Oral Favipiravir Exposure and Pharmacodynamic Effects in Outpatient Adults with Acute Influenza.

BACKGROUND: The pharmacokinetics of oral favipiravir and the relationships of plasma concentrations to antiviral effects are incompletely studied in influenza. METHODS: Serial plasma samples were collected from adults with uncomplicated influenza who were randomized to favipiravir (1800 mg BID on day 1, 800 mg BID on days 2 to 5)(N = 827) or placebo (N = 419) in two phase 3 trials. Post hoc analyses assessed the frequency of reaching an average Cmin ≥20ug/ml, its association with antiviral efficacy, and factors associated with reduced favipiravir exposure. RESULTS: Wide inter-individual variability existed in favipiravir concentrations, and this regimen failed to reach an average Cmin >20ug/ml in 41-43% of participants. Those attaining this threshold showed greater reductions in nasopharyngeal infectious virus titers on treatment days 2 and 3 (approximately 0.3-0.4 log10TCID50/ml) and lower viral titer AUCs compared to those who did not. Those with average Cmin <20ug/ml had over 2-fold higher mean ratios of the metabolite T-705-M1 to favipiravir, consistent with greater metabolism, and were more likely to weigh >80 kg (61.5-64%). CONCLUSIONS: Higher favipiravir levels with average Cmin >20ug/ml were associated with larger antiviral effects and more rapid illness alleviation compared to placebo and to favipiravir recipients with lower average Cmin values in uncomplicated influenza.

A case report of a brain herniation secondary to cryptococcal meningitis with elevated intracranial pressure in a patient with Human Immunodeficiency Virus/Acquired immunodeficiency syndrome (HIV/AIDS).

Background: Cryptococcal meningitis is a major opportunistic infection in individuals with HIV. The worldwide annual incidence is estimated to be approximately one million cases per year, with the most significant burden in sub-Saharan Africa. HIV-associated cryptococcal meningitis continues to have a high mortality rate despite widespread availability and use of HAART. Case: 36-year-old male with a past medical history of AIDS and a CD4 count of 35 cells/mm3 presented with altered mental status initially thought to be related to using crystalline methamphetamine as reported by EMS. However, a lumbar puncture performed in the emergency department showed elevated CSF opening pressure of 29 cmH2O and positive CSF and serum cryptococcal antigen. The patient was admitted and commenced treatment according to the current IDSA guideline but continued to have waxing and waning mental status. On the fourth day of admission, he complained of headache, had a witnessed seizure, and was taken emergently for a CT scan of the brain, which was negative for any acute intracranial process, but suffered a cardiac arrest before it could be done. He was intubated and transferred to the intensive care unit. CT brain follow-up showed anoxic encephalopathy, development of marked cerebral edema, and complete effacement of the basilar cisterns, suggestive of downward transtentorial herniation; he continued to deteriorate and expired on the seventh day of admission. Objectives: 1.Describe a case of brain death secondary to increased intracranial pressure due to cryptococcal meningitis in a patient with HIV/AIDS.2.Explain the mechanisms of elevation in intracranial pressure in patients with cryptococcal meningitis.3.Discuss the options for managing elevated intracranial pressure in patients with cryptococcal meningitis.4.Create awareness in the medical community about the importance of prompt and efficient management of increased intracranial pressure in patients with cryptococcal meningitis. Conclusion: This case highlights the importance of aggressive management of elevated intracranial pressure in cryptococcal meningitis. It reiterates the need for more data regarding the optimal timing and frequency of therapeutic lumbar puncture and the use of temporary lumbar drainage catheters and ventriculostomy to manage this potentially fatal complication.

Favipiravir Treatment of Uncomplicated Influenza in Adults: Results of Two Phase 3, Randomized, Double-Blind, Placebo-Controlled Trials.

