Analysis of Mortality in Patients Treated With Phenylephrine in Septic Shock.

BACKGROUND: Phenylephrine is a selective α1-receptor agonist used to manage shock. Current guidelines for septic shock recommend limited utilization of phenylephrine due to the lack of evidence available. This deviates from previous guidelines, which had recommendations of when utilization may be appropriate. OBJECTIVE: The primary objective of this study was to evaluate mortality in patients receiving phenylephrine for the management of septic shock. METHODS: This was a retrospective chart review from September 2015 to September 2017 evaluating all adult patients admitted to an intensive care unit (ICU) on vasopressors for management of septic shock. Patients were divided into 2 groups, those treated with phenylephrine and those treated without phenylephrine. The primary outcome was mortality. Secondary objectives included days on vasopressors and ICU length of stay. Two subgroup analyses were performed: 1 for phenylephrine as first-line therapy and 1 for patients with tachycardia at initiation of vasopressors. Patients started on phenylephrine for salvage therapy were excluded from this study. RESULTS: 499 patients enrolled in the study. 148 (32%) were enrolled in the phenylephrine group. Phenylephrine was associated with an increase in mortality (56% vs 41%; p = 0.003). There was no difference in the days on vasopressors or ICU length of stay. Patients who had ongoing tachycardia were associated with increased mortality with phenylephrine (54% vs 36%, p = 0.02). There was no difference in mortality when phenylephrine was started as the initial vasopressor. CONCLUSION: Utilization of phenylephrine in septic shock patients, especially those with ongoing tachycardia, was associated with an increased rate of mortality.

Retrospective analysis of anti-inflammatory therapies during the first wave of COVID-19 at a community hospital.

BACKGROUND: Our understanding of the severe acute respiratory syndrome coronavirus 2 has evolved since the first reported cases in December 2019, and a greater emphasis has been placed on the hyper-inflammatory response in severely ill patients. The purpose of this study was to determine risk factors for mortality and the impact of anti-inflammatory therapies on survival. AIM: To determine the impact of various therapies on outcomes in severe coronavirus disease 2019 patients with a focus on anti-inflammatory and immune-modulating agents. METHODS: A retrospective analysis was conducted on 261 patients admitted or transferred to the intensive care unit in two community hospitals between March 12, 2020 and June 17, 2020. Totally 167 patients received glucocorticoid (GC) therapy. Seventy-three patients received GC alone, 94 received GC and tocilizumab, 28 received tocilizumab monotherapy, and 66 received no anti-inflammatory therapy. RESULTS: Patient survival was associated with GC use, either alone or with tocilizumab, and decreased vasopressor requirements. Delayed administration of GC was found to decrease the survival benefit of GC therapy. No difference in survival was found with varying anticoagulant doses, convalescent plasma, tocilizumab monotherapy; prone ventilation, hydroxychloroquine, azithromycin, or intravenous ascorbic acid use. CONCLUSION: This analysis demonstrated the survival benefit associated with anti-inflammatory therapy of GC, with or without tocilizumab, with the combination providing the most benefit. More studies are needed to assess the optimal timing of anti-inflammatory therapy initiation.

A 33-mRNA Classifier Is Able to Produce Inflammopathic, Adaptive, and Coagulopathic Endotypes with Prognostic Significance: The Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis (ORANGES) Trial.

BACKGROUND: Retrospective analysis of the transcriptomic host response in sepsis has demonstrated that sepsis can be separated into three endotypes-inflammatory (IE), adaptive (AE), and coagulopathic (CE), which have demonstrated prognostic significance. We undertook a prospective transcriptomic host response analysis in a subgroup of patients enrolled in the Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis (ORANGES) trial. METHODS: Blood was obtained from 51 patients and profiled using a pre-established 33-mRNA classifier to determine sepsis endotypes. Endotypes were compared to therapy subgroups and clinical outcomes. RESULTS: We redemonstrated a statistically significant difference in mortality between IE, AE, and CE patients, with CE patients demonstrating the highest mortality (40%), and AE patients the lowest mortality (5%, p = 0.032). A higher CE score was a predictor of mortality; coronary artery disease (CAD) and elevated CE scores were associated with an increase in mortality (CAD: HR = 12.3, 95% CI 1.5-101; CE score: HR = 15.5 95% CI 1.15-211). Kaplan-Meier (KM) analysis of the entire cohort (n = 51) demonstrated a decrease survival in the CE group, p = 0.026. KM survival analysis of hydrocortisone, ascorbic acid, and thiamine (HAT) therapy and control patients not receiving steroids (n = 45) showed CE and IE was associated with a decrease in survival (p = 0.003); of interest, there was no difference in survival in CE patients after stratifying by HAT therapy (p = 0.18). These findings suggest a possible treatment effect of corticosteroids, HAT therapy, endotype, and outcome. CONCLUSION: This subset of patients from the ORANGES trial confirmed previous retrospective findings that a 33-mRNA classifier can group patients into IE, AE, and CE endotypes having prognostic significance. A novel finding of this study identifying an association between endotype and corticosteroid therapy warrants further study in support of future diagnostic use of the endotyping classifier.

