The adequacy of user seal checking for N95 respirators compared to formal fit testing: A multicentred observational study.

OBJECTIVE: The objective of this study was to evaluate the adequacy of the user seal check (USC) in predicting N95 respirator fit. DESIGN: This was a prospective, observational study conducted from May to September 2020. SETTING: The study setting included three private intensive care units (ICUs) in Victoria, Australia. PARTICIPANTS: ICU staff members in three private ICUs in Melbourne and regional Victoria participated in this study. MAIN OUTCOME MEASURES: The main outcome measure is the proportion of participants who passed a USC and subsequently failed fit testing of an N95 respirator. INTERVENTION: Three different respirators were available: two N95 respirator brands and CleanSpace HALO® powered air-purifying respirator. Participants were sequentially tested on N95 respirators followed by powered air-purifying respirators until either successful fit testing or failure of all three respirators. The first N95 tested was based on the availability on the day of testing. The primary outcome was failure rate of fit testing on the first N95 respirator type passing a USC. RESULTS: Of 189 participants, 22 failed USC on both respirators, leaving 167 available for the primary outcome. Fifty-one of 167 (30.5%, 95% confidence interval = 23.7-38.1) failed fit testing on the first respirator type used that had passed a USC. CONCLUSION: USC alone was inadequate in assessing N95 respirator fit and failed to detect inadequate fit in 30% of participants. Mandatory fit testing is essential to ensure adequate respiratory protection against COVID-19 and other airborne pathogens. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12620001193965.

A living WHO guideline on drugs for covid-19

Updates: This is the fourteenth version (thirteenth update) of the living guideline, replacing earlier versions (available as data supplements). New recommendations will be published as updates to this guideline. Clinical question: What is the role of drugs in the treatment of patients with covid-19? Context: The evidence base for therapeutics for covid-19 is evolving with numerous randomised controlled trials (RCTs) recently completed and underway. Emerging SARS-CoV-2 variants and subvariants are changing the role of therapeutics. What is new?: The guideline development group (GDG) defined 1.5% as a new threshold for an important reduction in risk of hospitalisation in patients with non-severe covid-19. Combined with updated baseline risk estimates, this resulted in stratification into patients at low, moderate, and high risk for hospitalisation. New recommendations were added for moderate risk of hospitalisation for nirmatrelvir/ritonavir, and for moderate and low risk of hospitalisation for molnupiravir and remdesivir. New pharmacokinetic evidence was included for nirmatrelvir/ritonavir and molnupiravir, supporting existing recommendations for patients at high risk of hospitalisation. The recommendation for ivermectin in patients with non-severe illness was updated in light of additional trial evidence which reduced the high degree of uncertainty informing previous guidance. A new recommendation was made against the antiviral agent VV116 for patients with non-severe and with severe or critical illness outside of randomised clinical trials based on one RCT comparing the drug with nirmatrelvir/ritonavir. The structure of the guideline publication has also been changed; recommendations are now ordered by severity of covid-19. About this guideline: This living guideline from the World Health Organization (WHO) incorporates new evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF on the WHO website, with a summary version here in The BMJ. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact. Future recommendations: Recommendations on anticoagulation are planned for the next update to this guideline. Updated data regarding systemic corticosteroids, azithromycin, favipiravir and umefenovir for non-severe illness, and convalescent plasma and statin therapy for severe or critical illness, are planned for review in upcoming guideline iterations.

Influence of changing endotracheal tube cuff management on antibiotic use for ventilator-associated pneumonia in a tertiary intensive care unit.

