Simvastatin in Critically Ill Patients with Covid-19.

BACKGROUND: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2). RESULTS: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control. CONCLUSIONS: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).

Intravenous Vitamin C for Patients Hospitalized With COVID-19: Two Harmonized Randomized Clinical Trials.

Importance: The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain. Objective: To determine whether vitamin C improves outcomes for patients with COVID-19. Design, Setting, and Participants: Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents. Interventions: Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses). Main Outcomes and Measures: The primary outcome was a composite of organ support-free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from -1 organ support-free days for patients experiencing in-hospital death to 22 organ support-free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support-free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility. Results: Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support-free days was 7 (IQR, -1 to 17 days) for the vitamin C group vs 10 (IQR, -1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support-free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy. Conclusions and Relevance: In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support-free days and hospital survival. Trial Registration: ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP).

Frailty status, timely goals of care documentation and clinical outcomes in older hospitalised medical patients.

BACKGROUND: Hospitalised frail older patients are at risk of clinical deterioration. Early goals of care (GOC) documentation is vital to avoid futile/unwarranted interventions in the event of deterioration. AIMS: To investigate the impact of frailty on timely GOC and its association with clinical outcomes in hospitalised older patients. METHODS: This was a single-centre retrospective study of all medical patients aged ≥80 years admitted to the acute medical unit between 1/3/2015 and 31/8/2015, with GOC derived from electronic records. Frailty was measured using the Hospital Frailty Risk Score (HFRS) derived from hospital coding data. Primary outcome compared proportions of timely GOC within 72-h between frail (HFRS ≥ 5) and non-frail (HFRS < 5) patients. Exploratory secondary outcomes included in-hospital mortality, rapid response calls (RRC), prolonged length of stay (LOS) and 28-day readmission rates. RESULTS: Of the 1118 admitted patients, 529 (47.3%) were frail. Timely GOC occurred in 50% (559/1118), more commonly in frail patients (283/529, 53.5%) than non-frail patients (276/589, 46.9%), P = 0.027. Frailty was positively associated with timely GOC independent of age and gender (odds ratio = 1.28; 95% confidence interval = 1.01-163; P = 0.041). In univariable analyses, timely GOC was associated with greater in-hospital mortality, RRC, and hospital LOS in both frail and non-frail patients (all P < 0.05) and greater 28-day readmissions only among frail patients (P = 0.028). Multivariable regression demonstrated that timely GOC was associated only with in-hospital mortality in both frail and non-frail patients, independent of age and gender. CONCLUSION: Older frail hospitalised patients were more likely to have timely GOC than older non-frail patients. Timely GOC in such patients may avoid burdensome treatments.

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.

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis.

Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support. Objective: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality. Design, Setting, and Participants: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios. Exposures: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients). Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events. Results: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo. Conclusions and Relevance: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Predictors of ICU admission and long-term outcomes in overdose presentations to Emergency Department.

OBJECTIVE: To describe the characteristics of patients presenting to an Emergency Department (ED) following overdoses; to identify risk factors for intensive care unit (ICU) admission among these patients; and to identify the rate of mortality and repeat overdose presentations over four years. METHODS: Adult patients presenting to ED following drug overdose during 2014 were included. Data were collected from medical notes and hospital databases. RESULTS: During the study period, 654 patients presented to ED 800 times following overdose. Seventy-eight (9.8%) resulted in ICU admission, and 59 (7.4%) required intubation; 57.2% had no history of overdose presentations, and 72.9% involved patients with known psychiatric illness. Overdose of atypical antipsychotics (AAP), age and history of prior overdose independently predicted ICU admission. A third of patients (n = 196, 30%) had subsequent presentations to ED following overdose, in the four years from their index presentation, with an all-cause four-year mortality of 3.4% (n = 22). CONCLUSION: A history of overdose, use of AAP and older age were risk factors for ICU admission following ED presentations. Over a third of patients had repeat overdose presentation in the four-year follow-up with a mortality of 3.4%.

Prediction of ICU Delirium: Validation of Current Delirium Predictive Models in Routine Clinical Practice.

