COVID-19
ICNARC:
Third wave: ICNARC report for England, Wales and Northern Ireland and for Wales alone (8th April, 2022). Comparison of patient admitted 1st September 2020 to 30th April 2021 (Second wave) and 1st May onwards (Third wave). In Wales (n=737), patients have tended to be younger (median age 57 vs 60 years), have shorter prior hospital length of stay (median 1 vs 2 days; mean 2.1 vs 4.1 days following hospital admission), slightly less sick (similar APACHE II, but marginally better oxygenation P:F ratio 13.5 vs 12.6 kPa), and less likely to undergo invasive ventilation in the first 24 hours (33.6% [n=246] vs 50.3%) than “Second wave.” ICU mortality 32.3% (n=238), with 0.8% patients still in critical care (see Second wave mortality, below).
For England, Wales and Northern Ireland (n=16,727), notable trends in terms of age (median 56 vs 60 years) and pregnancy (currently or recently pregnant 25.5% vs 14%) Third vs Second wave. Slightly lower illness severity to those admitted in Wales alone (median APACHE II 13 vs 14 and P:F ratio 14.0 for EWNI vs 13.5 in Wales). Lower proportion invasively ventilated in first 24 hours versus Second wave (24.0% vs 30.7%). For England, percentage of patients admitted to critical care with COVID-19 unvaccinated initially decreased through 3rd wave from 74% in May to 27% in February 2022 (compared with unvaccinated proportion of general population which decreased from 35% to 7%). ICU mortality 29.5%, but 3.2% patients still in critical care. Median duration of ICU stay for survivors 6 days versus 7 days during wave 2.
Second wave: ICNARC report for England, Wales and Northern Ireland and for Wales alone: more than twice as many patients admitted since 1st September than in first wave for Wales (907 vs. 403) and for England, Wales and Northern Ireland (25,879 vs 10,927, June 2021).
Second wave patients arrived in Welsh ICUs sicker (median APACHE II 15 vs 14, P:F ratio 12.7 vs 17.5 kPa) and later (median 2 vs 1 days; mean 4.1 vs 2.4 days after hospital admission) than in first wave. A lower proportion of patients have been invasively ventilated in their first 24 hours in ICU (50% vs 69%), but this difference decreases when looking at invasive ventilation at any point during ICU stay (70% vs 81%). ICU mortality appears to have been higher (46% vs 38%), though duration of stay for survivors is shorter (10 vs 15 days). Patients managed within respiratory high care units for the entire duration of their non-invasive respiratory support have of course not been captured. Outcomes for those invasively ventilated appear to have been worse (ICU mortality 59% vs 45%), but it seems likely that there has been greater selection during second wave of those in whom non-invasive support has failed.
First wave: ICNARC report for Wales, 31st July (comparison with ICNARC report for England/ Wales/ Northern Ireland, 31st July): 399 patients (437 admissions, vs 13,379); 67% male (vs 70%), median age 57 (vs. 60); differences in distributions of ethnic mix, BMI and deprivation index vs England/Wales/NI as a whole; 89% (vs 90%) previously independent; APACHE II 14 (vs 15). 69% invasively ventilated in the first 24 hours of ICU stay (vs 59%). 82% invasively ventilated at some point during ICU stay (vs 72%). P:F ratio 18 kPa first 24 hours (vs 15.8). 62% survival to ICU discharge (vs 60%) and ICU LOS for survivors median 15 days (vs 12 days).*
Non-invasive respiratory support
RECOVERY-RS. Perkins et al, JAMA Jan 2022. UK multi-centre (n=48), three-arm, open-label, adaptive, randomised controlled trial: adult hospitalised patients with acute respiratory failure due to COVID-19 (suitable for treatment escalation) randomly assigned to receive CPAP, HFNO, or conventional oxygen therapy. Primary outcome: a composite of tracheal intubation or mortality within 30-days. 1273 participants (380 (29.9%) CPAP; 417 (32.8%) HFNO; 475 (37.3%) conventional oxygen therapy). Need for tracheal intubation or mortality within 30-days was lower in the CPAP group (CPAP 137 of 377 participants (36.3%) vs conventional oxygen therapy 158 of 356 participants (44.4%); unadjusted odds ratio 0.72; 95% CI 0.53 to 0.96, P=0.03). No difference between HFNO and conventional oxygen therapy (HFNO 184 of 415 participants (44.3%) vs conventional oxygen therapy 166 of 368 participants (45.1%); unadjusted odds ratio 0.97; 95% CI 0.73 to 1.29, P=0.85). Of note: trial stopped early (target enrolment 4002), high cross-over rate (23.6%) from standard oxygen group, mean FiO2 at study entry 0.6 and P:F ratio 18 kPa, decision to intubate that of treating team (rather than pre-defined criteria), only four cases of barotrauma attributed to use of CPAP.
