Skin-to-deltoid-muscle distance at three recommended sites for intramuscular vaccination in a population with obesity: an observational study

The study also explored i) the associations between skin-to-deltoid-muscle distance across the three recommended sites with sex, body mass index (BMI), and arm circumference, and ii) the proportion of participants with a skin-to-deltoid-muscle distance >20 millimetres (mm), in whom the standard 25mm needle length would not ensure deposition of vaccine within the deltoid muscle. method: When choosing the required needle length to achieve intramuscular vaccination in obese vaccine recipients, consideration needs to be given to the injection site location, sex, BMI and/or arm circumference, as these factors all influence the skin-to-deltoid-muscle distance. Published data report that a standard needle length (25mm) is suitable for most people with a body mass index (BMI) <25 kilograms [kg]/m2.48 However, progressively higher BMIs increase the likelihood of requiring a longer-than-standard needle length for deltoid intramuscular injection.810 Worldwide, immunisation guidelines vary in their instructions on how to choose the correct needle length based on BMI and body weight, or contain non-specific terms such as "larger arms".1113 An accurate measurement of BMI for a vaccine recipient is not always readily available and the interpretation of arm size is subjective, resulting in an increased risk of inappropriate needle length choice and subcutaneous vaccine delivery. An observational study of a SARS-CoV-2 mRNA vaccine, administered with needles of different lengths at the discretion of the vaccinator, did not demonstrate a difference in immunogenicity between those vaccinated with a needle of sufficient versus insufficient length to achieve intramuscular deposition of vaccine.14 However, there is evidence that intramuscular injection results in significantly better immune response compared to subcutaneous delivery of influenza and hepatitis B vaccines.15 Further, there is high-grade evidence that subcutaneous administration of different vaccine types (adjuvanted, live virus and non-adjuvanted) is associated with increased local side effects including abscess and granuloma formation, compared to intramuscular delivery.15" The location of the deltoid intramuscular injection site is defined variably between countries based on anatomical landmarks (Figure 1).

Effect of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Initiation on Organ Support-Free Days in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

IMPORTANCE: Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective: To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS: In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non-critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS: Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES: The primary outcome was organ support-free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS: On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support-free days among critically ill patients was 10 (-1 to 16) in the ACE inhibitor group (n = 231), 8 (-1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support-free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE: In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial.

Importance: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance: Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

When should a longer needle be used for intramuscular injection in obese patients? A combined analysis of New Zealand data.

AIM: To estimate thresholds for Body Mass Index (BMI) and arm circumference above which a longer needle is needed to ensure intramuscular (IM) delivery of a vaccine in the deltoid muscle at the site recommended by New Zealand (NZ) immunization guidelines. METHODS: A combined analysis of two studies, including 442 adults, with measurements of arm circumference, BMI and skin to deltoid muscle distance (SDMD) at the NZ immunization guideline-recommended IM injection site. Receiver Operator Characteristic curves identified arm circumference and BMI cut-points that gave 100% sensitivity for SDMD thresholds. These thresholds were: SDMD of 20 mm, accounting for a minimal penetration of 5 mm into muscle with the standard needle; and 25 mm, which is the length of a standard needle for IM injection, representing the depth this can reach. RESULTS: Cut-point values for arm circumference, at which a longer needle would be required, were higher for males than females: 35 cm versus 30 cm for the 20 mm cut-point, and 40 cm versus 36.7 cm for the 25 mm cut-point respectively. The BMI cut-points were also higher for male than females: 24.6 kg/m2 versus 23.7 kg/m2 for the 20 mm cut-point, and 38.2 kg/m2 vs 31.6 kg/m2 for the 25 mm cut-point respectively. CONCLUSION: Arm circumference and BMI cut-points provide practical measures from which to choose a needle length that increases the chance of successful IM vaccination. Based on our data, an arm circumference of 35 cm for men and 30 cm for women should prompt selection of a longer needle to ensure intramuscular injection at the deltoid site. Thresholds for the different skin to deltoid sites proposed internationally should be determined to enable successful IM vaccination in clinical practice beyond NZ.

ANZTCT Position Statement: COVID-19 Management in Haematopoietic Stem Cell Transplant and Chimeric Antigen Receptor T cell Patients.

Patients post haematopoietic stem cell transplant or CAR-T cell therapy face significant risk of morbidity and mortality from SARS-CoV19, due to their immunosuppressed state. As case numbers in Australia and New Zealand continue to rise, guidance on management in this high-risk population is needed. Whilst we have learnt much from international colleagues who faced high infection rates early in the pandemic, guidance relevant to local health system structures, medication availability and emerging therapies is essential to equip physicians to optimally manage our patients. This article is protected by copyright. All rights reserved.

