Liberal or Restrictive Transfusion Strategy in Patients with Traumatic Brain Injury.

BACKGROUND: The effect of a liberal transfusion strategy as compared with a restrictive strategy on outcomes in critically ill patients with traumatic brain injury is unclear. METHODS: We randomly assigned adults with moderate or severe traumatic brain injury and anemia to receive transfusion of red cells according to a liberal strategy (transfusions initiated at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (transfusions initiated at ≤7 g per deciliter). The primary outcome was an unfavorable outcome as assessed by the score on the Glasgow Outcome Scale-Extended at 6 months, which we categorized with the use of a sliding dichotomy that was based on the prognosis of each patient at baseline. Secondary outcomes included mortality, functional independence, quality of life, and depression at 6 months. RESULTS: A total of 742 patients underwent randomization, with 371 assigned to each group. The analysis of the primary outcome included 722 patients. The median hemoglobin level in the intensive care unit was 10.8 g per deciliter in the group assigned to the liberal strategy and 8.8 g per deciliter in the group assigned to the restrictive strategy. An unfavorable outcome occurred in 249 of 364 patients (68.4%) in the liberal-strategy group and in 263 of 358 (73.5%) in the restrictive-strategy group (adjusted absolute difference, restrictive strategy vs. liberal strategy, 5.4 percentage points; 95% confidence interval, -2.9 to 13.7). Among survivors, a liberal strategy was associated with higher scores on some but not all the scales assessing functional independence and quality of life. No association was observed between the transfusion strategy and mortality or depression. Venous thromboembolic events occurred in 8.4% of the patients in each group, and acute respiratory distress syndrome occurred in 3.3% and 0.8% of patients in the liberal-strategy and restrictive-strategy groups, respectively. CONCLUSIONS: In critically ill patients with traumatic brain injury and anemia, a liberal transfusion strategy did not reduce the risk of an unfavorable neurologic outcome at 6 months. (Funded by the Canadian Institutes of Health Research and others; HEMOTION ClinicalTrials.gov number, NCT03260478.).

Haemoglobin transfusion threshold in traumatic brain injury optimisation (HEMOTION): a multicentre, randomised, clinical trial protocol.

INTRODUCTION: Traumatic brain injury (TBI) is the leading cause of mortality and long-term disability in young adults. Despite the high prevalence of anaemia and red blood cell transfusion in patients with TBI, the optimal haemoglobin (Hb) transfusion threshold is unknown. We undertook a randomised trial to evaluate whether a liberal transfusion strategy improves clinical outcomes compared with a restrictive strategy. METHODS AND ANALYSIS: HEMOglobin Transfusion Threshold in Traumatic Brain Injury OptimizatiON is an international pragmatic randomised open label blinded-endpoint clinical trial. We will include 742 adult patients admitted to an intensive care unit (ICU) with an acute moderate or severe blunt TBI (Glasgow Coma Scale ≤12) and a Hb level ≤100 g/L. Patients are randomly allocated using a 1:1 ratio, stratified by site, to a liberal (triggered by Hb ≤100 g/L) or a restrictive (triggered by Hb ≤70 g/L) transfusion strategy applied from the time of randomisation to the decision to withdraw life-sustaining therapies, ICU discharge or death. Primary and secondary outcomes are assessed centrally by trained research personnel blinded to the intervention. The primary outcome is the Glasgow Outcome Scale extended at 6 months. Secondary outcomes include overall functional independence measure, overall quality of life (EuroQoL 5-Dimension 5-Level; EQ-5D-5L), TBI-specific quality of life (Quality of Life after Brain Injury; QOLIBRI), depression (Patient Health Questionnaire; PHQ-9) and mortality. ETHICS AND DISSEMINATION: This trial is approved by the CHU de Québec-Université Laval research ethics board (MP-20-2018-3706) and ethic boards at all participating sites. Our results will be published and shared with relevant organisations and healthcare professionals. TRIAL REGISTRATION NUMBER: NCT03260478.

Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit.

BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

Mortality and Pulmonary Embolism in Acute Respiratory Distress Syndrome From COVID-19 vs. Non-COVID-19.