OBJECTIVES: To investigate the ability of available delirium risk assessment tools to identify patients at risk of delirium in an Australian tertiary ICU. DESIGN: Prospective observational study. SETTING: An Australian tertiary ICU. PATIENTS: All patients admitted to the study ICU between May 8, 2017, and December 31, 2017, were assessed bid for delirium throughout their ICU stay using the Confusion Assessment Method for ICU. Patients were included in this study if they remained in ICU for over 24 hours and were excluded if they were delirious on ICU admission, or if they were unable to be assessed using the Confusion Assessment Method for ICU during their ICU stay. Delirium risk was calculated for each patient using the prediction of delirium in ICU patients, early prediction of delirium in ICU patients, and Lanzhou models. Data required for delirium predictor models were obtained retrospectively from patients medical records. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 803 ICU admissions during the study period, of which 455 met inclusion criteria. 35.2% (n = 160) were Confusion Assessment Method for ICU positive during their ICU admission. Delirious patients had significantly higher Acute Physiology and Chronic Health Evaluation III scores (median, 72 vs 54; p < 0.001), longer ICU (median, 4.8 vs 1.8 d; p < 0.001) and hospital stay (16.0 vs 8.16 d; p < 0.001), greater requirement of invasive mechanical ventilation (70% vs 21.4%; p < 0.001), and increased ICU mortality (6.3% vs 2.4%; p = 0.037). All models included in this study displayed moderate to good discriminative ability. Area under the receiver operating curve for the prediction of delirium in ICU patients was 0.79 (95% CI, 0.75-0.83); recalibrated prediction of delirium in ICU patients was 0.79 (95% CI, 0.75-0.83); early prediction of delirium in ICU patients was 0.72 (95% CI, 0.67-0.77); and the Lanzhou model was 0.77 (95% CI, 0.72-0.81). CONCLUSIONS: The predictive models evaluated in this study demonstrated moderate to good discriminative ability to predict ICU patients' risk of developing delirium. Models calculated at 24-hours post-ICU admission appear to be more accurate but may have limited utility in practice.

Predictors of respiratory failure in patients with Guillain-Barré syndrome: a systematic review and meta-analysis.

OBJECTIVE: To systematically review the literature regarding the ability of clinical features to predict respiratory failure in patients with Guillain-Barré syndrome (GBS). DATA SOURCES: We searched the PubMed and Ovid MEDLINE databases with the search terms "guillain barre syndrome" OR "acute inflammatory demyelinating polyneuropathy" OR "acute motor axonal neuropathy" OR "acute motor sensory axonal neuropathy" AND "respiratory failure" OR "mechanical ventilation". We excluded articles that did not report the results of original research (eg, review articles, letters), were case reports or series (ten or fewer patients), were not available in English, reported research in paediatric populations (16 years of age or younger), or were interventional studies. Article quality was assessed with the Newcastle-Ottawa quality assessment scale. DATA SYNTHESIS: Thirty-four relevant studies were identified. Short time from symptom onset to hospital admission (less than 7 days), bulbar (odds ratio [OR], 9.0; 95% CI, 3.94-20.6; P < 0.001) or neck weakness (OR, 6.36; 95% CI, 2.32-17.5; P < 0.001), and severe muscle weakness at hospital admission were associated with increased risk of intubation. Facial weakness (OR, 3.74; 95% CI, 2.05-6.81; P < 0.001) and autonomic instability (OR, 6.40; 95% CI, 2.83-14.5; P < 0.001) were significantly more frequent in patients requiring intubation in our meta-analyses; however, the differences were not statistically significant in individual multivariable analysis studies. Four predictive models have been developed to assess the risk of respiratory failure for patients with GBS, each with good to excellent discriminative power (area under the receiver operating characteristic curve, 0.79-0.96). CONCLUSIONS AND RELEVANCE: Early identification of GBS patients at risk of respiratory failure could reduce the rates of adverse outcomes associated with delayed intubation. Algorithms that predict a patient's risk of subsequent respiratory failure at hospital admission appear more reliable than individual clinical variables.

Impact of the introduction of an endotracheal tube attachment device on the incidence and severity of oral pressure injuries in the intensive care unit: a retrospective observational study.