Associated editorial by Zampieri here: “Based on the available evidence, it is reasonable to assume that noninvasive ventilation is probably beneficial to reduce the need for invasive mechanical ventilation in patients with COVID-19 who have acute respiratory failure, whereas the precise role of HFNO in patients with COVID-19 is far less clear. For the immediate future, CPAP may be recommended as a first-line therapy with combination HFNO and other hybrid approaches being considered tailored to the patient’s condition and tolerance.”
HENIVOT study. Greico et al, JAMA March 25th 2021. RCT (n=110). Median PF ratio 13 kPa, randomised to bilevel helmet NIV (PEEP 10 to 12, PS 10 to 12 cm H2O) or HFNO 60 l/min. Intubation rate significantly lower in the NIV group than in HFNO group (30% vs 51%; P = .03). Median number of days free of invasive mechanical ventilation within 28 days significantly higher in the NIV group than in the high-flow nasal oxygen group (28 vs 25; P = .04)
RECOVERY: Regeneron Monoclonal antibody combination
DHSC Therapeutic alert, 4th November 2021. Casirivimab and imdevimab for patients hospitalised with COVID-19 who have not mounted an antibody response of their own.
Horby et al. pre-print. RECOVERY press statement. 16th June, 2021. RCT: 9785 patients allocated to usual care plus REGEN-COV or usual care alone. This included 3153 (32%) seronegative patients, 5272 (54%) seropositive patients and 1360 (14%) patients with unknown baseline status. Among seronegative patients, 396 (24%) of 1633 patients allocated to REGEN-COV and 451 (30%) of 1520 patients allocated usual care died within 28 days (rate ratio 0.80; 95% CI 0.70-0.91; p=0.0010). For all randomised patients (irrespective of antibody status), 944 (20%) of 4839 patients allocated to REGEN-COV and 1026 (21%) of 4946 patients allocated usual care died within 28 days (rate ratio 0.94; 95% CI 0.86-1.03; p=0.17). The effect of REGEN-COV on mortality differed significantly between seropositive and seronegative patients (p value for heterogeneity = 0.001).
Anticoagulation / thromboprophylaxis
NICE NG-191. Updated 2nd September 2021. Note “Offer a standard prophylactic dose of a low molecular weight heparin as soon as possible, and within 14 hours of admission, to young people and adults with COVID-19 who need low-flow or high-flow oxygen, continuous positive airway pressure, non-invasive ventilation or invasive mechanical ventilation, and who do not have an increased bleeding risk… Only offer an intermediate or treatment dose of a low molecular weight heparin to young people and adults with COVID-19 who are receiving high-flow oxygen, continuous positive airway pressure, non-invasive ventilation or invasive mechanical ventilation as part of a clinical trial.”
