Janus kinase inhibitors for the treatment of COVID-19.

BACKGROUND: With potential antiviral and anti-inflammatory properties, Janus kinase (JAK) inhibitors represent a potential treatment for symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. They may modulate the exuberant immune response to SARS-CoV-2 infection. Furthermore, a direct antiviral effect has been described. An understanding of the current evidence regarding the efficacy and safety of JAK inhibitors as a treatment for coronavirus disease 2019 (COVID-19) is required. OBJECTIVES: To assess the effects of systemic JAK inhibitors plus standard of care compared to standard of care alone (plus/minus placebo) on clinical outcomes in individuals (outpatient or in-hospital) with any severity of COVID-19, and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (comprising MEDLINE, Embase, ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, medRxiv, and Cochrane Central Register of Controlled Trials), Web of Science, WHO COVID-19 Global literature on coronavirus disease, and the US Department of Veterans Affairs Evidence Synthesis Program (VA ESP) Covid-19 Evidence Reviews to identify studies up to February 2022. We monitor newly published randomised controlled trials (RCTs) weekly using the Cochrane COVID-19 Study Register, and have incorporated all new trials from this source until the first week of April 2022. SELECTION CRITERIA: We included RCTs that compared systemic JAK inhibitors plus standard of care to standard of care alone (plus/minus placebo) for the treatment of individuals with COVID-19. We used the WHO definitions of illness severity for COVID-19. DATA COLLECTION AND ANALYSIS: We assessed risk of bias of primary outcomes using Cochrane's Risk of Bias 2 (RoB 2) tool. We used GRADE to rate the certainty of evidence for the following primary outcomes: all-cause mortality (up to day 28), all-cause mortality (up to day 60), improvement in clinical status: alive and without need for in-hospital medical care (up to day 28), worsening of clinical status: new need for invasive mechanical ventilation or death (up to day 28), adverse events (any grade), serious adverse events, secondary infections. MAIN RESULTS: We included six RCTs with 11,145 participants investigating systemic JAK inhibitors plus standard of care compared to standard of care alone (plus/minus placebo). Standard of care followed local protocols and included the application of glucocorticoids (five studies reported their use in a range of 70% to 95% of their participants; one study restricted glucocorticoid use to non-COVID-19 specific indications), antibiotic agents, anticoagulants, and antiviral agents, as well as non-pharmaceutical procedures. At study entry, about 65% of participants required low-flow oxygen, about 23% required high-flow oxygen or non-invasive ventilation, about 8% did not need any respiratory support, and only about 4% were intubated. We also identified 13 ongoing studies, and 9 studies that are completed or terminated and where classification is pending. Individuals with moderate to severe disease Four studies investigated the single agent baricitinib (10,815 participants), one tofacitinib (289 participants), and one ruxolitinib (41 participants). Systemic JAK inhibitors probably decrease all-cause mortality at up to day 28 (95 of 1000 participants in the intervention group versus 131 of 1000 participants in the control group; risk ratio (RR) 0.72, 95% confidence interval (CI) 0.57 to 0.91; 6 studies, 11,145 participants; moderate-certainty evidence), and decrease all-cause mortality at up to day 60 (125 of 1000 participants in the intervention group versus 181 of 1000 participants in the control group; RR 0.69, 95% CI 0.56 to 0.86; 2 studies, 1626 participants; high-certainty evidence). Systemic JAK inhibitors probably make little or no difference in improvement in clinical status (discharged alive or hospitalised, but no longer requiring ongoing medical care) (801 of 1000 participants in the intervention group versus 778 of 1000 participants in the control group; RR 1.03, 95% CI 1.00 to 1.06; 4 studies, 10,802 participants; moderate-certainty evidence). They probably decrease the risk of worsening of clinical status (new need for invasive mechanical ventilation or death at day 28) (154 of 1000 participants in the intervention group versus 172 of 1000 participants in the control group; RR 0.90, 95% CI 0.82 to 0.98; 2 studies, 9417 participants; moderate-certainty evidence). Systemic JAK inhibitors probably make little or no difference in the rate of adverse events (any grade) (427 of 1000 participants in the intervention group versus 441 of 1000 participants in the control group; RR 0.97, 95% CI 0.88 to 1.08; 3 studies, 1885 participants; moderate-certainty evidence), and probably decrease the occurrence of serious adverse events (160 of 1000 participants in the intervention group versus 202 of 1000 participants in the control group; RR 0.79, 95% CI 0.68 to 0.92; 4 studies, 2901 participants; moderate-certainty evidence). JAK inhibitors may make little or no difference to the rate of secondary infection (111 of 1000 participants in the intervention group versus 113 of 1000 participants in the control group; RR 0.98, 95% CI 0.89 to 1.09; 4 studies, 10,041 participants; low-certainty evidence). Subgroup analysis by severity of COVID-19 disease or type of JAK inhibitor did not identify specific subgroups which benefit more or less from systemic JAK inhibitors. Individuals with asymptomatic or mild disease We did not identify any trial for this population. AUTHORS' CONCLUSIONS: In hospitalised individuals with moderate to severe COVID-19, moderate-certainty evidence shows that systemic JAK inhibitors probably decrease all-cause mortality. Baricitinib was the most often evaluated JAK inhibitor. Moderate-certainty evidence suggests that they probably make little or no difference in improvement in clinical status. Moderate-certainty evidence indicates that systemic JAK inhibitors probably decrease the risk of worsening of clinical status and make little or no difference in the rate of adverse events of any grade, whilst they probably decrease the occurrence of serious adverse events. Based on low-certainty evidence, JAK inhibitors may make little or no difference in the rate of secondary infection. Subgroup analysis by severity of COVID-19 or type of agent failed to identify specific subgroups which benefit more or less from systemic JAK inhibitors. Currently, there is no evidence on the efficacy and safety of systemic JAK inhibitors for individuals with asymptomatic or mild disease (non-hospitalised individuals).

