The clinical practice of palliative sedation in patients dying from COVID-19: a retrospective chart review.

BACKGROUND: Clinical experts experienced challenges in the practice of palliative sedation (PS) during the COVID-19 pandemic. Rapid deterioration in patients' situation was observed while the indications for starting PS seemed to differ compared to other terminal patients. It is unclear to which extent clinical trajectories of PS differ for these COVID patients compared to regular clinical practice of PS. OBJECTIVES: To describe the clinical practice of PS in patients with COVID versus non-COVID patients. METHODS: A retrospective analysis of data from a Dutch tertiary medical centre was performed. Charts of adult patients who died with PS during hospitalisation between March '20 and January '21 were included. RESULTS: During the study period, 73 patients received PS and of those 25 (34%) had a COVID infection. Refractory dyspnoea was reported as primary indication for starting PS in 84% of patients with COVID compared to 33% in the other group (p < 0.001). Median duration of PS was significantly shorter in the COVID group (5.8 vs. 17.1 h, p < 0.01). No differences were found for starting dosages, but median hourly dose of midazolam was higher in the COVID group (4.2 mg/hr vs. 2.4 mg/hr, p < 0.001). Time interval between start PS and first medication adjustments seemed to be shorter in COVID patients (1.5 vs. 2.9 h, p = 0.08). CONCLUSION: PS in COVID patients is characterized by rapid clinical deterioration in all phases of the trajectory. What is manifested by earlier dose adjustments and higher hourly doses of midazolam. Timely evaluation of efficacy is recommended in those patients.

Safety, Tolerability, and Pharmacokinetics of the Novel Antiviral Agent Ensitrelvir Fumaric Acid, a SARS-CoV-2 3CL Protease Inhibitor, in Healthy Adults.

Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1, n = 50) and multiple (part 2, n = 33) ascending oral doses. Effect of food on the pharmacokinetics of ensitrelvir, differences in pharmacokinetics of ensitrelvir between Japanese and white participants, and effect of ensitrelvir on the pharmacokinetics of midazolam (a cytochrome P450 3A [CYP3A] substrate) were also assessed. In part 1, Japanese participants were randomized to placebo or ensitrelvir at doses of 20, 70, 250, 500, 1,000, or 2,000 mg. In part 2, Japanese and white participants were randomized to placebo or once-daily ensitrelvir at loading/maintenance dose 375/125 mg or 750/250 mg for 5 days. Most treatment-related adverse events observed were mild in severity and were resolved without treatment. Plasma exposures showed almost dose proportionality, and geometric mean half-life of ensitrelvir following the single dose was 42.2 to 48.1 h. Food intake reduced Cmax and delayed Tmax of ensitrelvir but did not impact the area under the curve (AUC), suggesting suitability for administration without food restriction. Compared with Japanese participants, plasma exposures were slightly lower for white participants. Ensitrelvir affected the pharmacokinetics of CYP3A substrates because of increase in AUC of midazolam coadministered with ensitrelvir 750/250 mg on day 6. In conclusion, ensitrelvir was well-tolerated and demonstrated favorable pharmacokinetics, including a long half-life, supporting once-daily oral dosing. These results validate further assessments of ensitrelvir in participants with SARS-CoV-2 infection.

Severe cortical damage associated with COVID-19 case report.

Symptoms of COVID-19, as reported during the SARS-CoV-2 pandemic in 2019-2020, are primarily respiratory and gastrointestinal, with sparse reports on neurological manifestations. We describe the case of a 17-year old female with Cornelia de Lange syndrome and well controlled epilepsy, who sustained significant cortical injury during a COVID-19 associated multi-inflammatory syndrome.

[A comparative study on clinical effects of dexmedetomidine and midazolam on patients with severe coronavirus disease 2019 on non-invasive ventilation].