BACKGROUND: We conducted double-blind, placebo-controlled trials assessing the efficacy and tolerability of favipiravir in acute influenza. METHODS: Otherwise healthy adults with influenza-like symptoms and fever of ≤48 hours were randomized to favipiravir (1800 mg twice daily [BID] on day 1, 800 mg BID on days 2-5) or placebo tablets (1:1 in US316; 3:1 in US317). The primary efficacy endpoint was the time to illness alleviation when 6 influenza symptoms were self-rated as absent or mild and fever was absent in the intention-to-treat, influenza-infected participants. RESULTS: In US316 (301 favipiravir, 322 placebo), favipiravir was associated with a 14.4-hour reduction (median, 84.2 vs 98.6 hours; P = .004) in time to illness alleviation vs placebo. In US317 (526 favipiravir, 169 placebo), favipiravir did not significantly reduce time to alleviation (median, 77.8 vs 83.9 hours). In both trials favipiravir was associated with reduced viral titers, RNA load area under the curve over days 1-5, and median times to cessation of virus detection (P < .001). Aside from asymptomatic hyperuricemia, no important differences in adverse events were found. CONCLUSIONS: This favipiravir dosing regimen demonstrated significant antiviral efficacy but inconsistent illness alleviation in uncomplicated influenza. Studies of higher doses and antiviral combinations for treating serious influenza and other RNA viral infections are warranted. Clinical Trials Registration. NCT02026349; NCT02008344.

Favipiravir for Treatment of Outpatients With Asymptomatic or Uncomplicated Coronavirus Disease 2019: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND: Favipiravir, an oral, RNA-dependent RNA polymerase inhibitor, has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite limited data, favipiravir is administered to patients with coronavirus disease 2019 (COVID-19) in several countries. METHODS: We conducted a phase 2, double-blind, randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV-2 reverse-transcription polymerase chain reaction assay (RT-PCR) within 72 hours of enrollment. Participants were randomized to receive placebo or favipiravir (1800 mg twice daily [BID] day 1, 800 mg BID days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis. RESULTS: We randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (standard deviation, 12.5 years) and 57 (49%) were women. We found no difference in time to shedding cessation overall (hazard ratio [HR], 0.76 favoring placebo [95% confidence interval {CI}, .48-1.20]) or in subgroups (age, sex, high-risk comorbidities, seropositivity, or symptom duration at enrollment). We detected no difference in time to symptom resolution (initial: HR, 0.84 [95% CI, .54-1.29]; sustained: HR, 0.87 [95% CI, .52-1.45]) and no difference in transition mutation accumulation in the viral genome during treatment. CONCLUSIONS: Our data do not support favipiravir at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher favipiravir doses are effective and safe for patients with COVID-19. CLINICAL TRIALS REGISTRATION: NCT04346628.

US201 Study: A Phase 2, Randomized Proof-of-Concept Trial of Favipiravir for the Treatment of COVID-19.

BACKGROUND: Favipiravir is used to treat influenza, and studies demonstrate that it has antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We performed a randomized, open-label, multicenter, phase 2 proof-of-concept trial of favipiravir in hospitalized adult patients with polymerase chain reaction (PCR)-positive coronavirus disease 2019 (COVID-19). Patients were randomized to standard of care (SOC) or favipiravir treatment (1800mg per os twice a day [b.i.d.] on day 1, followed by 1000mg b.i.d. for 13 days). The primary end point was time to viral clearance on day 29. RESULTS: Fifty patients were enrolled and stratified by disease severity (critical disease, severe disease, or mild to moderate disease). Nineteen patients were censored from the event of viral clearance based on being SARS-CoV-2 PCR-negative at the study outset, being PCR-positive at day 29, or because of loss to follow-up. Data from the 31 remaining patients who achieved viral clearance show enhanced viral clearance in the favipiravir group compared with the SOC group by day 29, with 72% of the favipiravir group and 52% of the SOC group being evaluable for viral clearance through day 29. The median time to viral clearance was 16.0 days (90% CI, 12.0 to 29.0) in the favipiravir group and 30.0 days (90% CI, 12.0 to 31.0) in the SOC group. A post hoc analysis revealed an effect in the subgroup of patients who were neutralizing antibody-negative at randomization. Treatment-emergent adverse events were equally distributed between the groups. CONCLUSIONS: We demonstrate that favipiravir can be safely administered to hospitalized adults with COVID-19 and believe that further studies are warranted. CLINICALTRIALSGOV REGISTRATION: NCT04358549.