Therapeutic advances in COVID-19.

Over 2 years have passed since the start of the COVID-19 pandemic, which has claimed millions of lives. Unlike the early days of the pandemic, when management decisions were based on extrapolations from in vitro data, case reports and case series, clinicians are now equipped with an armamentarium of therapies based on high-quality evidence. These treatments are spread across seven main therapeutic categories: anti-inflammatory agents, antivirals, antithrombotics, therapies for acute hypoxaemic respiratory failure, anti-SARS-CoV-2 (neutralizing) antibody therapies, modulators of the renin-angiotensin-aldosterone system and vitamins. For each of these treatments, the patient population characteristics and clinical settings in which they were studied are important considerations. Although few direct comparisons have been performed, the evidence base and magnitude of benefit for anti-inflammatory and antiviral agents clearly outweigh those of other therapeutic approaches such as vitamins. The emergence of novel variants has further complicated the interpretation of much of the available evidence, particularly for antibody therapies. Importantly, patients with acute and chronic kidney disease were under-represented in many of the COVID-19 clinical trials, and outcomes in this population might differ from those reported in the general population. Here, we examine the clinical evidence for these therapies through a kidney medicine lens.

What variables should inform needle length choice for deltoid intramuscular injection? A systematic review.

OBJECTIVES: (1) Assess the distribution of skin-to-deltoid-muscle distance (SDMD) at the deltoid intramuscular (IM) injection site; (2) its relationship with demographic and anthropometric variables and (3) Consider the findings in relation to clinical guidance on IM injection, such as COVID-19 vaccines. DESIGN: Systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SOURCES: MEDLINE, EMBASE, ClinicalTrials.gov, Cochrane Library, CINAHL and SCOPUS between June and July 2021 with no publication date limit. ELIGIBILITY CRITERIA: Studies reporting measurements of the SDMD in living adults aged 16 years and older, at the deltoid IM injection site, published in English were considered. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers performed each stage of screening, data extraction and quality assessments using the Joanna Briggs Institute Critical Appraisal Checklist for analytical cross sectional studies. RESULTS: 16 105 papers were identified, of which 11 studies were suitable for review, representing 1414 participants. Heterogeneity in the definition of the deltoid IM injection site, locations measured and methods of measurement precluded meta-analysis. Evidence from ultrasound SDMD measurements demonstrated some patients in all but 'underweight' body mass index (BMI) categories, may require needles longer than 25 mm for successful IM injection. Calliper measurements overestimated SDMD compared with ultrasound. Female sex, higher BMI categories and greater weight in women were associated with greater SDMD. CONCLUSIONS: The reviewed evidence was insufficient to inform definitive needle length 'cut points' for IM injection based on demographic or anthropomorphic variables. Contemporary clinical guidance currently based on this evidence, including the site of injection and choice of needle length, may result in subcutaneous administration in a small proportion of recipients, particularly if obese or of female sex. PROSPERO REGISTRATION NUMBER: CRD42021264625.

COVID-19 vaccination and the skin to deltoid MUSCLE distance in adults with diabetes.

Objectives: To estimate the proportion of adult diabetics with a skin to deltoid muscle distance (SDMD) of > 25 mm, representing a distance greater than the standard needle length used for intramuscular COVID-19 vaccination, and to assess whether anthropometric measurements predict ultrasound SDMD measurements. Design: Non-interventional cross-sectional study. Setting: Single site, non-clinical setting, Wellington, New Zealand. Participants: One hundred participants (50 females) aged at least 18 years diagnosis with diabetes. All participants completed the study. Main outcome measures: The proportions of participants with a SDMD > 25 mm and a SDMD > 20 mm (indicating that the needle would not have penetrated at least 5 mm into the deltoid, which is considered necessary to ensure deposition of vaccine into muscle); the relationship between anthropometric measurements (body weight, body height, body mass index (BMI), skinfold thickness, arm circumference) and SDMD measured by ultrasound. Results: The proportion (95 %CI) of participants with a SDMD > 25 mm was 6/100; 6 % (2.2 to 12.6), and the proportion with a SDMD > 20 mm was 11 % (5.6 to 18.8), of which 9/11 had a BMI ≥ 30 kg/m2 and 9/11 were female. The strongest relationships between anthropometric measurements and SDMD were with arm circumference (r = 0.76, P < 0.001) and BMI (r = 0.73, P < 0.001). Arm circumference and BMI were the best predictors of SDMD measurements with AUC for ROC curves of 0.99 and 0.94 above the 25 mm cut point, 0.97 and 0.89 above the 20 mm cut point respectively. Conclusions: The standard needle length of 25 mm is likely to be insufficient to ensure deposition of COVID-19 vaccine within the deltoid muscle in a small but important proportion of obese adults with diabetes. Arm circumference and BMI are simple measurements that could identify those that need a long needle to ensure successful intramuscular vaccine administration. Funding: Ruth Maud Ring Spencer Estate; Health Research Council of New Zealand (Independent Research Organisation).