Purpose: There may be a difference in respiratory mechanics, inflammatory markers, and pulmonary emboli in COVID-19 associated ARDS vs. ARDS from other etiologies. Our purpose was to determine differences in respiratory mechanics, inflammatory markers, and incidence of pulmonary embolism in patients with and without COVID-19 associated ARDS admitted in the same period and treated with a similar ventilation strategy. Methods: A cohort study of COVID-19 associated ARDS and non COVID-19 patients in a Saudi Arabian center between June 1 and 15, 2020. We measured respiratory mechanics (ventilatory ratio (VR), recruitability index (RI), markers of inflammation, and computed tomography pulmonary angiograms. Results: Forty-two patients with COVID-19 and 43 non-COVID patients with ARDS comprised the cohort. The incidence of "recruitable" patients using the recruitment/inflation ratio was slightly lower in COVID-19 patients (62 vs. 86%; p = 0.01). Fifteen COVID-19 ARDS patients (35.7%) developed a pulmonary embolism as compared to 4 (9.3%) in other ARDS patients (p = 0.003). In COVID-19 patients, a D-Dimer ≥ 5.0 mcg/ml had a 73% (95% CI 45-92%) sensitivity and 89% (95% CI 71-98%) specificity for predicting pulmonary embolism. Crude 60-day mortality was higher in COVID-19 patients (35 vs. 15%; p = 0.039) but three multivariate analysis showed that independent predictors of 60-day mortality included the ventilatory ratio (OR 3.67, 95% CI 1.61-8.35), PaO2/FIO2 ratio (OR 0.93; 95% CI 0.87-0.99), IL-6 (OR 1.02, 95% CI 1.00-1.03), and D-dimer (OR 7.26, 95% CI 1.11-47.30) but not COVID-19 infection. Conclusion: COVID-19 patients were slightly less recruitable and had a higher incidence of pulmonary embolism than those with ARDS from other etiologies. A high D-dimer was predictive of pulmonary embolism in COVID-19 patients. COVID-19 infection was not an independent predictor of 60-day mortality in the presence of ARDS.

Optic Nerve Sheath Diameter Ultrasound for Raised Intracranial Pressure: A Literature Review and Meta-analysis of its Diagnostic Accuracy.

Optic nerve sheath diameter (ONSD) ultrasound is becoming increasingly more popular for estimating raised intracranial pressure (ICP). We performed a systematic review and analysis of the diagnostic accuracy of ONSD when compared to the standard invasive ICP measurement. METHOD: We performed a systematic search of PUBMED and EMBASE for studies including adult patients with suspected elevated ICP and comparing sonographic ONSD measurement to a standard invasive method. Quality of studies was assessed using the QUADAS-2 tool by two independent authors. We used a bivariate model of random effects to summarize pooled sensitivity, specificity, and diagnostic odds ratio (DOR). Heterogeneity was investigated by meta-regression and sub-group analyses. RESULTS: We included 18 prospective studies (16 studies including 619 patients for primary outcome). Only one study was of low quality, and there was no apparent publication bias. Pooled sensitivity was 0.9 [95% confidence intervals (CI): 0.85-0.94], specificity was 0.85 (95% CI: 0.8-0.89), and DOR was 46.7 (95% CI: 26.2-83.2) with partial evidence of heterogeneity. The Area-Under-the-Curve of the summary Receiver-Operator-Curve was 0.93 (95% CI: 0.91-0.95, P < .05). No covariates were significant in the meta-regression. Subgroup analysis of severe traumatic brain injury and parenchymal ICP found no heterogeneity. ICP and ONSD had a correlation coefficient of 0.7 (95% CI: 0.63-0.76, P < .05). CONCLUSION: ONSD is a useful adjunct in ICP evaluation but is currently not a replacement for invasive methods where they are feasible.

Galectin-9, a Player in Cytokine Release Syndrome and a Surrogate Diagnostic Biomarker in SARS-CoV-2 Infection.