Instrument Development: Knowledge, Attitudes, and Confidence in Palliative Care Concepts Held by Trauma and Neuroscience Intensive Care Nurses.

BACKGROUND AND PURPOSE: Unique pressures impact trauma intensive care unit (TICU) nurses in their provision of care for severely injured patients. When it becomes clinically obvious that these patients may not survive, TICU nurses must continue life-saving measures while at the same time consider a palliative care consultation. In order to facilitate this referral, TICU nurses need to have the appropriate knowledge, attitude, and confidence in doing so. The purpose of this study is to refine an instrument that aims to support this process. METHODS: A convenience sample of 42 respondents completed the Knowledge, Attitudinal, and Experiential Survey on Advance Directive (KAESAD). RESULTS: Domains with the highest Cronbach's alpha value were "professional attitudes" (α = .995) and "clinical experiences" (α = .999). CONCLUSIONS: Reliability assessments suggest that most domains of the instrument have strong internal consistency, and with a larger sample size, future studies may elucidate how nurse educators can use this instrument to target areas for continuing education.

A Collaborative Academic-Practice Approach to Meeting Educational and Workforce Needs.

This article describes an innovative academic-practice partnership designed to promote new nurse competency and meet employer needs for graduates with in-demand knowledge and competencies in specialty patient populations. Three practice partners identified areas of need and with the school of nursing developed specialty nursing elective courses with precepted clinical experiences.

Intracellular conversion and in vivo dose response of favipiravir (T-705) in rodents infected with Ebola virus.

During the 2013-2016 Ebola virus (EBOV) outbreak in West Africa, our team at USAMRIID evaluated the antiviral activity of a number of compounds, including favipiravir (T-705), in vitro and in mouse and nonhuman primate (NHP) models of Ebola virus disease. In this short communication, we present our findings for favipiravir in cell culture and in mice, while an accompanying paper presents the results of NHP studies. We confirmed previous reports that favipiravir has anti-EBOV activity in mice. Additionally, we found that the active form of favipiravir is generated in mice in tissues relevant for the pathogenesis of EBOV infection. Finally, we observed that protection can be achieved in mice down to 8 mg/kg/day, which is lower than the dosing regimens previously reported. An accompanying paper reports the results of treating nonhuman primates infected with EBOV or with Marburg virus with oral or intravenous favipiravir.

Efficacy of favipiravir (T-705) in nonhuman primates infected with Ebola virus or Marburg virus.

Favipiravir is a broad-spectrum antiviral agent that has demonstrated efficacy against Ebola virus (EBOV) in rodents. However, there are no published reports of favipiravir efficacy for filovirus infection of nonhuman primates (NHPs). Here we evaluated the pharmacokinetic profile of favipiravir in NHPs, as well as in vivo efficacy against two filoviruses, EBOV and Marburg virus (MARV). While no survival benefit was observed in two studies employing once- or twice-daily oral dosing of favipiravir during EBOV infection of NHPs, an antiviral effect was observed in terms of extended time-to-death and reduced levels of viral RNA. However, oral dosing in biosafety level-4 (BSL-4) presents logistical and technical challenges, and repeated anesthesia events may potentially worsen survival outcome in animals. For the third study of treatment of MARV infection, we therefore made use of catheters, jackets, and tethers for intravenous (IV) dosing and blood collection, which minimized the requirement for repeated anesthesia events. When MARV infection was treated with IV favipiravir, five of six animals (83%) survived infection, while all untreated NHPs succumbed. An accompanying report presents the results of favipiravir treatment of EBOV infection in mice.

Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen.