Validation of Bleeding Risk Prediction Scores for Patients With Major Bleeding on Direct Oral Anticoagulants.

BACKGROUND: Direct oral anticoagulants (DOACs) offer many benefits over vitamin K antagonists (VKAs) but still carry a significant risk of major bleeding. Bleeding risk prediction scores such as the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, and Drugs/Alcohol (HAS-BLED), Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk, and Stroke (HEMORR2HAGES), Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), Registro Informatizado Enfermedad TromboEmbólica (RIETE), and CHEST scores were validated or evaluated for use with VKAs and parenteral anticoagulants, but evidence for use with DOACs is lacking. OBJECTIVE: This study aims to evaluate bleeding risk prediction scores for DOAC patients presenting with major bleeding. METHODS: A retrospective analysis of patients presenting from 2015 to 2018 was performed. Patients were separated into bleed and nonbleed groups. The primary objective was to assess the diagnostic accuracy of the bleeding risk prediction scores utilizing the receiver operating characteristic (ROC) curve. RESULTS: A total of 126 patients were included in the analyses. The areas under the curve (AUC) for the ROC curves of the HAS-BLED, HEMORR2HAGES, ATRIA, RIETE, and CHEST scores were 0.645, 0.675, 0.580, 0.638, and 0.667, respectively. CONCLUSION AND RELEVANCE: The HAS-BLED, HEMORR2HAGES, RIETE, and CHEST scores were found to have sufficient diagnostic accuracy for predicting risk of major bleeding in our study population; however, no score was identified as having an AUC greater than 0.7. Caution may be considered when utilizing these scores for patients on DOACs.

Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial.

BACKGROUND: Sepsis is a major public health burden resulting in 25% to 30% in-hospital mortality and accounting for over 20 billion dollars of US hospital costs. RESEARCH QUESTION: Does hydrocortisone, ascorbic acid, thiamine (HAT) therapy improve clinical outcomes in sepsis and septic shock? STUDY DESIGN AND METHODS: This was a randomized, double-blinded, placebo-controlled trial conducted from February 2018 to June 2019, assessing an HAT treatment bundle for the management of septic and septic shock patients admitted to an ICU. The primary outcomes were resolution of shock and change in Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes included 28-day mortality, ICU mortality, hospital mortality, procalcitonin clearance (PCT-c), hospital length of stay (LOS), ICU LOS, and ventilator-free days. RESULTS: One hundred thirty-seven patients were randomized to the treatment group (n = 68) and comparator group (n = 69), respectively, with no significant differences in baseline characteristics. A statistically significant difference was found in the time patients required vasopressors, indicating quicker reversal of shock in the HAT group compared with the comparator group (27 ± 22 vs 53 ± 38 hours, P < .001). No statistically significant change in SOFA score was found between groups 3 (1 - 6) vs 2 (0 - 4), P = .17. No significant differences were found between study arms in ICU and hospital mortality, ICU and hospital LOS, ventilator free days, and PCT-c. INTERPRETATION: Our results suggest that the combination of IV ascorbic acid, thiamine, and hydrocortisone significantly reduced the time to resolution of shock. Additional studies are needed to confirm these findings and assess any potential mortality benefit from this treatment. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03422159; URL: www.clinicaltrials.gov.

Prevalence of impostor phenomenon and assessment of well-being in pharmacy residents.