BACKGROUND: Endotracheal tube (ETT) fasteners such as the AnchorFast™ claim to assist with the prevention of oral pressure injuries in intubated patients, however evidence to support their clinical efficacy is limited. This retrospective observational study aimed to investigate the impact of the introduction of the AnchorFast™ device on the incidence of oral pressure injuries in mechanically ventilated patients. METHODS: Data was collected from patient case notes and clinical incident reports for October 2010 to June 2013 (pre-AnchorFast) and July 2013 to March 2016 (post-AnchorFast). Incidence and location of oral pressure injuries associated with securing device, and compliance with institutional policies related to reducing oral pressure injuries were recorded. RESULTS: Incidence of oral pressure injuries increased from 1.53/100 intubated patients in the pre-AnchorFast period to 3.73/100 intubated patients in the post-AnchorFast period (IRR = 2.43, 95%CI = 1.35-4.38; p = 0.003). Across both study periods, patients with an ETT secured using AnchorFast™ had significantly increased risk of oral pressure injuries (IRR = 2.03, 95%CI = 1.17-3.51; p = 0.02). There was also a significant difference in location of pressure injuries sustained with ETTs secured using cloth tapes (53.6% in corner of the mouth) vs. AnchorFast™ (75% on the lips) (p = 0.008). Among patients with oral pressure injuries, compliance with institutional policies relating to the prevention of pressure injuries was significantly greater after the introduction of the AnchorFast™ (9.1% vs 64.5%, p = 0.004). CONCLUSIONS: The incidence of oral pressure injuries increased significantly following the introduction of the AnchorFast™ device. Further research is required to establish the reasons for this observed increase to and identify ways to reduce the risk of pressure injuries with ETT securement devices.

Relationship between diurnal patterns in Rapid Response Call activation and patient outcome.

BACKGROUND: The Rapid Response Call (RRC) is a system designed to escalate care to a specialised team in response to the detection of patient deterioration. To date, there have been few studies which have explored the relationship between time of day of RRC and patient outcome. OBJECTIVE: To examine the relationship between the time of RRC activations and patient outcome. METHOD: All adult inpatients with a RRC in non-critical care wards of a metropolitan Australian hospital in 2012 were retrospectively reviewed. RRCs occurring between 18:00-07:59 were defined as 'out of hours'. RESULTS: There were 892 RRC during the study period. RRCs out of hours were associated with a higher rate of ICU admissions immediately after the RRC (19.4% vs. 12.3%, p<0.001). Patients experiencing an out-of-hours RRC were more likely to have an in-hospital cardiopulmonary arrest (OR=1.7, p<0.04). In-hospital mortality rate was significantly higher for patients with out-of-hours RRCs (35.5% vs. 25.0%, p=0.014). After adjusting for confounders out-of-hours RRC were independently associated with increased need for ICU admissions and in-hospital mortality. CONCLUSION: The diurnal timing of RRCs appears to have significant implications for patient mortality and morbidity, patient outcomes are worse if RRC occurs out of hours. This finding has implications for staffing and resource allocation.

Direct and indirect mechanisms for wild-type SOD1 to enhance the toxicity of mutant SOD1 in bigenic transgenic mice.

Co-expression of wild-type human superoxide dismutase 1 (WT-hSOD1) with ALS mutant hSOD1 accelerates disease onset relative to mice expressing only mutant protein. Here, we analyzed the effect of co-expressed WT-hSOD1 in two established mutant mouse models (L126Z and G37R), and a new model that expresses the first 102 amino acids of SOD1 with mutations at histidines 46, 48 and 63 to eliminate Cu binding (Cu-V103Z). A subset of Cu-V103Z mice developed paralysis between 500 and 730 days. Similar to mice expressing L126Z-SOD1, the spinal cords of this new model showed SOD1 immunoreactive fibrillar inclusions. Co-expression of WT-hSOD1 with Cu-V103Z SOD1 moderately accelerated the age to paralysis, similar in magnitude to WT/L126Z mice. In either combination of these bigenic mice, the severity of fibrillar inclusion pathology was diminished and unreactive to antibodies specific for the C terminus of WT protein. Co-expression of WT-hSOD1 fused to yellow fluorescent protein (WT-hSOD1:YFP) with G37R-hSOD1 produced earlier disease, and spinal cords of paralyzed bigenic mice showed YFP fluorescent inclusion-like structures. In bigenic L126Z/WT-hSOD1:YFP mice, disease was not accelerated and WT-hSOD1:YFP remained diffusely distributed. A combination of split luciferase complementation assays and affinity capture-binding assays demonstrated that soluble G37R-hSOD1 efficiently and tightly bound soluble WT-hSOD1, whereas soluble forms of the Cu-V103Z and L126Z variants demonstrated low affinity. These data indicate that WT-hSOD1 may indirectly augment the toxicity of mutant protein by competing for protective factors, but disease onset seems to be most accelerated when WT-hSOD1 interacts with mutant SOD1 and becomes misfolded.

