 16) or hydroxocobalamin (n = 19)., Measurements and Main Results: Mean arterial pressure, systemic vascular resistance, and vasopressor exposures were recorded before and after medication administration. Change in time-averaged norepinephrine equivalents in the hour after administration was the primary outcome. The average norepinephrine equivalent observed at baseline in this cohort was 0.347 µg/kg/min. Methylene blue patients had greater Acute Physiological Assessment and Chronic Health Evaluation II scores (29.8 v 22.2; p = 0.01) and trended toward greater European System for Cardiac Operative Risk Evaluation II values (26.8% v 15.1%; p = 0.07). Methylene blue and hydroxocobalamin were associated with increased mean arterial pressure and systemic vascular resistance 1 hour after administration (10.6 mmHg and 192 dyn*sec/cm 5 ; p = 0.01 and p = 0.01, respectively; 11.8 mmHg and 254 dyn*sec/cm 5 ; p = 0.002 and p = 0.015, respectively). Hemodynamic changes were not different between the rescue therapy groups (p = 0.79 and p = 0.53, respectively). No significant differences were observed within the 1-hour change in time-averaged norepinephrine equivalents for either agent or when methylene blue and hydroxocobalamin were compared (0.012 ± 0.218 µg/kg/min v -0.037 ± 0.027 µg/kg/min; p = 0.46, respectively). When compared with baseline time-averaged norepinephrine equivalent (0.326 ± 0.106 µg/kg/min), only hydroxocobalamin was associated with decreased vasopressor requirements at the 1-hour (0.255 ± 0.129 µg/kg/min; p = 0.03) and 4-hour time points (0.247 ± 0.180 µg/kg/min; p = 0.04) post-administration., Conclusion: Methylene blue and hydroxocobalamin increased mean arterial pressures and systemic vascular resistance without significantly decreasing time-averaged norepinephrine exposure in the hour after administration., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose of Review: This review summarizes current treatment options for echinocandin-resistant Candida spp. (ERC) and azole-resistant Aspergillus fumigatus (ARAF), emphasizing recent in vitro/in vivo data, clinical reports, and consensus statements., Recent Findings: Advances in ERC and ARAF treatment are limited to specific antifungal combinations and dose optimization but remain reliant on amphotericin products. Although novel antifungals may provide breakthroughs in the treatment of resistant fungi, these agents are not yet available. Early identification and appropriate treatment remain a paramount, albeit elusive, task., Summary: When either ERC or ARAF are suspected or proven, amphotericin products remain the cornerstone of initial therapy. For ERC, azoles are de-escalation options for susceptible isolates in stable patients to avoid amphotericin toxicities. Although combination echinocandin with high-dose salvage posaconazole or isavuconazole may be attempted in ARAF, it requires careful consideration following patient stabilization. Future research defining optimal therapies and early identification of ERC and ARAF is of extreme importance., Competing Interests: Compliance with Ethics Guidelines Conflict of Interest