AIMS: The antiviral agent favipiravir is likely to be co-prescribed with acetaminophen (paracetamol). The present study evaluated the possiblility of a pharmacokinetic interaction between favipiravir and acetaminophen, in vitro and in vivo. METHODS: The effect of favipivir on the transformation of acetaminophen to its glucuronide and sulfate metabolites was studied using a pooled human hepatic S9 fraction in vitro. The effect of acute and extended adminstration of favipiravir on the pharmacokinetics of acetaminophen and metabolites was evaluated in human volunteers. RESULTS: Favipiravir inhibited the in vitro formation of acetaminophen sulfate, but not acetaminophen glucuronide. In human volunteers, both acute (1 day) and extended (6 days) administration of favipiravir slightly but significantly increased (by about 20 %) systemic exposure to acetaminophen (total AUC), whereas Cmax was not significantly changed. AUC for acetaminophen glucuronide was increased by 23 to 35 % above control by favipiravir, while AUC for acetaminophen sulfate was reduced by about 20 % compared to control. Urinary excretion of acetaminophen sulfate was likewise reduced to 44 to 65 % of control values during favipiravir co-administration, while excretion of acetaminophen glucuronide increased to 17 to 32 % above control. CONCLUSION: Favipiravir inhibits acetaminophen sulfate formation in vitro and in vivo. However the increase in systemic exposure to acetaminophen due to favipiravir co-administration, though statistically significant, is small in magnitude and unlikely to be of clinical importance.

Bedside assessment of tissue oxygen saturation monitoring in critically ill adults: an integrative review of the literature.

Objective. Tissue oxygen saturation (StO2) monitoring is a noninvasive technology with the purpose of alerting the clinician of peripheral hypoperfusion and the onset of tissue hypoxia. This integrative review examines the rigor and quality of studies focusing on StO2 monitoring in adult critically ill patients. Background. Clinicians must rapidly assess adverse changes in tissue perfusion while minimizing potential complications associated with invasive monitoring. The noninvasive measurement of tissue oxygen saturation is based on near-infrared spectroscopy (NIRS), an optical method of illuminating chemical compounds which absorb, reflect, and scatter light directed at that compound. Methods. An integrative review was conducted to develop a context of greater understanding about complex topics. An Integrative review draws on multiple experimental and nonexperimental research methodologies. Results. Fourteen studies were graded at the C category. None reported the use of probability sampling or demonstrated a cause-and-effect relationship between StO2 values and patient outcomes. Conclusions. Future research should be based on rigorous methods of sampling and design in order to enhance the internal and external validity of the findings.

Does race affect readmission to hospital after critical illness?

OBJECTIVE: To examine the influence of race on 7-day hospital readmission rates after discharge of critically ill patients. METHODS: Racial status is a risk factor for early (within 7 days) hospital readmission after initial recovery from critical illness and respiratory failure. This was a retrospective cohort study that took place in a 350-bed community hospital. Adult patients who received mechanical ventilation during their intensive care unit stay were included. Study subjects were categorized as white, black (non-Hispanic), Hispanic, and Asian/other. The main outcome measure was readmission to the hospital within 7 days of discharge. Secondary outcomes were hospital mortality and durations of hospital and intensive care unit stay. Comparisons were made across racial groups. RESULTS: Of 772 patients, 172 (22.3%) died, and 96 of the 591 discharged patients (16.2%) were readmitted within 7 days. Race was not a determinant of rapid readmission: 11.6% of blacks (P = .2), 20.6% of Hispanics (P = .3) and 16.5% of whites were readmitted within 7 days. Readmitted patients were more likely to have been discharged to a rehabilitation or extended care facility rather than to home (22.1% vs 2.2%, P < .0001). Readmitted patients tended to have had prolonged duration of mechanical ventilation > or = 30 days (41% vs 15.1%, P = .004), to be aged > or = 80 years (24.4% vs 13.9%, P = .005), and to be female (19.5% vs 13.7%, P = .04). Multivariate logistic regression analyses demonstrated that discharge to a place other than home (odds ratio 10.1, 95% confidence interval 3.6-28.3) and prolonged duration of mechanical ventilation (odds ratio 2.8, 95% confidence interval 1.1-6.9) were independently associated with readmission. Race did not significantly influence in-hospital mortality. Overall, the deceased were older and more likely to be female, and had longer durations of mechanical ventilation and medical and surgical intensive care unit stays. CONCLUSION: Contrary to our hypothesis, race was not associated with rapid readmission or mortality of critically ill patients. Factors independently associated with rapid readmission were mechanical ventilation beyond 29 days and disposition to an acute rehabilitation or skilled nursing facility. Further studies are required to ascertain whether these factors are generalizable or idiosyncratic to our institution.

A capstone teaching project for undergraduate nursing students: development of a visual teaching-learning tool.