The ATTACC, ACTIV-4a, and REMAP-CAP Investigators. NEJM 4th August, 2021.Therapeutic Anticoagulation with Heparin in non-Critically Ill Patients with Covid-19. Hospitalised patients (without respiratory or cardiovascular support) randomly assigned to therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis. Primary outcome was organ support–free days and number of days free of cardiovascular or respiratory organ support up to day 21 (among patients who survived to hospital discharge). 2219 patients (1171 in therapeutic dose heparin, and 1048 in usual care thrombo-prophylaxis: 26.5% received “intermediate dose”). Probability that therapeutic-dose anticoagulation increased organ support–free days was 98.6%. Adjusted difference in survival to hospital discharge without organ support among therapeutic-dose anticoagulation was 4% higher. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.
Associated editorial, ten Cate. NEJM 4th August 2021.
Inspiration trial. Intermediate-dose vs standard-dose prophylactic anticoagulation for patients with COVID-19 admitted to the Intensive Care Unit. JAMA, March 2021. 562 patients; composite primary outcome (venous or arterial thrombosis, treatment with ECMO, or mortality within 30 days) in 45.7% of patients in the intermediate-dose thrombo-prophylaxis group and 44.1% of patients in the standard-dose thrombo-prophylaxis group - not statistically significant (odds ratio, 1.06).
High versus low dose dexamethasone: the COVID Steroid 2 trial
Munch et al. JAMA October 21st, 2021. RCT (n=982), international multi-centre, hospitalised patients receiving 10 l/min oxygen or mechanical ventilation: 12mg dexamethasone vs 6 mg dexamethasone for up to 10 days. No significant difference in organ support-free days, 28-day mortality or serious adverse events.
Granholm et al. November 10th, 2021. Secondary Bayesian analysis. Adjusted mean difference of primary outcome - days alive without life support at day 28 - was 1.3 days (95% CrI −0.3 to 2.9; 94.2% probability of benefit). “We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.”
RECOVERY: aspirin
Horby et al. pre-print. RECOVERY press statement. 8th June, 2021. RCT. 7351 patients allocated to receive aspirin and 7541 patients to usual care. 1222 (17%) patients allocated to aspirin and 1299 (17%) patients allocated to usual care died within 28 days (rate ratio 0·96; 95% confidence interval [CI] 0·89-1·04; p=0·35). Patients allocated aspirin had a slightly shorter duration of hospitalisation (median 8 vs. 9 days) and a higher proportion were discharged from hospital alive within 28 days (75% vs. 74%; rate ratio 1·06; 95% CI 1·02-1·10; p=0·0062).
GIRFT
Variability in COVID-19 in-hospital mortality rates between national health service trusts and regions in England. Lancet April 25th, 2021. 86,356 patients with a confirmed diagnosis of COVID-19 March–July 2020 included in the study, of whom 22,944 (26.6%) died in hospital with COVID-19 as the primary cause. Trusts with the largest baseline number of beds and a greater proportion of patients admitted to critical care had the lowest in-hospital mortality rates.
Vaccine-induced Immune Thrombotic Thrombocytopoenia (VITT)
Case series of thrombotic events following AstraZeneca vaccine (Germany / Austria), Greinacher et al. NEJM 10th April 2021 (n=11), and case series following AstraZeneca vaccine (Norway), Schultz et al. NEJM 9th April 2021 (n=5): Immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, clinically mimicking autoimmune heparin-induced thrombocytopenia. Platelet activation inhibited by high levels of heparin, receptor–blocking monoclonal antibody, and immune globulin. However, “anticoagulant options should include nonheparin anticoagulants used for the management of heparin-induced thrombocytopenia, unless a functional test has excluded heparin-dependent enhancement of platelet activation.”
Intensive Care Society guidance, 9th April 2021.