BACKGROUND: Routine deflation of the endotracheal tube (ETT) cuff of critically ill patients receiving MV is common in Australia and New Zealand. Literature about ventilatorassociated pneumonia (VAP) and antibiotic use rates with different ETT cuff maintenance practices is lacking. OBJECTIVE: To determine the impact of a change in ETT cuff maintenance from a minimal leak technique to pressure manometry on the administration of antibiotics for VAP. DESIGN, SETTING AND PARTICIPANTS: A prospective, pre- post observational study conducted in a metropolitan tertiary referral intensive care unit. We analysed data from 178 patients receiving MV for > 48 hours during 13 weeks of minimal leak test ETT cuff technique (pre-intervention, n = 92) or 13 weeks of cuff pressure manometry (postintervention, n = 86), separated by 3 weeks' "wash-out". MAIN OUTCOME MEASURES: Primary outcome was the number of patients receiving antibiotics for the indication of VAP. Secondary outcomes were incidence of ventilatorassociated surveillance events, lengths of stay (LOSs) and mortality. RESULTS: Antibiotics were administered for VAP in 24 patients (26.1%) in the pre-intervention period compared with 11 post-intervention patients (12.8%). The univariate antibiotic administraion rate per 100 ventilation days was 15.3% (95% CI, 12.6%-18.4%) v 6.8% (95% CI, 4.9%- 9.3%), and the incident rate ratio (IRR) was 0.45 (95% CI, 0.31-0.64); P < 0.001). After adjustment for ventilation duration, IRR was 0.55 (95% CI, 0.24-1.27); P = 0.160. The ventilator-associated complication incidence rate was lower in the post-intervention group (11.4% v 16.3%; IRR, 0.70 [95% CI, 0.51-0.95]; P = 0.018). After adjustment for duration of MV, IRR was 0.66 (95% CI, 0.25-1.70); P = 0.387. Antibiotic administration for VAP was associated with increased ICU and hospital LOSs, but not with mortality. CONCLUSIONS: ETT cuff pressure manometry is associated with a reduced rate of antibiotic administration for a diagnosis of VAP compared with a minimal leak test technique.

Targeted therapeutic mild hypercapnia after cardiac arrest: A phase II multi-centre randomised controlled trial (the CCC trial).

BACKGROUND: In intensive care observational studies, hypercapnia after cardiac arrest (CA) is independently associated with improved neurological outcome. However, the safety and feasibility of delivering targeted therapeutic mild hypercapnia (TTMH) for such patients is untested. METHODS: In a phase II safety and feasibility multi-centre, randomised controlled trial, we allocated ICU patients after CA to 24h of targeted normocapnia (TN) (PaCO2 35-45mmHg) or TTMH (PaCO2 50-55mmHg). The primary outcome was serum neuron specific enolase (NSE) and S100b protein concentrations over the first 72h assessed in the first 50 patients surviving to day three. Secondary end-points included global measure of function assessment at six months and mortality for all patients. RESULTS: We enrolled 86 patients. Their median age was 61 years (58, 64 years) and 66 (79%) were male. Of these, 50 patients (58%) survived to day three for full biomarker assessment. NSE concentrations increased in the TTMH group (p=0.02) and TN group (p=0.005) over time, with the increase being significantly more pronounced in the TN group (p(interaction)=0.04). S100b concentrations decreased over time in the TTMH group (p<0.001) but not in the TN group (p=0.68). However, the S100b change over time did not differ between the groups (p(interaction)=0.23). At six months, 23 (59%) TTMH patients had good functional recovery compared with 18 (46%) TN patients. Hospital mortality occurred in 11 (26%) TTMH patients and 15 (37%) TN patients (p=0.31). CONCLUSIONS: In CA patients admitted to the ICU, TTMH was feasible, appeared safe and attenuated the release of NSE compared with TN. These findings justify further investigation of this novel treatment.

Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial.