The purpose of this article is to describe an original teaching-learning capstone project designed to promote active learning by senior nursing students as they transition to professional practice. The centerpiece of the capstone experience is the creation of a three-dimensional educational tool called a Visual Project, which addresses the learning needs of patients, their families, or the nursing staff. Students create their project during the spring semester of their senior year, when they are paired with an experienced, baccalaureate-prepared nurse preceptor. Students present their projects to both the nursing unit in which they worked and the faculty and students of the nursing school. Students consistently express a sense of accomplishment when they present their projects and recognize that they themselves have undergone the same teaching-learning process that was the focus of their project.

Weaning readiness and fluid balance in older critically ill surgical patients.

BACKGROUND: Few studies address predictors for successful weaning of older adults from mechanical ventilation. OBJECTIVE: To develop a clinical profile of older patients who are successfully weaned from long-term mechanical ventilation. METHODS: Forty patients in the trauma and surgical intensive care unit who were at least 60 years old were enrolled in the study after 3 days of active weaning and were monitored daily until successfully weaned or until the end of the 14-day study. Hemodynamic and gas exchange variables, fluid balance, oxygen cost of breathing, and scores on the Burns Weaning Assessment Program were analyzed. RESULTS: Compared with patients who were not weaned, successfully weaned patients required mechanical ventilation for 5.3 days, started active weaning earlier (mean 10.7 vs 14.5 days, P = .04), had lower mean negative daily fluid balances in the beginning (-0.394 vs 1.107 L, P = .004), and had lower mean net cumulative fluid balances (6.856 vs 16.212 L) at the time of enrollment. They also maintained both a lower mean net cumulative fluid balance (10.753 vs 25.049 L, P= .02) and a negative daily fluid balance (-0.389 vs 1.904 L, P = .03) throughout. Their mean central venous pressure decreased over time and was significantly lower (P<.001). CONCLUSION: Persistent positive fluid balance in older surgical patients is associated with prolonged mechanical ventilation. Estimates of fluid balance might be useful in weaning older patients from long-term mechanical ventilation.

Lights! Camera! Action!: video projects in the classroom.

We report on two classroom video projects intended to promote active student involvement in their classroom experience during a year-long medical-surgical nursing course. We implemented two types of projects, Nursing Grand Rounds and FPBTV. The projects are templates that can be applied to any nursing specialty and can be implemented without the use of video technology. During the course of several years, both projects have proven effective in encouraging students to promote pattern recognition of characteristic features of common illnesses, to develop teamwork strategies, and to practice their presentation skills in a safe environment among their peers. The projects appealed to students because they increased retention of information and immersed students in the experience of becoming experts about an illness or a family of medications. These projects have enabled students to become engaged and invested in their own learning in the classroom.

Weaning older patients from long-term mechanical ventilation: a pilot study.

BACKGROUND: As older persons in the intensive care unit increasingly require long-term mechanical ventilation, accurate indications of readiness for weaning from ventilatory support are needed to avoid premature extubation. OBJECTIVE: To describe temporal changes in pulmonary and systemic variables in older adults receiving long-term mechanical ventilation. METHODS: After 3 days of unsuccessful attempts at weaning from ventilatory support, 10 trauma and surgical patients more than 60 years old were monitored daily. Previously reported predictors of the duration of mechanical ventilation and weaning outcome were measured, including hemodynamic and gas exchange variables, oxygen cost of breathing, and the score on the Burns Weaning Assessment Program. RESULTS: The 6 patients who could be weaned from ventilatory support were younger (median age, 71.5 years) than the 4 patients who could not be weaned (median age, 80 years). Patients who could be weaned were ready for weaning by day 11 of their stay in the intensive care unit and required an additional 5.5 days of mechanical ventilation; those who could not be weaned were not ready for weaning until day 17. All patients initially had increases in oxygen consumption during weaning; those who were successfully weaned had decreases before extubation. Respiratory rate, maximal inspiratory pressure, the ratio of Pao2 to fraction of inspired oxygen, and mean arterial pressure were higher in patients who could be weaned, and oxygen cost of breathing and central venous pressure were lower CONCLUSION: Further study of weaning in older adults is warranted.