British Society of Haematology Expert Panel Guidance, 7th April 2021
JCVI statement on use of the AstraZeneca COVID vaccine, 7th April 2021
Winton Centre for Risk and Evidence Communication (University of Cambridge), 7th April 2021
IL-6 receptor inhibitors:
DHSC / NHS Interim Guidance IL-6 receptor inhibitors, Sept 12th 2021
RECOVERY Lancet May 1st, 2021. RCT. Hypoxic patients (SaO2 <92% or requiring oxygen) with CRP 75 mg/L or more (n=4116). 562 (14%) patients invasively ventilated, 1686 (41%) receiving non-invasive respiratory support, and 1868 (45%) receiving oxygen only. 621 (31%) of 2022 patients allocated tocilizumab and 729 (35%) of 2094 patients allocated usual care died within 28 days (rate ratio 0·86; p=0·007). Patients randomised to tocilizumab more likely to be discharged from hospital alive at 28 days (57% vs. 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). For patients not receiving invasive mechanical ventilation at randomisation, those allocated tocilizumab less likely to reach a composite endpoint of invasive mechanical ventilation or death (35% vs. 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001).
REMAP-CAP NEJM Feb 25th, 2021. RCT. Critically ill patients requiring organ support: Tocilizumab (n=353), sarilumab (n=48) or control (n=402). Primary outcome: ordinal scale combining in-hospital mortality (assigned −1) and days free of organ support to day 21. Median organ support-free days were 10, 11 and 0 for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios 1.64 for tocilizumab and 1.76 for sarilumab, i.e. >99.9% and 99.5% probabilities of superiority compared with control. Tocilizumab and sarilumab effective across all secondary outcomes, including 90-day survival, time to ICU and hospital discharge.
Veiga et al. TOCIBRAS, BMJ 21st Jan 2021. RCT. Patients requiring oxygen or mechanical ventilation. Tocilizumab (n=65) or standard care (n=64). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Associated editorial.
Salama et al. (EMPACTA trial), NEJM Jan 7th 2021. RCT. Hospitalised, non-invasively ventilated patients (positive selction for high risk and ethnic minority groups): Tocilizumab (n=249) vs placebo (n= 128). Significantly lower composite outcome (death or mechanical ventilation) day 28 (12% intervention, 19% placebo), but did not improve survival.
Janus kinase (JAK) inhibitor: Baricitinib
Marconi et al. Pre-print. RCT. Hospitalised patients: remdesivir plus baricitinib (n=764) or remdesivir alone (n=761). The primary endpoint was proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28. 27.8% of participants receiving baricitinib vs 30.5% receiving placebo progressed to primary endpoint (podds ratio 0.85, 95% CI 0.67-1.08; p=0.18). 28-day all-cause mortality was 8.1% for baricitinib and 13.1% for placebo (hazard ratio [HR] 0.57, 95% CI 0.41-0.78; nominal p=0.002).
Kalil et al. (ACTT-2 trial), NEJM 4th March 2021. RCT. Hospitalised patients (including those receiving oxygen, non-invasive or invasive respiratory support, or ECMO): Remdesivir plus baricitinib (n=515) or remdesivir alone (n=518). Patients receiving baricitinib had a median time to recovery of 7 days vs 8 days with control (P=0.03), higher improved clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6), and lower progression to a composite outcome of death or ventilation. Patients on high-flow oxygen or noninvasive ventilation at enrollment time to recovery was 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality did not significantly differ.
GenOMICC
Genetic mechanisms of critical illness in COVID-19. Pairo-Castineira et al, Nature, December 2020. Identification of 5 genes associated with critical illness in COVID-19: IFNAR2, TYK2, OAS1, DPP9 and CCR2: these associations indicate potential benefit from therapies which increase interferon signalling, antagonise monocyte activation and lung infiltration, or specifically target harmful inflammatory pathways. The study provides profound evidence on which to base the prioritisation of agents (and timing of administration) in clinical trials.
*These data derive from the ICNARC Case Mix Programme Database. The Case Mix Programme is the national clinical audit of patient outcomes from adult critical care coordinated by the Intensive Care National Audit & Research Centre (ICNARC). For more information on the representativeness and quality of these data, please contact ICNARC.