Early spontaneous breathing for acute respiratory distress syndrome in individuals with COVID-19.

BACKGROUND: Acute respiratory distress syndrome (ARDS) represents the most severe course of COVID-19 (caused by the SARS-CoV-2 virus), usually resulting in a prolonged stay in an intensive care unit (ICU) and high mortality rates. Despite the fact that most affected individuals need invasive mechanical ventilation (IMV), evidence on specific ventilation strategies for ARDS caused by COVID-19 is scarce. Spontaneous breathing during IMV is part of a therapeutic concept comprising light levels of sedation and the avoidance of neuromuscular blocking agents (NMBA). This approach is potentially associated with both advantages (e.g. a preserved diaphragmatic motility and an optimised ventilation-perfusion ratio of the ventilated lung), as well as risks (e.g. a higher rate of ventilator-induced lung injury or a worsening of pulmonary oedema due to increases in transpulmonary pressure). As a consequence, spontaneous breathing in people with COVID-19-ARDS who are receiving IMV is subject to an ongoing debate amongst intensivists. OBJECTIVES: To assess the benefits and harms of early spontaneous breathing activity in invasively ventilated people with COVID-19 with ARDS compared to ventilation strategies that avoid spontaneous breathing. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (which includes CENTRAL, PubMed, Embase, Clinical Trials.gov WHO ICTRP, and medRxiv) and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies from their inception to 2 March 2022. SELECTION CRITERIA: Eligible study designs comprised randomised controlled trials (RCTs) that evaluated spontaneous breathing in participants with COVID-19-related ARDS compared to ventilation strategies that avoided spontaneous breathing (e.g. using NMBA or deep sedation levels). Additionally, we considered controlled before-after studies, interrupted time series with comparison group, prospective cohort studies and retrospective cohort studies. For these non-RCT studies, we considered a minimum total number of 50 participants to be compared as necessary for inclusion. Prioritised outcomes were all-cause mortality, clinical improvement or worsening, quality of life, rate of (serious) adverse events and rate of pneumothorax. Additional outcomes were need for tracheostomy, duration of ICU length of stay and duration of hospitalisation. DATA COLLECTION AND ANALYSIS: We followed the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Two review authors independently screened all studies at the title/abstract and full-text screening stage. We also planned to conduct data extraction and risk of bias assessment in duplicate. We planned to conduct meta-analysis for each prioritised outcome, as well as subgroup analyses of mortality regarding severity of oxygenation impairment and duration of ARDS. In addition, we planned to perform sensitivity analyses for studies at high risk of bias, studies using NMBA in addition to deep sedation level to avoid spontaneous breathing and a comparison of preprints versus peer-reviewed articles. We planned to assess the certainty of evidence using the GRADE approach. MAIN RESULTS: We identified no eligible studies for this review. AUTHORS' CONCLUSIONS: We found no direct evidence on whether early spontaneous breathing in SARS-CoV-2-induced ARDS is beneficial or detrimental to this particular group of patients.  RCTs comparing early spontaneous breathing with ventilatory strategies not allowing for spontaneous breathing in SARS-CoV-2-induced ARDS are necessary to determine its value within the treatment of severely ill people with COVID-19. Additionally, studies should aim to clarify whether treatment effects differ between people with SARS-CoV-2-induced ARDS and people with non-SARS-CoV-2-induced ARDS.