IMPORTANCE: Effective therapy has not been established for patients with agitated delirium receiving mechanical ventilation. OBJECTIVE: To determine the effectiveness of dexmedetomidine when added to standard care in patients with agitated delirium receiving mechanical ventilation. DESIGN, SETTING, AND PARTICIPANTS: The Dexmedetomidine to Lessen ICU Agitation (DahLIA) study was a double-blind, placebo-controlled, parallel-group randomized clinical trial involving 74 adult patients in whom extubation was considered inappropriate because of the severity of agitation and delirium. The study was conducted at 15 intensive care units in Australia and New Zealand from May 2011 until December 2013. Patients with advanced dementia or traumatic brain injury were excluded. INTERVENTIONS: Bedside nursing staff administered dexmedetomidine (or placebo) initially at a rate of 0.5 µg/kg/h and then titrated to rates between 0 and 1.5 µg/kg/h to achieve physician-prescribed sedation goals. The study drug or placebo was continued until no longer required or up to 7 days. All other care was at the discretion of the treating physician. MAIN OUTCOMES AND MEASURES: Ventilator-free hours in the 7 days following randomization. There were 21 reported secondary outcomes that were defined a priori. RESULTS: Of the 74 randomized patients (median age, 57 years; 18 [24%] women), 2 withdrew consent later and 1 was found to have been randomized incorrectly, leaving 39 patients in the dexmedetomidine group and 32 patients in the placebo group for analysis. Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo (median, 144.8 hours vs 127.5 hours, respectively; median difference between groups, 17.0 hours [95% CI, 4.0 to 33.2 hours]; P = .01). Among the 21 a priori secondary outcomes, none were significantly worse with dexmedetomidine, and several showed statistically significant benefit, including reduced time to extubation (median, 21.9 hours vs 44.3 hours with placebo; median difference between groups, 19.5 hours [95% CI, 5.3 to 31.1 hours]; P < .001) and accelerated resolution of delirium (median, 23.3 hours vs 40.0 hours; median difference between groups, 16.0 hours [95% CI, 3.0 to 28.0 hours]; P = .01). Using hierarchical Cox modeling to adjust for imbalanced baseline characteristics, allocation to dexmedetomidine was significantly associated with earlier extubation (hazard ratio, 0.47 [95% CI, 0.27-0.82]; P = .007). CONCLUSIONS AND RELEVANCE: Among patients with agitated delirium receiving mechanical ventilation in the intensive care unit, the addition of dexmedetomidine to standard care compared with standard care alone (placebo) resulted in more ventilator-free hours at 7 days. The findings support the use of dexmedetomidine in patients such as these. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01151865.

Safety evaluation of a trial of lipocalin-directed sodium bicarbonate infusion for renal protection in at-risk critically ill patients.

BACKGROUND: Urine alkalinisation with sodium bicarbonate decreases renal oxidative stress and might attenuate sepsisassociated acute kidney injury (s-AKI). The safety and feasibility of urine alkalinisation in patients at risk of s-AKI has never been tested. METHODS: We randomly assigned patients at risk of s-AKI (those with systemic inflammatory response syndrome [SIRS], oliguria and elevated [≥150 µg/L] serum neutrophil gelatinase-associated lipocalin [sNGAL] concentration) to receive sodium bicarbonate (treatment group) or sodium chloride (placebo group) in a 0.5 mmol/kg bolus followed by an infusion of 0.2 mmol/kg/hour. RESULTS: Among 50 patients with SIRS and oliguria, 25 (50%) had an elevated sNGAL concentration. Of these, 13 were randomised to receive sodium bicarbonate and 12 to receive sodium chloride infusion. Study drugs were infused for a mean period of 25.9 hours (SD, 10 hours). Severe electrolyte abnormalities occurred in seven patients (28%) (four [30.8%] in the treatment group and three [25%] in the placebo group). These abnormalities resulted in early protocol cessation in six patients (24%) and study drug suspension in one patient (4%). This adverse event rate was judged to be unacceptable and the study was terminated early. There was no difference between the two groups in sNGAL or urinary NGAL concentrations over time, occurrence of acute kidney injury, requirement for renal replacement therapy, hospital length-of-stay or mortality. CONCLUSION: Administration of sodium bicarbonate and sodium chloride solutions to patients at risk of s-AKI was associated with frequent major electrolyte abnormalities and early protocol cessation. The tested protocol does not appear safe or feasible.

Medication chart intervention improves inpatient thromboembolism prophylaxis.