The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. In this study, we observed massive elevation of plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls (HCs). By using the receiver operating characteristic (ROC) curve, we found that a baseline of 2,042 pg/ml plasma Gal-9 can differentiate SARS-CoV-2-infected from noninfected individuals with high specificity/sensitivity (95%). Analysis of 30 cytokines and chemokines detected a positive correlation of the plasma Gal-9 with C-reactive protein (CRP) and proinflammatory cytokines/chemokines such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IP-10, MIP-1α, and MCP-1 but an inverse correlation with transforming growth factor ß (TGF-ß) in COVID-19 patients. In agreement, we found enhanced production of IL-6 and TNF-α by monocytes and NK cells of COVID-19 patients once treated with the recombinant human Gal-9 in vitro Also, we observed that although the cell-membrane expression of Gal-9 on monocytes does not change in COVID-19 patients, those with higher Gal-9 expression exhibit an activated phenotype. Furthermore, we noted significant downregulation of surface Gal-9 in neutrophils from COVID-19 patients compared to HCs. Our further investigations indicated that immune activation following SARS-CoV-2 infection results in Gal-9 shedding from neutrophils. The strong correlation of Gal-9 with proinflammatory mediators suggests that inhibition of Gal-9 may severe as a therapeutic approach in COVID-19 infection. Besides, the plasma Gal-9 measurement may be used as a surrogate diagnostic biomarker in COVID-19 patients.IMPORTANCE The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. We observed substantial elevation of the plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls. Gal-9 is an abundant protein in many immune and nonimmune cells. We found that Gal-9 detection assay can differentiate SARS-CoV-2-infected from noninfected individuals with a specificity/sensitivity of 95%. Importantly, we found a positive correlation of the plasma Gal-9 with a wide range of proinflammatory biomarkers in COVID-19 patients. In agreement, we found enhanced expression and production of such proinflammatory molecules by immune cells of COVID-19 patients once treated with Gal-9 in vitro Our results propose Gal-9 as an important contributing factor in cytokine release syndrome; therefore, Gal-9 inhibition may serve as a beneficial therapeutic approach by suppressing the hyperimmune activation in COVID-19 patients.

Therapeutic plasma exchange in patients with life-threatening COVID-19: a randomised controlled clinical trial.

Assessment of efficacy of therapeutic plasma exchange (TPE) following life-threatening COVID-19. This was an open-label, randomised clinical trial of ICU patients with life-threatening COVID-19 (positive RT-qPCR plus ARDS, sepsis, organ failure, hyperinflammation). Study was terminated after 87/120 patients enrolled. Standard treatment plus TPE (n = 43) versus standard treatment (n = 44), and stratified by PaO2/FiO2 ratio (>150 vs. ≤150), were compared. Primary outcomes were 35-day mortality and TPE safety. Secondary outcomes were association between TPE and mortality, improvement in SOFA score, change in inflammatory biomarkers, days on mechanical ventilation (MV), and ICU length of stay (LOS). Eighty-seven patients [median age 49 (IQR 34-63) years; 82.8% male] were randomised (44 standard care; 43 standard care plus TPE). Days on MV (P = 0.007) and ICU LOS (P = 0.02) were lower in the TPE group. 35-Day mortality was non-significantly lower in the TPE group (20.9% vs. 34.1%; Kaplan-Meier, P = 0.582). TPE was associated with increased lymphocytes and ADAMTS-13 activity and decreased serum lactate, lactate dehydrogenase, ferritin, d-dimers and interleukin-6. Multivariable regression analysis provided several predictors of 35-day mortality: PaO2/FiO2 ratio (HR, 0.98, 95% CI 0.96-1.00; P = 0.02]; ADAMTS-13 activity (HR, 0.89, 95% CI 0.82-0.98; P = 0.01); pulmonary embolism (HR, 3.57, 95% CI 1.43-8.92; P = 0.007). Post-hoc analysis revealed a significant reduction in SOFA score for TPE patients (P < 0.05). In critically-ill COVID-19 patients, addition of TPE to standard ICU therapy was associated with faster clinical recovery and no increased 35-day mortality.

Resumption of Cardiac Activity after Withdrawal of Life-Sustaining Measures.

BACKGROUND: The minimum duration of pulselessness required before organ donation after circulatory determination of death has not been well studied. METHODS: We conducted a prospective observational study of the incidence and timing of resumption of cardiac electrical and pulsatile activity in adults who died after planned withdrawal of life-sustaining measures in 20 intensive care units in three countries. Patients were intended to be monitored for 30 minutes after determination of death. Clinicians at the bedside reported resumption of cardiac activity prospectively. Continuous blood-pressure and electrocardiographic (ECG) waveforms were recorded and reviewed retrospectively to confirm bedside observations and to determine whether there were additional instances of resumption of cardiac activity. RESULTS: A total of 1999 patients were screened, and 631 were included in the study. Clinically reported resumption of cardiac activity, respiratory movement, or both that was confirmed by waveform analysis occurred in 5 patients (1%). Retrospective analysis of ECG and blood-pressure waveforms from 480 patients identified 67 instances (14%) with resumption of cardiac activity after a period of pulselessness, including the 5 reported by bedside clinicians. The longest duration after pulselessness before resumption of cardiac activity was 4 minutes 20 seconds. The last QRS complex coincided with the last arterial pulse in 19% of the patients. CONCLUSIONS: After withdrawal of life-sustaining measures, transient resumption of at least one cycle of cardiac activity after pulselessness occurred in 14% of patients according to retrospective analysis of waveforms; only 1% of such resumptions were identified at the bedside. These events occurred within 4 minutes 20 seconds after a period of pulselessness. (Funded by the Canadian Institutes for Health Research and others.).