Admission Blood Glucose in the Emergency Department is Associated with Increased In-Hospital Mortality in Nontraumatic Critically Ill Patients.

BACKGROUND: Abnormal admission blood glucose was reported as a useful predictor of outcome in critically ill patients. OBJECTIVES: To identify patients at higher risk, this study aimed to evaluate the relationship between admission blood glucose levels and patient mortality during the management of nontraumatic critically ill patients in the emergency department (ED). METHODS: In this prospective, single-center observational study in a German university ED, all adult patients admitted to the resuscitation room of the ED were included between September 1, 2014 and August 31, 2015. Directly after resuscitation room admission, blood samples for admission blood glucose were taken, and adult patients were divided into groups according to predefined cut-offs between the admission blood glucose. Study endpoint was in-hospital mortality. RESULTS: During the study period, 532 patients were admitted to the resuscitation room. The data of 523 patients (98.3%) were available for analysis. The overall in-hospital mortality was 34.2%. In comparison with an in-hospital mortality of 25.2% at an admission blood glucose of 101-136 mg/dL (n = 107), admission blood glucose of ≤ 100 mg/dL (n = 25, odds ratio [OR] 6.30, 95% confidence interval [CI] 2.44-16.23, p < 0.001), 272-361 mg/dL (n = 63, OR 2.53, 95% CI 1.31-4.90, p = 0.007), and ≥ 362 mg/dL (n = 44, OR 2.96, 95% CI 1.42-6.18, p = 0.004) were associated with a higher mortality. CONCLUSIONS: Abnormal admission blood glucose is associated with a high in-hospital mortality. Admission blood glucose is an inexpensive and rapidly available laboratory parameter that may predict mortality and help to identify critically ill patients at risk in a general nontraumatic critically ill ED patient cohort. The breakpoint for in-hospital mortality may be an admission blood glucose ≤ 100 and ≥ 272 mg/dL.

[Lactate in emergency medicine]. / Lactat in der Notfallmedizin.

The basis of all metabolic processes in the human body is the production and metabolism of carriers of energy. Lactate is the end-product of anaerobic glycolysis. Lactate can serve as a substrate for gluconeogenesis and as an oxidation substrate. Hyperlactatemia can be detected as the result of a multitude of acute events (e.g. shock, sepsis, cardiac arrest, trauma, seizure, ischemia, diabetic ketoacidosis, thiamine deficiency, liver failure and intoxication). Hyperlactatemia can be associated with increased mortality, therefore in emergency medicine the search for the cause of hyperlactatemia is just as important as an effective causal treatment. Repetitive measurements of lactate are components of several treatment algorithms as observation of the dynamic development of blood lactate concentrations can help to make a better assessment of the acute medical condition of the patient and to evaluate the effectiveness of the measures undertaken.