Dalbavancin offers a possible treatment option for infectious peritonitis associated with peritoneal dialysis (PD) due to its coverage of Gram-positive bacteria and pharmacokinetic properties. We aimed to evaluate the clinical pharmacokinetics (PK) and pharmacodynamics of dalbavancin in a prospective, randomized, open-label, crossover PK study of adult patients with end-stage renal disease ESRD who were receiving PD. Sampling occurred prior to a single 30-min infusion of dalbavancin at 1,500 mg and at 1, 2, 3, 4, and 6 h and 7 and 14 days postadministration. Concentration-time data were analyzed via noncompartmental analysis. Pharmacodynamic parameters against common infectious peritonitis-causing pathogens were evaluated. Ten patients were enrolled. Patients were a median of 55 years old and had a median weight of 78.2 kg, 50% were female, and 70% were Caucasian. The terminal plasma half-life of dalbavancin was 181.4 ± 35.5 h. The day 0 to day 14 dalbavancin mean area under the curve (AUC) was 40,573.2 ± 9,800.3 mg·h/liter. The terminal-phase half-life of dalbavancin within the peritoneal fluid was 4.309 × 10 8 ± 1.140 × 10 9  h. The day 0 to day 14 dalbavancin mean peritoneal fluid AUC was 2,125.0 ± 1,794.3 mg·h/liter. The target plasma AUC/MIC was attained with the intravenous dose in all 10 patients for all Staphylococcus and Streptococcus species at the recommended MIC breakpoints. The intraperitoneal arm of the study was stopped early, because the first 3 patients experienced moderate to severe pain and bloating within 1 h following the administration of dalbavancin. Dalbavancin at 1,500 mg administered intravenously can be utilized without dose adjustment in peritoneal dialysis patients and will likely achieve the necessary peritoneal fluid concentrations to treat peritonitis caused by typical Gram-positive pathogens., (Copyright © 2020 American Society for Microbiology.)

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.

The parenterally administered direct thrombin inhibitors (DTIs) argatroban and bivalirudin are effective anticoagulants for acute heparin-induced thrombocytopenia (HIT) treatment. The activated partial thromboplastin time (aPTT) has classically been used as the monitoring test to assess degree of anticoagulation, however concerns exist with using aPTT to monitor DTI therapy. In this observational study plasma samples from DTI treated patients were analyzed by aPTT, dilute thrombin time (dTT) and ecarin chromogenic assay (ECA) to delineate results into concordant and discordant groups. Discordant samples were further analyzed via liquid chromatography with tandem mass spectrometry (LC MS/MS). In total 101 patients with 198 samples were evaluated. Discordance between tests were frequent (59% of DTI treated patients). Bivalirudin aPTT vs dTT discordance was observed in 45% (57/126) of samples. Amongst bivalirudin samples with test discordance dTT results were more likely to be concordant with LC MS/MS than the aPTT (77% vs 9%, p < 0.0001). Argatroban aPTT vs dTT discordance was observed in 43% (31/72) and aPTT vs ECA discordance was observed in 40% (29/72) of samples. Amongst argatroban samples with test discordance both the dTT and ECA tests were more likely to have concordant results with LC MS/MS than the aPTT (88% vs 9%, p < 0.0001 for both dTT and ECA tests). There were no differences between discordant and concordant patient groups in a composite outcome of bleeding/thrombosis rate (23% vs 27%, p = 0.689). Further investigation is warranted to elucidate the effect of suitable monitoring assays on patient outcomes in the setting of DTI therapy.

Cancer increases risk for venous thromboembolism. Incident thrombocytopenia increases hemorrhagic risk. Hospitalized adults with a cancer diagnosis who received subcutaneous dalteparin in doses adjusted according to platelet count were retrospectively evaluated. Outcomes of interest included nadir platelet counts, transfusions, thromboembolism, and hemorrhage. During a 2-year period of observation, 1854 cancer patients received individualized inpatient treatment with dalteparin. Transfusion was required in 38 of 77 (49.4%) patients with nadir platelet counts < 25 × 10 9 cells/L as compared with 16 of 75 (21.3%) patients whose nadir platelet counts were 25-50 × 10 9 cells/L [risk ratio (RR) 2.31; 95% CI 1.42 to 3.78, p < 0.001] and 45 of 1657 (2.7%) patients with platelet counts > 50 × 10 9 cells/L (RR - 8.07; 95% CI - 4.79 to - 13.59, p < 0.001). Transfusions were administered primarily as supportive therapy. Among transfusion recipients, new or recurrent venous thromboembolism was documented in 2.6%, 0%, and 2.2% of patients with nadir platelet counts of < 25, 25-50, or > 50 × 10 9 cells/L, respectively (p > 0.9 for all comparisons). Acute blood loss or major bleeding was documented in 10.5%, 12.5%, and 15.6% of patients with platelet counts of < 25, 25-50, or > 50 × 10 9 cells/L, respectively (p > 0.9 for all comparisons). Among hospitalized cancer patients who received individualized dalteparin treatment, transfusion requirements varied inversely with platelet count. Irrespective of platelet counts, occurrence rates for venous thromboembolism and acute hemorrhage were similar across all treatment groups. Individualized dalteparin treatment provided a consistent pattern of safety and effectiveness.