Nafamostat Mesylate for Treatment of COVID-19 in Hospitalised Patients: A Structured, Narrative Review.

The search for clinically effective antivirals against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is ongoing. Repurposing of drugs licensed for non-coronavirus disease 2019 (COVID-19) indications has been extensively investigated in laboratory models and in clinical studies with mixed results. Nafamostat mesylate (nafamostat) is a drug licensed in Japan and Korea for indications including acute pancreatitis and disseminated intravascular coagulation. It is available only for continuous intravenous infusion. In vitro human lung cell line studies with nafamostat demonstrate high antiviral potency against SARS-CoV-2 (half maximal inhibitory concentration [IC50] of 0.0022 µM [compared to remdesivir 1.3 µM]), ostensibly via inhibition of the cellular enzyme transmembrane protease serine 2 (TMPRSS2) preventing viral entry into human cells. In addition, the established antithrombotic activity is hypothesised to be advantageous given thrombosis-associated sequelae of COVID-19. Clinical reports to date are limited, but indicate a potential benefit of nafamostat in patients with moderate to severe COVID-19. In this review, we will explore the pre-clinical, pharmacokinetic and clinical outcome data presently available for nafamostat as a treatment for COVID-19. The recruitment to ongoing clinical trials is a priority to provide more robust data on the safety and efficacy of nafamostat as a treatment for COVID-19.

The effect of needle length and skin to deltoid muscle distance in adults receiving an mRNA COVID-19 vaccine.

BACKGROUND: The mRNA COVID vaccines are only licensed for intramuscular injection but it is unclear whether successful intramuscular administration is required for immunogenicity. METHODS: In this observational study, eligible adults receiving their first ComirnatyTM/BNT162b2 dose had their skin to deltoid muscle distance (SDMD) measured by ultrasound. The relationship between SDMD and height, weight, body mass index, and arm circumference was assessed. Three needle length groups were identified: 'clearly sufficient' (needle exceeding SDMD by >5 mm), 'probably sufficient' (needle exceeding SDMD by ≤ 5 mm), and 'insufficient' (needle length ≤ SDMD). Baseline and follow-up finger prick blood samples were collected and the primary outcome variable was mean spike antibody levels in the three needle length groups. RESULTS: Participants (n = 402) had a mean age of 34.7 years, BMI 29.1 kg/m2, arm circumference 37.5 cm, and SDMD 13.3 mm. The SDMD was >25 mm in 23/402 (5.7%) and >20 mm in 61/402 (15.2%) participants. Both arm circumference (≥40 cm) and BMI (≥33 kg/m2) were able to identify those with a SDMD of >25 mm, the length of a standard injection needle, with a sensitivity of 100% and specificities of 71.2 and 79.9%, respectively. Of 249/402 (62%) participants with paired blood samples, there was no significant difference in spike antibody titres between needle length groups. The mean (SD) spike BAU/mL was 464.5 (677.1) in 'clearly sufficient needle length' (n = 217) compared with 506.4 (265.1) in 'probably sufficient' (n = 21, p = 0.09), and 489.4 (452.3) in 'insufficient needle length' (n = 11, p = 0.65). CONCLUSIONS: A 25 mm needle length is likely to be inadequate to ensure vaccine deposition within the deltoid muscle in a small proportion of adults. Vaccine-induced spike antibody titres were comparable in those vaccinated with a needle of sufficient versus insufficient length suggesting deltoid muscle deposition may not be required for an adequate antibody response to mRNA vaccines.

