Investigating a Novel Two-Bag N-Acetylcysteine Regimen for Acetaminophen Toxicity.

BACKGROUND: Acetaminophen toxicity remains one of the most common causes of liver failure and is treated with a course of n-acetylcysteine (NAC). This exceptionally effective medication is traditionally administered using a complicated three-bag protocol that is prone to administration errors. OBJECTIVE: We aimed to assess whether switching to a novel two-bag protocol (150 mg/kg over 1 h followed by 150 mg/kg over 20 h) reduced administration errors while not increasing liver injury or anaphylactoid reactions. METHODS: This was a retrospective chart review of hospital encounters for patients with acetaminophen toxicity, comparing outcomes before and after the change from a three-bag protocol to a two-bag protocol at two affiliated institutions. The primary outcome was incidence of medication errors with secondary outcomes including acute liver injury (ALI) and incidence of non-anaphylactoid allergic reactions (NAAR). The study was approved by the health system's Institutional Review Board. RESULTS: 483 encounters were included for analysis (239 in the three-bag and 244 in the two-bag groups). NAAR were identified in 11 patients with no difference seen between groups. Similarly, no differences were seen in ALI. Medication administration errors were observed significantly less often in the two-bag group (OR 0.24) after adjusting for confounders. CONCLUSION: Transitioning to a novel two-bag NAC regimen decreased administration errors. This adds to the literature that two-bag NAC regimens are not only safe but also may have significant benefits over the traditional NAC protocol.

Evaluation of fixed versus variable dosing of 4-factor prothrombin complex concentrate for emergent warfarin reversal.

STUDY OBJECTIVE: This study compares the safety and efficacy of a fixed dose of 4-factor prothrombin complex concentrate (4FPCC) to the FDA-approved variable dosing for reversal of warfarin-induced anticoagulation. METHODS: This was a single-center, prospective, open-label, randomized controlled trial with subjects randomized to 4FPCC at a fixed dose of 1500 IU or the FDA-approved variable dosing regimen. The primary efficacy outcome (reversal success) was defined as a post-intervention international normalized ratio (INR) of less than or equal to 1.5. Given that 4FPCC is the standard of care for reversal of warfarin-induced anticoagulation an active-controlled approach was employed with the two dosing regimens compared based on efficacy, cost, and safety outcomes. RESULTS: 71 subjects (34 in the fixed dose group and 37 in the variable dose group) completed the study. There were no significant differences in age, gender, weight, initial INR, or indication for 4FPCC administration between the two treatment groups. Reversal success in the fixed-dose group was 61.8%, while in the variable dose group reversal success was 89.2%. Reversal success in the fixed-dose group was significantly lower than the rate of reversal success in the variable dose group (27.4% lower, p = 0.011). CONCLUSION: The results of this study provide evidence that fixed dosing results in lower reversal success rates as compared to variable dosing of 4FPCC for warfarin-induced anticoagulation.

Auxora versus standard of care for the treatment of severe or critical COVID-19 pneumonia: results from a randomized controlled trial.

BACKGROUND: Calcium release-activated calcium (CRAC) channel inhibitors stabilize the pulmonary endothelium and block proinflammatory cytokine release, potentially mitigating respiratory complications observed in patients with COVID-19. This study aimed to investigate the safety and efficacy of Auxora, a novel, intravenously administered CRAC channel inhibitor, in adults with severe or critical COVID-19 pneumonia. METHODS: A randomized, controlled, open-label study of Auxora was conducted in adults with severe or critical COVID-19 pneumonia. Patients were randomized 2:1 to receive three doses of once-daily Auxora versus standard of care (SOC) alone. The primary objective was to assess the safety and tolerability of Auxora. Following FDA guidance, study enrollment was halted early to allow for transition to a randomized, blinded, placebo-controlled study. RESULTS: In total, 17 patients with severe and three with critical COVID-19 pneumonia were randomized to Auxora and nine with severe and one with critical COVID-19 pneumonia to SOC. Similar proportions of patients receiving Auxora and SOC experienced ≥ 1 adverse event (75% versus 80%, respectively). Fewer patients receiving Auxora experienced serious adverse events versus SOC (30% versus 50%, respectively). Two patients (10%) receiving Auxora and two (20%) receiving SOC died during the 30 days after randomization. Among patients with severe COVID-19 pneumonia, the median time to recovery with Auxora was 5 days versus 12 days with SOC; the recovery rate ratio was 1.87 (95% CI, 0.72, 4.89). Invasive mechanical ventilation was needed in 18% of patients with severe COVID-19 pneumonia receiving Auxora versus 50% receiving SOC (absolute risk reduction = 32%; 95% CI, - 0.07, 0.71). Outcomes measured by an 8-point ordinal scale were significantly improved for patients receiving Auxora, especially for patients with a baseline PaO2/FiO2 = 101-200. CONCLUSIONS: Auxora demonstrated a favorable safety profile in patients with severe or critical COVID-19 pneumonia and improved outcomes in patients with severe COVID-19 pneumonia. These results, however, are limited by the open-label study design and small patient population resulting from the early cessation of enrollment in response to regulatory guidance. The impact of Auxora on respiratory complications in patients with severe COVID-19 pneumonia will be further assessed in a planned randomized, blinded, placebo-controlled study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04345614 . Submitted on 7 April 2020.

Clozapine usage increases the incidence of pneumonia compared with risperidone and the general population: a retrospective comparison of clozapine, risperidone, and the general population in a single hospital over 25 months.

The aim of this study was to determine whether the incidence of pneumonia in patients taking clozapine was more frequent compared with those taking risperidone or no atypical antipsychotics at all before admission to a tertiary care medical center. This was a retrospective, case-matched study of 465 general medicine patients over a 25 month period from 1 July 2010 to 31 July 2012. Detailed electronic medical records were analyzed to explore the association between the use of two atypical antipsychotics and incidence of pneumonia. Of the 155 patients in the clozapine group, 54 (34.8%) had documented pneumonia compared with 22 (14.2%) in the risperidone group and 18 (11.6%) in the general population group. Clozapine, when compared with the untreated general population, was associated with an increased risk of pneumonia (odds ratio=4.07; 95% confidence interval=2.25-7.36). There was, however, no significant increase in the risk of pneumonia associated with the use of risperidone (odds ratio=1.26; 95% confidence interval=0.65-2.45). Clozapine use is associated with increased risk of pneumonia that may be related to immunologic factors or side effects of sedation and drooling that make aspiration more likely, although causative mechanisms require further investigation. These findings suggest that providers should use added caution in choosing candidates for clozapine therapy.