BACKGROUND: Inpatient VTE prophylaxis is underused. This study evaluated the effectiveness of the low-cost, multifaceted Australian National Inpatient Medication Chart (NIMC) intervention on improving the quality of VTE prophylaxis and reducing disease. The NIMC intervention incorporated (1) a VTE risk stratification and appropriate prophylaxis guidance tool, (2) a prophylaxis contraindication screening instrument, and (3) a prophylaxis prescription prompt. METHODS: Retrospective analysis of 2,371 consecutive medical and surgical admissions was performed at a regional referral hospital over 1 year both before and after the intervention. Outcomes measured included the frequency of prophylaxis use, timing of prophylaxis initiation, adherence of the prescribed prophylaxis regimen to guidelines, incidence of VTE disease, and prophylaxis-related complications. RESULTS: Following NIMC intervention, prophylaxis use increased from 52.7% to 66.5% in medical patients and from 77.5% to 89.1% in surgical patients (P < .001). This increase was still evident 12 months postintervention. After intervention, prophylaxis initiated on admission increased from 65.0% to 83.6% in medical patients and from 60.7% to 78.0% in surgical patients (P < .01); adherence rates to recommended guidelines increased from 55.6% to 71.0% in medical patients and from 53.6% to 75.6% in surgical patients (P < .01). More VTE risk factors independently triggered prophylaxis usage postintervention. The improved quality of prophylaxis did not significantly reduce VTE incidence (risk ratio, 0.88; 95% CI, 0.48-1.62). The rate of prophylaxis-related complications remained similar before and after intervention. CONCLUSIONS: The multifaceted NIMC intervention resulted in a sustained increase in appropriate and timely VTE prophylaxis in medical and surgical inpatients.

Maternal severity of illness across levels of care: a prospective, cross-sectional study.

BACKGROUND: The severity of illness of women experiencing severe maternal morbidity has not been quantified outside of the intensive care setting yet is likely to have a bearing on clinical needs. AIM: To examine severity of illness in women with severe maternal morbidity. METHODS: A prospective observational study of critically ill pregnant and postpartum women was undertaken in intensive care units (ICU), high dependency units (HDU) and delivery suites (DS) of seven tertiary-level hospitals in Melbourne, during 2002-2004. Severity of illness was scored using the Acute Physiology and Chronic Health Evaluation version II (APACHE II) and Therapeutic Intervention Scoring System 28 items (TISS 28). RESULTS: 137 women participated in the study: ICU (n=33), HDU (n=46) and DS (n=58). The mean APACHE II score was 8.6 (95% CI 7.7-9.5) and mean TISS 28 score was 22.5 (95% CI 21.2-23.9). Women in ICU were sicker according to both APACHE II (mean 12.6, 95% CI 8.3-16.9) and TISS 28 (mean 31.5, 95% CI 28.2-35.5) compared to women not admitted to ICU (p<.005). There was no difference in the mean APACHE II scores of women in HDU (7.7, 95% CI 5.5-9.9) and DS (7.0, 95% CI 5.2-8.8; p=.20). Women born outside of Australia were more likely to be admitted to ICU (OR 3.27, 95% CI 1.19-8.97). Known risk factors like multiple pregnancy, age≥35 years and nulliparity were not associated with ICU admission. CONCLUSIONS: There was no difference in the severity of illness in women cared for in HDU and DS. It was not possible to predict which women would require ICU admission. Measurement of severity of illness adds a valuable dimension to the study of severe maternal morbidity.

The incidence of acute kidney injury in patients with traumatic brain injury.

There is limited information on the incidence of acute kidney injury (AKI) in patients with traumatic brain injury (TBI) although AKI may contribute to morbidity and mortality. We investigated the incidence of AKI in patients with moderate and severe TBI and the association of AKI with risk factors and outcomes in these patients. We studied all TBI patients over 16 years of age admitted to the two designated trauma hospitals in the state of Victoria, Australia from 1 January to 31 December 2008. Patients were included if they had head trauma and presented with a Glasgow coma scale (GCS) <13. Prospectively collected data from the hospital trauma registries, ICUs, and pathology databases were analyzed retrospectively. Risk injury failure loss end (RIFLE) criteria were used to categorize renal function. The incidence of AKI was 9.2% (19/207). Patients who developed AKI were older, had higher severity of illness scores, and a lower GCS. Overall 42.1% of these patients died in hospital compared with 18.1% in patients without AKI. In univariable linear regression analysis, age, severity of illness, and admitting hospital were associated with AKI. After multivariable logistic regression, the occurrence of AKI was associated with age (p < 0.001) and higher APACHE III scores (p = 0.016). AKI is relatively common even in patients with TBI. Its association with age and APACHE III scores helps identify patients at higher risk of AKI.