Prophylaxis in healthcare workers during a pandemic: a model for a multi-centre international randomised controlled trial using Bayesian analyses.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has exposed the disproportionate effects of pandemics on frontline workers and the ethical imperative to provide effective prophylaxis. We present a model for a pragmatic randomised controlled trial (RCT) that utilises Bayesian methods to rapidly determine the efficacy or futility of a prophylactic agent. METHODS: We initially planned to undertake a multicentre, phase III, parallel-group, open-label RCT, to determine if hydroxychloroquine (HCQ) taken once a week was effective in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in healthcare workers (HCW) aged ≥ 18 years in New Zealand (NZ) and Ireland. Participants were to be randomised 2:1 to either HCQ (800 mg stat then 400 mg weekly) or no prophylaxis. The primary endpoint was time to Nucleic Acid Amplification Test-proven SARS-CoV-2 infection. Secondary outcome variables included mortality, hospitalisation, intensive care unit admissions and length of mechanical ventilation. The trial had no fixed sample size or duration of intervention. Bayesian adaptive analyses were planned to occur fortnightly, commencing with a weakly informative prior for the no prophylaxis group hazard rate and a moderately informative prior on the intervention log hazard ratio centred on 'no effect'. Stopping for expected success would be executed if the intervention had a greater than 0.975 posterior probability of reducing the risk of SARS-CoV-2 infection by more than 10%. Final success would be declared if, after completion of 8 weeks of follow-up (reflecting the long half-life of HCQ), the prophylaxis had at least a 0.95 posterior probability of reducing the risk of SARS-CoV-2 infection by more than 10%. Futility would be declared if HCQ was shown to have less than a 0.10 posterior probability of reducing acquisition of SARS-CoV-2 infection by more than 20%. DISCUSSION: This study did not begin recruitment due to the marked reduction in COVID-19 cases in NZ and concerns regarding the efficacy and risks of HCQ treatment in COVID-19. Nonetheless, the model presented can be easily adapted for other potential prophylactic agents and pathogens, and pre-established collaborative models like this should be shared and incorporated into future pandemic preparedness planning. TRIAL REGISTRATION: The decision not to proceed with the study was made before trial registration occurred.

Clinical features of patients hospitalised with COVID-19 from February to October 2020, during the early waves of the pandemic in New Zealand.

AIM: As New Zealand transitions towards endemic SARS-CoV-2, understanding patient factors predicting severity, as well as hospital resourcing requirements will be essential for future planning. METHODS: We retrospectively enrolled patients hospitalised with COVID-19 from 26 February to 5 October 2020 as part of the COVID-19 HospitalisEd Patient SeverIty Observational Study NZ (COHESION). Data on demographics, clinical course and outcomes were collected and analysed as a descriptive case series. RESULTS: Eighty-four patients were identified across eight district health boards. Forty-one (49%) were male. The median age was 58 years [IQR: 41.7-70.3 years]. By ethnicity, hospitalisations included 38 NZ European (45%), 19 Pasifika (23%), 13 Maori (15%), 12 Asian (14%) and 2 Other (2%). Pre-existing co-morbidities included hypertension (26/82, 32%), obesity (16/66, 24%) and diabetes (18/81, 22%). The median length of stay was four days [IQR: 2-15 days]. Twelve patients (12/83, 14%) were admitted to an intensive care unit or high dependency unit (ICU/HDU). Ten (10/83, 12%) patients died in hospital of whom seven (70%) were not admitted to ICU/HDU; the median age at death was 83 years. CONCLUSION: Despite initially low case numbers in New Zealand during 2020, hospitalisation with COVID-19 was associated with a high mortality and hospital resource requirements.

Effect of Antiplatelet Therapy on Survival and Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

IMPORTANCE: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. OBJECTIVE: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONS: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURES: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group. CONCLUSIONS AND RELEVANCE: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial.

PURPOSE: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). METHODS: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. RESULTS: We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (- 1 to 15), 0 (- 1 to 9) and-1 (- 1 to 7), respectively, compared to 6 (- 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). CONCLUSION: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.

The impacts of New Zealand's COVID-19 epidemic response on community antibiotic use and hospitalisation for pneumonia, peritonsillar abscess and rheumatic fever.

BACKGROUND: The rate of community antibiotic use in New Zealand (NZ) is high and some may be unnecessary. Non-pharmaceutical public health interventions (Alert Levels) were implemented in 2020 to reduce the spread of COVID-19 in NZ and were likely to have affected antibiotic prescribing. METHODS: We aimed to identify the impact of these public health interventions on community antibiotic dispensing. We also examined rates of hospitalisation with infectious diseases that could be influenced by changing community antibiotic use. A retrospective review of two national databases was undertaken. FINDINGS: 1.17 million people received 1.19 million prescriptions for antibiotics between 23/02/2020 and 18/07/2020. Antibiotic dispensing rates fell from 14 prescriptions per 1000 population per week during pre-Alert Level weeks to 9 prescriptions per 1000 population per week (a reduction of 36%) during the weeks of COVID Alert Level 3-4. Large reductions were seen with antibiotics predominantly used for respiratory- or urinary-tract infections. Hospital discharges with sentinel infections did not increase over this period; pneumonia discharges during Alert Level weeks were lower than in 2017-2019 (3 vs 6 discharges per 100,000 population). INTERPRETATION: A large reduction in community antibiotic dispensing was observed in NZ during the implementation of non-pharmaceutical public health interventions to eliminate COVID-19. Despite this marked reduction in antibiotic use, there was no increase in rates of hospitalisation for sentinel infections that community antibiotic use could prevent. These findings suggest that countries with high rates of antibiotic use could significantly reduce their use without an increase in morbidity. FUNDING: No financial support received.