A Novel Computerized Test for Detecting and Monitoring Visual Attentional Deficits and Delirium in the ICU.

OBJECTIVES: Delirium in the ICU is associated with poor outcomes but is under-detected. Here we evaluated performance of a novel, graded test for objectively detecting inattention in delirium, implemented on a custom-built computerized device (Edinburgh Delirium Test Box-ICU). DESIGN: A pilot study was conducted, followed by a prospective case-control study. SETTING: Royal Infirmary of Edinburgh General ICU. PATIENTS: A pilot study was conducted in an opportunistic sample of 20 patients. This was followed by a validation study in 30 selected patients with and without delirium (median age, 63 yr; range, 23-84) who were assessed with the Edinburgh Delirium Test Box-ICU on up to 5 separate days. Presence of delirium was assessed using the Confusion Assessment Method for the ICU. MEASUREMENTS AND MAIN RESULTS: The Edinburgh Delirium Test Box-ICU involves a behavioral assessment and a computerized test of attention, requiring patients to count slowly presented lights. Thirty patients were assessed a total of 79 times (n = 31, 23, 15, 8, and 2 for subsequent assessments; 38% delirious). Edinburgh Delirium Test Box-ICU scores (range, 0-11) were lower for patients with delirium than those without at the first (median, 0 vs 9.5), second (median, 3.5 vs 9), and third (median, 0 vs 10.5) assessments (all p < 0.001). An Edinburgh Delirium Test Box-ICU score less than or equal to 5 was 100% sensitive and 92% specific to delirium across assessments. Longitudinally, participants' Edinburgh Delirium Test Box-ICU performance was associated with delirium status. CONCLUSIONS: These findings suggest that the Edinburgh Delirium Test Box-ICU has diagnostic utility in detecting ICU delirium in patients with Richmond Agitation and Sedation Scale Score greater than -3. The Edinburgh Delirium Test Box-ICU has potential additional value in longitudinally tracking attentional deficits because it provides a range of scores and is sensitive to change.

Characteristics and outcomes of patients with drug overdose requiring admission to Intensive Care Unit.

OBJECTIVE: Approximately 20% of patients admitted to hospital with drug overdose will require intensive care unit (ICU) admission. An understanding of the characteristics of these patients may assist with their management and identify those patients at risk of multiple hospital presentations due to drug overdose. Our aim was to examine the characteristics of patients admitted to ICU following drug overdoses and identify the predictors of multiple hospital presentations due to drug overdose. METHODS: Patients admitted to a metropolitan ICU over a three-year period following drug overdoses were identified using ICU patient databases, and their medical records. RESULTS: There were 254 admissions due to drug overdoses. The majority of overdoses were intentional (82.7%) and included multiple agents (68.1%). Two-thirds of patients had psychiatric diagnosis, and 54% had documented history of substance use disorders. In-hospital mortality was 2.8%. Over half of patients admitted had documented history of prior hospital presentation due to overdoses. Personality disorder and schizophrenia were independent predictors of multiple hospital presentations due to overdoses. CONCLUSION: Personality disorders or schizophrenia were independent predictors of patients with multiple overdose presentations. Preventative strategies focusing on these patients may reduce the incidence of their hospital presentations and ICU admissions.

Factors influencing quality of sleep among non-mechanically ventilated patients in the Intensive Care Unit.

