Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R, et al. N Engl J Med. 2020 Nov 5;383(19):1827-1837.
Given the impact of COVID-19 on a global level with our healthcare systems to effectively treat this devastating multi-systemic viral infection and help improve outcomes there have been numerous pathways taken. Many of our treatment algorithms have been on a trial basis as we learned more about the virus and its effects and what potential options are available. Remdesivir, an RNA polymerase inhibitor has shown to have potent antiviral activity and efficacy in animal models for Covid-19. A randomized, multicenter, open-label, phase -3 trial was performed to evaluate the efficacy of remdesivir for either 5 or 10 days in patients who were confirmed to have SARS-Cov-2 infection. The criteria for enrollment was testing positive, having an oxygen saturation of 94% or less while on room air or on oxygen via noninvasive administration and having radiologic evidence of pneumonia. Each patient was administered a 200mg IV dose on the first day and subsequently a 100mg IV daily dose for a total of 5 days or 10 days. Patients were enrolled from March 6 2020 to March 26 2020. The primary outcome was clinical status on day 14 which was assessed on a 7 point ordinal scale ( 1- death; 2- hospitalized, receiving invasive mechanical ventilation or ECMO; 3- hospitalized, receiving noninvasive ventilation or high-flow oxygen devices; 4- hospitalized, requiring low-flow supplemental oxygen; 5- hospitalized, not requiring supplemental oxygen but receiving ongoing medical care (related or not related to Covid-19); 6- hospitalized, requiring neither supplemental oxygen nor ongoing medical care (other than that specified in the protocol for remdesivir administration); and 7- not hospitalized).
Secondary outcomes were evaluating the adverse events that patients incurred while receiving remdesivir (eg. nausea, elevation of ALT, respiratory failure, constipation). 200 patients were enrolled in the 5-day group and 197 were enrolled in the 10-day group. Demographic characteristics were balanced in both arms however the baseline disease characteristics were not. Patients in the 10-day group had a worse clinical status from a respiratory standpoint than those in the 5-day group. In terms of efficacy, 86% of both groups completed the course of treatment. In the 5-day group, 8% were discharged prior to course completion and 4% had adverse events. In the 10-day group 35% were discharged prior to completion, 11% had adverse events and 6% died. 65% of patients demonstrated a clinical improvement of at least 2 points on the 7-point scale after a 5-day course as compared to 54% in the 10-day group at 14 days. The median time to recovery was 10 days in the 5-day group and 11 days in the 10-day group. The safety of remdesivir were similar in both groups; 70% of patients had adverse events in the 5-day group compared to 74% in the 10-day group. The most common were nausea, acute respiratory failure, increased ALT and constipation. The most serious was respiratory failure. Increase in laboratory values (ALT, creatinine clearance) were found to be transient and was thought to be increased by the effects of the virus on the liver and kidney. As with efficacy the safety outcomes were associated with the disease severity at baseline. Overall, after adjustments for disease severity the outcomes as measured by the number of end points: clinical status at day 14, time to clinical improvement, recovery and death from any cause were similar in both groups. This however was not observed in patients who were on mechanical ventilation. Although it appears that, the 5-day group trended toward better outcomes it was noted that at 5 days for both groups there was a generalized trend to better outcomes, which suggests that the differences were not due to treatment duration but the imbalance in baseline disease characteristics between them. This trial suggests that if remdesivir is truly an active agent for Covid-19 treatment supplies that are likely to be limited can be conserved with shorter durations of therapy with similar outcomes, especially given the current spikes in this global viral pandemic.
Early Detection of Patients at Risk of Developing a Post-Traumatic Stress Disorder After an ICU Stay. Wawer E, Viprey M, Floccard B, Saoud M, Subtil F, Wafa H, Rheims E, Rimmele T, Poulet E. Crit Care Med. 2020 Nov;48(11):1572-1579.
Post-Traumatic Stress Disorder (PTSD) is a disorder that has been found to be prevalent among our trauma patients that has a profound impact on their quality of life. It appears that it may be under-diagnosed in our patient population and steps to early identification may improve prognostic outcomes. This study aimed to evaluate the diagnostic accuracy of the Impact Event Scale-Revisited (IES-R) after ICU discharge to predict PTSD at 3 months. It was performed at a single center, in patients who were admitted to the ICU for 2 or more days over the age of 18 from September 2017 to April 2018. Patients enrolled in the study completed the IES-R and the Peritraumatic Dissociative Experiences Questionnaire (PDEQ) within 8 days after their ICU discharge and the IES-R 3 months later via phone. The IES-R was utilized as it is a more recent validated tool for screening for post-traumatic stress symptoms or to follow patients with PTSD, it requires 5 to 10 minutes to administer, and is a commonly used scale. The psychometric characteristics have a sensitivity of 100% and specificity of 85% as compared to the gold standard scale- Clinician-Administered PTSD Scale (CAPS) for ICU patients. Primary outcomes were to evaluate the diagnostic accuracy of this screening tool to detect PTSD symptoms at 3 months and the secondary outcomes were to explore possible identifiable risk factors for PTSD.
As this was measured in the first month after a trauma, an IES-R greater than or equal to 12 within 8 days after ICU discharge defined the presence of acute stress symptoms. A PDEQ greater than or equal to 15 defined the presence of peritraumatic dissociation experiences, a symptom that is a risk factor for PTSD and can be present in acute stress disorder but which is not evaluated by the IES-R. At 3 months an IES-R greater than or equal to 35 was used to define patients with PTSD symptoms and an IES-R between 12 and 34 was used define partial PTSD. 174 patients were screened within 8 days of ICU discharge and 145 were assessed at 3 months. The median age was between 61 and 62, the majority were male, 25% had an education level greater than high school and 2/3 had a psychiatric history. Of the 145 patients screened at 3 months, 13% had an IES-R greater than or equal to 35, and 17% had a score between 12 and 34. From initial screening within 8 days of ICU discharge and at 3 months, IES-R score increased for 32.4%, decreased for 55.2% and did not change for 12.4%. Factors identified with an associated risk of PTSD at 3 months were having a previous psychiatric history (anxiety disorder, depression, previous PTSD, addiction), an ongoing psychotropic treatment, a PDEQ greater than or equal to 15 and an IES-R greater than or equal to 12 (acute stress symptoms). Further analysis demonstrated that a previous history of anxiety disorder and IES-R greater than or equal to 12 within 8 days of ICU discharge were significantly associated with PTSD symptoms at 3 months. Based on this study use of the IES-R early after ICU discharge has a good ability to predict PTSD symptoms at 3 months and a score less than 12 within 8 days excludes risk of developing PTSD symptoms. Patients with acute stress disorder at discharge were more at risk of PTSD symptoms. Approximately 1/3 of patients at 3 month follow up were found to have PTSD symptoms after ICU discharge which may serve to highlight the potential psychological impact of an ICU stay on patients. Of note at 3 month follow up patients, demonstrating PTSD symptoms stated that they approached a psychiatrist since ICU discharge and were prescribed an antidepressant. Furthermore, this study demonstrated that many patients who had symptoms of PTSD did not know that it could be treated. It appears that this easy to administer tool can be utilized to screen and identify high risk patients for a disorder that has a profound impact on their quality of life and can aid in providing a diagnosis and modes of treatment to help improve patient outcome.