Elevated admission lactate levels in the emergency department are associated with increased 30-day mortality in non-trauma critically ill patients.

BACKGROUND: Elevated blood lactate levels were reported as useful predictors of clinical outcome and mortality in critically ill patients. To identify higher-risk patients, this investigation evaluated the relationship between patient mortality and admission lactate levels during the management of non-trauma critically ill patients in the emergency department (ED). METHODS: In this prospective, single centre observational study in a German university ED, all adult patients who were admitted to the ED resuscitation room were evaluated between September 1, 2014 and August 31, 2015. Blood samples for blood gas analysis, including lactate levels, were obtained immediately at admission. Study endpoint was 30-day mortality. RESULTS: During the study period, 532 patients were admitted to the resuscitation room of the ED. The data of 523 patients (98.3%) were available. The overall 30-day mortality was 34.2%. Patients presenting to the resuscitation room with admission lactate levels < 2.0 mmol/l had a 30-day mortality of 22.7%, while admission lactate levels above 8.0 mmol/l were associated with higher mortality (8.0-9.9 mmol/l: OR: 2.83, 95%CI: 1.13-7.11, p = 0.03, and ≥ 10 mmol/l: OR: 7.56, 95%CI: 4.18-13.77, p < 0.001). CONCLUSION: High lactate levels at admission are associated with an increased 24-h and 30-day mortality. These measurements may be used not only to predict mortality, but to help identify patients at risk for becoming critically ill. The breakpoint for mortality may be an ALL ≥8.0 mmol/l.

Early Lactate Dynamics in Critically Ill Non-Traumatic Patients in a Resuscitation Room of a German Emergency Department (OBSERvE-Lactate-Study).

BACKGROUND: Management of critically ill non-trauma patients in the resuscitation room of an emergency department (ED) is very challenging, and it is difficult to identify patients with a higher risk of death. Previous studies have shown that lactate indices can predict survival for selected diseases and syndromes. OBJECTIVE: As reported for other patient populations, we set out to determine whether admission lactate or lactate dynamics (LD) within 24 h can predict 30-day mortality in unselected critically ill non-traumatic patients. METHODS: In this retrospective study over a 1-year period, admission lactate, time weighted average lactate (LacTW) and LD of all critically ill adult patients admitted from ED to intensive care unit were analyzed. A linear regression model was implemented to estimate lactate data 1 h after admission. RESULTS: The admission lactate, LacTW, and LD within 24 h were analyzed from 392 critically ill patients. The overall 30-day mortality rate was around 29%. Admission lactate (4.1 ± 4.0 mmol/L vs. 6.6 ± 6.1 mmol/L; p < 0.01) and LacTW (1.8 ± 1.7 mmol/L vs. 4.1 ± 4.8 mmol/L; p < 0.01) were different between survivors and non-survivors. LD between survivors and non-survivors did not differ at 1 h, 6 h, 12 h, or 24 h. After excluding patients with out-of-hospital or in-hospital cardiac arrest during resuscitation room management, admission lactate and LD between survivors and non-survivors did not differ at 1 h, 12 h, and 24 h. LD at 6 h (44% ± 42% vs. 33% ± 58%; p = 0.042) and LacTW (1.7 ± 1.6 mmol/L vs. 2.6 ± 3.0 mmol/L; p < 0.01) did differ. CONCLUSIONS: In critically ill ED patients initially requiring treatment in a resuscitation room setting, LD at 6 h and LacTW may predict their survival beyond 30 days. These findings need to be confirmed in a prospective study design.