PURPOSE: The purpose of this study was to quantify the prevalence of impostor phenomenon (IP) and to assess well-being in pharmacy residents, as well as analyze the effects of demographics on these outcomes. METHODS: A cross-sectional, survey-based study was performed. Pharmacy residency program directors and pharmacy directors were asked to forward an invitation email to actively enrolled postgraduate year 1 (PGY1) and postgraduate year 2 pharmacy residents in March 2019. The survey used the Clance Impostor Phenomenon Scale (CIPS) to identify IP and the Mayo Clinic Resident/Fellow Well-Being Index (RWBI) to assess resident well-being. RESULTS: Survey respondents were mostly female, enrolled in PGY1 programs and single with no children. Of the 720 responses included in the study, 57.5% (n = 414) were identified as "impostors" (CIPS score of ≥62), with a mean CIPS score of 64.0 (SD, 15.0). Prior mental health treatment and increased hours worked per week were significant predictors of IP. The greatest correlation was found in those working greater than 80 hours per week compared to less than 60 hours per week (ß = 9.845; P < 0.001). The mean RWBI score was 4.2 (SD, 1.8), with 47.8% (n = 344) of residents scoring ≥5, the cutoff for identifying those at greatest risk of distress. Age, previous mental health treatment, and increasing hours worked per week were significant predictors of RWBI ≥5. CIPS and RWBI scores were found to exhibit weak but significant correlation (ρ = 0.357; P < 0.001). CONCLUSION: Pharmacy residents displayed significantly higher prevalence of IP vs comparable groups as well as significantly more distress with potential for a personal and/or professional consequence.

Clinical utility of midodrine and methylene blue as catecholamine-sparing agents in intensive care unit patients with shock.

Shock is common in the intensive care unit, affecting up to one third of patients. Treatment of shock is centered upon managing hypotension and ensuring adequate perfusion via administration of fluids and catecholamine vasopressors. Due to the risks associated with catecholamine vasopressors, interest has grown in using catecholamine-sparing agents such as midodrine and methylene blue. Midodrine is an orally administered alpha-1 adrenergic agonist while methylene blue is an intravenously administered blue dye used to restore vascular tone and increase blood pressure. Separate MEDLINE, Scopus, and Embase database searches were conducted to assess literature revolving around these agents. Examples of search terms included "midodrine", "methylene blue", "critically ill", "shock", and "catecholamine-sparing." Several studies have evaluated their use in patients with shock and found potential benefits in terms of causing significant elevations in blood pressure and hastening catecholamine vasopressor discontinuation with few adverse effects; however, robust evidence is lacking for these off-label indications. Because of the variety of dosing strategies used and the incongruences between patient populations, it is also challenging to define finite recommendations. This review aims to summarize current evidence for the use of midodrine and methylene blue as catecholamine-sparing agents in critically ill patients with resolving or refractory shock.

Importance of Pharmacy Involvement in the Treatment of Sepsis.

Purpose: A review of the impact of pharmacists on appropriate medication selection, timing of administration, and as members of a multidisciplinary sepsis response team. Summary: Early goal-directed therapy (EGDT), currently recommended by the 2013 Surviving Sepsis Campaign guidelines for the management of patients with sepsis, includes the administration of appropriate antibiotics in patients with septic shock within the first hour. Multidisciplinary teams containing pharmacists have been shown to decrease time to antibiotic delivery, time to antibiotic administration, and patient mortality. The pharmacist can act as a drug information resource, expedite the medication verification and procurement process, and offer suggestions on how to better manage the patients. Pharmacists are often consulted for dosing and antibiotic selection recommendations for patients with sepsis, but they can also help increase the appropriateness of antibiotics selected. Additional recommendations and interventions made by pharmacists include fluid management and vasopressor facilitation for the more severe patients. A sepsis management team that included a pharmacist increased the number of patients receiving appropriate antibiotics within the first hour by as much as 22-fold. Another study has demonstrated that intensive care units with a pharmacist are associated with a 4% decrease in sepsis patient mortality compared to those without a pharmacist. Conclusion: Multidisciplinary teams containing pharmacists have been shown to decrease time to administration of antibiotics, increase appropriate selection of medications, and decrease mortality; they may also decrease overall health care costs.