AIM: To investigate the self-reported quality of sleep of non-mechanically ventilated patients admitted to an ICU, and to identify barriers to sleep in this setting. METHOD: Patients admitted to the ICU of Frankston Hospital over a two month period who had spent at least one night in the ICU, and had not received mechanical ventilation were surveyed as they were discharged from the ICU. This survey required patients to rate the quality of their sleep in the ICU and at home immediately prior to hospitalisation on a 10cm visual analogue scale; and to identify perceived barriers to sleep in the ICU and at home prior to hospitalisation. RESULTS: 56 respondents were surveyed during the study period. Median age was 74 years (range=18-92 years); median ICU length of stay was 1 day (range=1-7 days). Overall, respondents rated their quality of sleep in ICU (median=4.9/10) as significantly worse than at home immediately prior to ICU admission (median=7.15/10; Z=-3.02, p<0.002); however 44% of respondents rated their quality of sleep in ICU as better, or no worse, than at home immediately prior to hospitalisation. Sub-group analysis revealed that among patients with reduced quality of sleep (<5/10) prior to hospitalisation, 71.4% rated their quality of sleep in ICU as better, or no worse, than at home prior to hospitalisation, with no significant difference between sleep quality ratings in ICU and at home (p=0.341). Respondents identified the following as barriers to sleep in the ICU: noise levels overnight (53.6%); discomfort (33.9%); pain (32.1%); being awoken for procedures (32%); being attached to medical devices (28.6%); stress/anxiety (26.8%); and light levels (23.2%). CONCLUSION: Pre-hospitalisation sleep quality appears to be an important influence on sleep in ICU. Many barriers to sleep in the ICU identified by respondents are potentially modifiable.

Inter-rater reliability of the Reaper Oral Mucosa Pressure Injury Scale (ROMPIS): A novel scale for the assessment of the severity of pressure injuries to the mouth and oral mucosa.

BACKGROUND: Patients who are intubated in the ICU are at risk of developing pressure injuries to the mouth and lips from endotracheal tubes. Clear documentation is important for pressure wound care; however, no validated instruments currently exist for the staging of pressure injuries to the oral mucosa. Instruments designed for the assessment of pressure injuries to other bodily regions are anatomically unsuited to the lips and mouth. OBJECTIVES: This study aimed to develop and then assess the reliability of a novel scale for the assessment of pressure injuries to the mouth and oral mucosa. METHODS: The Reaper Oral Mucosa Pressure Injury Scale (ROMPIS) was developed in consultation with ICU nurses, clinical nurse educators, Intensivists, and experts in pressure wound management. ICU nurses and portfolio-holders in pressure wound care from Peninsula Health (Victoria, Australia) were invited to use the ROMPIS to stage 19 de-identified clinical photographs of oral pressure injuries via secure online survey. Inter-rater reliability (IRR) was calculated using Krippendorff's alpha (α). RESULTS: Among ICU nurses (n=52), IRR of the ROMPIS was α=0.307; improving to α=0.463 when considering only responses where injuries were deemed to be stageable using the ROMPIS (i.e. excluding responses where respondents considered an injury to be unstageable). Among a cohort of experts in pressure wound care (n=8), IRR was α=0.306; or α=0.443 excluding responses indicating that wounds were unstageable. CONCLUSIONS: An instrument for the assessment and monitoring of pressure injuries to the mouth and lips has practical implications for patient care. This preliminary study indicates that the ROMPIS instrument has potential to be used clinically for this purpose; however, the performance of this scale may be somewhat reliant on the confidence or experience of the ICU nurse utilising it. Further validation is required.

The Outcome and Predictors of Mortality in Patients Therapeutically Cooled Postcardiac Arrest.

PURPOSE: To review the outcomes of patients postcardiac arrest admitted to a metropolitan intensive care unit (ICU) where therapeutic hypothermia is practiced. MATERIALS AND METHODS: Patients admitted from 2004 to 2012 were reviewed. The management protocol included cooling to 33°C for 24 hours. The primary outcome assessed was hospital mortality. Secondary outcome measures included mortality in patients admitted to ICU after in-hospital cardiac arrest (IHCA) when compared to those with out-of-hospital cardiac arrest (OHCA) and to review initial cardiac rhythm as an indicator of mortality. RESULTS: A total of 330 patients were included. The overall hospital mortality was 58.1%. Hospital mortality was significantly higher in patients who had OHCA when compared to IHCA (62.5% vs 51%; P = .04). Patients who had asystole and pulseless electrical activity (PEA) had a higher mortality when compared to ventricular tachycardia/ventricular fibrillation (VT/VF) arrest (81.7% vs 67.8% vs 41.9%, respectively; P < .01). CONCLUSION: Patients admitted to ICU postcardiac arrest after therapeutic cooling have a high mortality. An initial rhythm of VT/VF confers a mortality benefit when compared to asystole and PEA.