Concern for bacterial resistance and treatment failure with vancomycin trough concentrations < 10 μg/mL have led guidelines to increase goal concentrations. There is a paucity of data evaluating vancomycin dosage necessary to achieve goals in the neonatal intensive care unit (NICU). We aimed to evaluate the implementation of a new vancomycin dosing guideline in improving trough target attainment. This retrospective study evaluated neonates in the NICU treated with vancomycin between January 2009 and December 2015. Therapeutic trough concentration attainment (10-20 μg/mL) was compared between neonates receiving vancomycin per old versus new dosing guidelines. Vancomycin trough concentrations, modeled pharmacodynamic target attainment, and nephrotoxicity were compared between groups. A total of 212 vancomycin trough concentrations (n = 91 old and n = 121 new guideline) were evaluated in 182 unique neonates. The mean ± standard deviation trough concentration achieved was 18.0 ± 7.3 μg/mL vs 8.9 ± 4.8 μg/mL in the new and old guidelines, respectively (P < .01). The new guideline resulted in a higher percentage of neonates achieving trough concentrations of 10 to 20 μg/mL (62% vs 29%; P < .01) and decreased the percentage of neonates with subtherapeutic trough concentrations (9% vs 69%; P < .01). Pharmacokinetic modeling identified postmenstrual age, days of life, and urine output as predictors of vancomycin clearance and resultant trough and area under the curve values (P < .01 for all). Trough concentrations >10 μg/mL ensured area under the curve /minimum inhibitory concentration >400 in >90% of neonates when bacteria minimum inhibitory concentration was ≤ 1 μg/mL. Nephrotoxicity was similar between groups (8.3% vs 7.7%; P = .99). In conclusion, a vancomycin nomogram designed to achieve trough concentration of 10 to 20 μg/mL improves pharmacodynamic target attainment in neonates in the NICU., (© 2019, The American College of Clinical Pharmacology.)

Background: Timely initiation of physical, occupational, and speech therapy in critically ill patients is crucial to reduce morbidity and improve outcomes. Over a 5-year time interval, we sought to determine the utilization of these rehabilitation therapies in the USA., Methods: We performed a retrospective cohort study utilizing a large, national administrative database including ICU patients from 591 hospitals. Patients over 18 years of age with acute respiratory failure requiring invasive mechanical ventilation within the first 2 days of hospitalization and for a duration of at least 48 h were included., Results: A total of 264,137 patients received invasive mechanical ventilation for a median of 4.0 [2.0-8.0] days. Overall, patients spent a median of 5.0 [3.0-10.0] days in the ICU and 10.0 [7.0-16.0] days in the hospital. During their hospitalization, 66.5%, 41.0%, and 33.2% (95% CI = 66.3-66.7%, 40.8-41.2%, 33.0-33.4%, respectively) received physical, occupational, and speech therapy. While on mechanical ventilation, 36.2%, 29.7%, and 29.9% (95% CI = 36.0-36.4%, 29.5-29.9%, 29.7-30.1%) received physical, occupational, and speech therapy. In patients receiving therapy, their first physical therapy session occurred on hospital day 5 [3.0-8.0] and hospital day 6 [4.0-10.0] for occupational and speech therapy. Of all patients, 28.6% (95% CI = 28.4-28.8%) did not receive physical, occupational, or speech therapy during their hospitalization. In a multivariate analysis, patients cared for in the Midwest and at teaching hospitals were more likely to receive physical, occupational, and speech therapy (all P < 0.05). Of patients with identical covariates receiving therapy, there was a median of 61%, 187%, and 70% greater odds of receiving physical, occupational, and speech therapy, respectively, at one randomly selected hospital compared with another (median odds ratio 1.61, 2.87, 1.70, respectively)., Conclusions: Physical, occupational, and speech therapy are not routinely delivered to critically ill patients, particularly while on mechanical ventilation in the USA. The utilization of these therapies varies according to insurance coverage, geography, and hospital teaching status, and at a hospital level.