OBJECTIVE: To compare the therapeutic effects and safety of dexmedetomidine and midazolam on patients with severe coronavirus disease 2019 (COVID-19) who received non-invasive ventilation. METHODS: Patients with COVID-19 who needed non-invasive ventilation in one critical care medicine ward of Wuhan Jinyintan Hospital during the team support period from the department of critical care medicine of Renmin Hospital of Wuhan University from January 23rd to February 15th in 2020 were investigated retrospectively. Ramsay score, mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), arterial oxygen partial pressure (PaO2) before sedation and at 1, 12, 24 hours after sedation, sleep time were collected, and the side effects such as excessive sedation, fall of tongue, abdominal distension, aspiration, bradycardia, escalation to invasive mechanical ventilation during 24 hours were also collected. According to different sedative drugs, patients were divided into the control group (without sedative drugs), dexmedetomidine group and midazolam group. The changes of indicators among the three groups were compared. RESULTS: Fourteen patients were injected with dexmedetomidine (loading dose of 1 µg/kg for 10 minutes, maintained at 0.2-0.7 µg×kg-1×h-1); 9 patients were injected with midazolam (loading dose of 0.05 mg/kg for 2 minutes, maintained at 0.02-0.10 mg×kg-1×h-1); 12 patients didn't use sedative drugs due to limitations of previous hospital or patients' rejection. In dexmedetomidine group and midazolam group, the Ramsay score was maintained at 2-3 points after sedation, which were higher than those of control group at different time points after sedation, and there was no significant difference between dexmedetomidine group and midazolam group. MAP of dexmedetomidine group and midazolam group decreased gradually after sedation. MAP after 1-hour sedation was significantly lower than that before sedation, and MAP after 24 hours sedation was significantly lower than that in the control group [mmHg (1 mmHg = 0.133 kPa): 109.7±11.5, 107.1±12.3 vs. 121.1±13.3, both P < 0.05]. HR decreased gradually after sedation treatment, which was significantly lower after 12 hours of sedation than that before sedation, and HR in dexmedetomidine group was significantly lower than that in control group after 12 hours of sedation (bpm: 84.0±13.9 vs. 92.8±15.4 at 12 hours; 81.0±16.7 vs 92.6±12.7 at 24 hours, both P < 0.05). PaO2 increased and RR decreased in all three groups after ventilation. PaO2 in dexmedetomidine group and midazolam group were significantly higher than that in the control group after 12 hours of sedation [cmH2O (1 cmH2O = 0.098 kPa): 79.0±6.5, 79.0±8.9 vs. 70.0±7.8, both P < 0.05]; the decreases of RR in dexmedetomidine group and midazolam group were significant than that in control group after 1 hour of sedation (bpm: 34.0±3.9, 33.8±4.6 vs. 39.0±3.6, both P < 0.05). There were no differences of MAP, HR, PaO2 and RR between dexmedetomidine group and midazolam group at different time points. The sleep duration in dexmedetomidine group and midazolam group were significantly longer than that in the control group (hours: 4.9±1.9, 5.8±2.4 vs. 3.0±1.8, both P < 0.05), but there was no difference between dexmedetomidine group and midazolam group (P > 0.05). Adverse events occurred in all three groups. In midazolam group, there were 2 cases of excessive sedation with fall of tongue and abdominal distension, including 1 case of aspiration, 1 case receiving intubation due to refractory hypoxemia and 1 case due to unconsciousness. In dexmedetomidine group, there were 2 cases of bradycardia, 1 case of intubation due to refractory hypoxemia. In control group, 4 cases underwent intubation due to refractory hypoxemia. CONCLUSIONS: Non-invasive mechanical ventilation is an important respiratory support technology for patients with severe COVID-19. Appropriate sedation can increase the efficiency of non-invasive mechanical ventilation. Dexmedetomidine is more effective and safer than midazolam in these patients, but attention should be paid to HR and blood pressure monitoring.

End-of-life care in COVID-19: An audit of pharmacological management in hospital inpatients.

BACKGROUND: Hospital clinicians have had to rapidly develop expertise in managing the clinical manifestations of COVID-19 including symptoms common at the end of life, such as breathlessness and agitation. There is limited evidence exploring whether end-of-life symptom control in this group requires new or adapted guidance. AIM: To review whether prescribing for symptom control in patients dying with COVID-19 adhered to existing local guidance or whether there was deviation which may represent a need for revised guidance or specialist support in particular patient groups. DESIGN/SETTING: A retrospective review of the electronic patient record of 61 hospital inpatients referred to the specialist palliative care team with swab-confirmed COVID-19 who subsequently died over a 1-month period. Intubated patients were excluded. RESULTS: In all, 83% (40/48) of patients were prescribed opioids at a starting dose consistent with existing local guidelines. In seven of eight patients where higher doses were prescribed, this was on specialist palliative care team advice. Mean total opioid dose required in the last 24 h of life was 14 mg morphine subcutaneous equivalent, and mean total midazolam dose was 9.5 mg. For three patients in whom non-invasive ventilation was in place higher doses were used. CONCLUSION: Prescription of end-of-life symptom control drugs for COVID-19 fell within the existing guidance when supported by specialist palliative care advice. While some patients may require increased doses, routine prescription of higher starting opioid and benzodiazepine doses beyond existing local guidance was not observed.