Automatic Population of the Case Report Forms for an International Multifactorial Adaptive Platform Trial Amid the COVID-19 Pandemic.

OBJECTIVES: To automatically populate the case report forms (CRFs) for an international, pragmatic, multifactorial, response-adaptive, Bayesian COVID-19 platform trial. METHODS: The locations of focus included 27 hospitals and 2 large electronic health record (EHR) instances (1 Cerner Millennium and 1 Epic) that are part of the same health system in the United States. This paper describes our efforts to use EHR data to automatically populate four of the trial's forms: baseline, daily, discharge, and response-adaptive randomization. RESULTS: Between April 2020 and May 2022, 417 patients from the UPMC health system were enrolled in the trial. A MySQL-based extract, transform, and load pipeline automatically populated 499 of 526 CRF variables. The populated forms were statistically and manually reviewed and then reported to the trial's international data coordinating center. CONCLUSIONS: We accomplished automatic population of CRFs in a large platform trial and made recommendations for improving this process for future trials.

Transgenic mice expressing caspase-6-derived N-terminal fragments of mutant huntingtin develop neurologic abnormalities with predominant cytoplasmic inclusion pathology composed largely of a smaller proteolytic derivative.

Recent studies have implicated an N-terminal caspase-6 cleavage product of mutant huntingtin (htt) as an important mediator of toxicity in Huntington's disease (HD). To directly assess the consequences of such fragments on neurologic function, we produced transgenic mice that express a caspase-6 length N-terminal fragment of mutant htt (N586) with both normal (23Q) and disease (82Q) length glutamine repeats. In contrast to mice expressing N586-23Q, mice expressing N586-82Q accumulate large cytoplasmic inclusion bodies that can be visualized with antibodies to epitopes throughout the N586 protein. However, biochemical analyses of aggregated mutant huntingtin in these mice demonstrated that the inclusion bodies are composed largely of a much smaller htt fragment (terminating before residue 115), with lesser amounts of full-length N586-82Q fragments. Mice expressing the N586-82Q fragment show symptoms typical of previously generated mice expressing mutant huntingtin fragments, including failure to maintain weight, small brain weight and reductions in specific mRNAs in the striatum. Uniquely, these N586-82Q mice develop a progressive movement disorder that includes dramatic deficits in motor performance on the rotarod and ataxia. Our findings suggest that caspase-6-derived fragments of mutant htt are capable of inducing novel HD-related phenotypes, but these fragments are not terminal cleavage products as they are subject to further proteolysis. In this scenario, mutant htt fragments derived from caspase 6, or possibly other proteases, could mediate HD pathogenesis via a 'hit and run' type of mechanism in which caspase-6, or other larger N-terminal fragments, mediate a neurotoxic process before being cleaved to a smaller fragment that accumulates pathologically.

ICU nurse preceptors' perceptions of benefits, rewards, supports and commitment to the preceptor role: A mixed-methods study.

This paper explores Intensive Care nurses' perceptions of benefits, rewards, supports and their commitment to the role of preceptor. A questionnaire, consisting of Likert-scales and open-ended questions was used to collect data during October 2018. Preceptors were committed to their role. Correlations were found between preceptors' perceptions of benefits or rewards and commitment to the role (p = 0.003, r2 = 0.39) and perceptions of support and commitment to the role (p = .001, r2 = 0.46). Altruistic benefits were perceived to be of the greatest importance. Participants who recognised the importance of preceptorship for the organisation were more likely to be committed to the role. Eighty-three percent of respondents reported a lack of consistency in allocation to work with their preceptee. Qualitative results elucidated themes of helping, personal professional development, the opportunity to teach, and organisational improvement. Supports as barriers and enablers to successful preceptorship were discussed in terms of peer and leadership support, role preparation, the logistics of the environment, role conflict, and consistency of allocation to work in a preceptorship dyad. Commitment to the preceptor role may be increased by highlighting organisational benefits of preceptorship, increasing consistency of contact between preceptorship dyads, and increasing access to supports and preparation.