Background: Invasive fungal infections are a major cause of morbidity and mortality. Newer antifungals may provide similar efficacy with improved safety compared to older more established treatments. This study aimed to compare clinically relevant safety and efficacy outcomes in real world patients treated with isavuconazole, voriconazole, or posaconazole., Methods: This single center retrospective matched cohort study evaluated adults between January 2015 and December 2017. The primary outcome was a composite safety analysis of antifungal related QTc prolongation, elevated liver function tests (> 5 times ULN), or any documented adverse drug event. Key secondary outcomes included: individual safety events, 30-day readmissions, magnitude of drug interactions with immunosuppressive therapy, and overall cost., Results: A total of 100 patients were included: 34 patients in the voriconazole group and 33 patients within each of the isavuconazole and posaconazole groups. The composite safety outcome occurred in 40% of the total cohort and was different between isavuconazole (24.2%), voriconazole (55.9%), and posaconazole (39.4%; p = 0.028). Change in QTc (p < 0.01) and magnitude of immunosuppression dose reduction (p = 0.029) were different between the three groups. No differences in mortality, length of stay, readmission, or infection recurrence were observed between groups (p > 0.05 for all). The overall medication cost, when including therapeutic drug monitoring, was not different between treatments (p = 0.36)., Conclusions: Patients treated with isavuconazole resulted in fewer composite safety outcomes, driven by decreased incidence of QTc prolongation, compared to patients treated with voriconazole or posaconazole. Overall drug cost was not significantly different between the treatment therapy options.

Study Objective: To assess whether a macrolide-based antibiotic treatment strategy reduces in-hospital mortality, decreases hospital readmissions, or improves other clinically important outcomes compared with a non-macrolide antibiotic treatment strategy in critically ill patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD)., Design: Propensity score-matched pharmacoepidemiologic cohort study., Data Source: Premier's Perspective Hospital Database., Patients: A total of 28,700 adults aged 40 years or older who were admitted to one of 566 United States intensive care units and had the primary diagnosis of AECOPD between January 2010 and December 2014 and received antibiotic treatment within 2 days of hospital admission were included. Patients were divided into macrolide (11,602 patients [40%]) or non-macrolide (17,098 patients [60%]) antibiotic treatment groups. Propensity score analysis successfully matched 8660 patients in each treatment group., Measurements and Main Results: In the matched cohort, the macrolide treatment group was not associated with decreased hospital mortality after day 2 (3.0% vs 3.3%, p=0.28), intensive care unit length of stay (2 days vs 2 days, p=0.12), hospital length of stay (6 days vs 6 days, p=0.86), or length of assisted ventilation (3 days vs 3 days, p=0.71), compared with the non-macrolide treatment group. However, a macrolide-based antibiotic regimen was associated with an overall reduction in 30-day hospital readmissions (7.3% vs 8.8%, p<0.01), increased time to next all-cause (159 vs 130 days, p<0.01) or AECOPD (200 vs 175 days, p=0.03) readmission, and decreased hospital costs ($32,730 vs $34,021, p<0.01)., Conclusion: The results of this study suggest that inclusion of a macrolide antibiotic in the treatment regimen may have both acute and sustained benefits in critically ill patients admitted to the intensive care unit with an AECOPD, including reductions in hospital readmissions and improvements in time to next readmission., (© 2019 Pharmacotherapy Publications, Inc.)