Residual Lung Injury in Patients Recovering From COVID-19 Critical Illness: A Prospective Longitudinal Point-of-Care Lung Ultrasound Study.

Scarce data exist regarding the natural history of lung lesions detected on ultrasound in those who survive severe COVID-19 pneumonia. OBJECTIVE: We performed a prospective analysis of point-of-care ultrasound (POCUS) findings in critically ill COVID-19 patients during and after hospitalization. METHODS: We enrolled 171 COVID-19 intensive care unit patients. POCUS of the lungs was performed with phased array (2-4 MHz), convex (2-6 MHz) and linear (10-15 MHz) transducers, scanning 12 lung areas. Chest computed tomography angiography was performed to exclude suspected pulmonary embolism. Survivors were clinically and sonographically evaluated during a 4 month period for evidence of residual lung injury. Chest computed tomography angiography and echocardiography were used to exclude pulmonary hypertension (PH) and chest high-resolution-computed-tomography to exclude interstitial lung disease (ILD) in symptomatic survivors. RESULTS: Cox regression analysis showed that lymphocytopenia (hazard ratio [HR]: 0.88, 95% confidence intervals [CI]: 0.68-0.96, p = .048), increased lactate (HR: 1.17, 95% CI: 0.94-1.46, p = 0.049), and D-dimers (HR: 1.21, 95% CI: 1.03-1.44, p = .03) were mortality predictors. Non-survivors had increased incidence of pulmonary abnormalities (B-lines, pleural line irregularities, and consolidations) compared to survivors (p < .05). During follow-up, POCUS with clinical and laboratory parameters integrated in the semi-quantitative Riyadh-Residual-Lung-Injury scale had sensitivity of 0.82 (95% CI: 0.76-0.89) and specificity of 0.91 (95% CI: 0.94-0.95) in predicting ILD. The prevalence of PH and ILD (non-specific-interstitial-pneumonia) was 7% and 11.8%, respectively. CONCLUSION: POCUS showed ability to monitor the evolution of severe COVID-19 pneumonia after hospital discharge, supporting its integration in clinical predictive models of residual lung injury.

Peripheral neuropathy in severe COVID-19 resolved with therapeutic plasma exchange.

Peripheral neuropathies including Guillain-Barré syndrome may be linked to life-threatening COVID-19. Plasma exchange is a safe rescue therapy in severe COVID-19 with associated neurological manifestations and thromboinflammation.

Therapeutic plasma exchange in adult critically ill patients with life-threatening SARS-CoV-2 disease: A pilot study.

PURPOSE: We investigated the effect of therapeutic plasma exchange (TPE) on life-threatening COVID-19; presenting as acute respiratory distress syndrome (ARDS) plus multi-system organ failure and cytokine release syndrome (CRS). MATERIALS AND METHODS: We prospectively enrolled ten consecutive adult intensive care unit (ICU) subjects [7 males; median age: 51 interquartile range (IQR): 45.1-55.9 years old] with life-threatening COVID-19 infection. All had ARDS [PaO2/FiO2 ratio: 110 (IQR): 95.5-135.5], septic shock, CRS and deteriorated within 24 h of ICU admission despite fluid resuscitation, antibiotics, hydroxychloroquine, ARDS-net and prone position mechanical ventilation. All received 5-7 TPE sessions (dosed as 1.0 to 1.5 plasma volumes). RESULTS: All of the following significantly normalized (p < 0.05) following the TPE completion, when compared to baseline: Sequential Organ Function Assessment score, PaO2/FiO2 ratio, levels of lymphocytes, total bilirubin, lactate dehydrogenase, ferritin, C-reactive protein and interleukin-6. No adverse effects from TPE were observed. Acute kidney injury and pulmonary embolism were observed in 10% and 20% of patients, respectively. The duration of mechanical ventilation was 9 (IQR: 7 to 12) days, the ICU length of stay was 15 (IQR: 13.2 to 19.6) days and the mortality on day-28 was 10%. CONCLUSION: TPE demonstrates a potential survival benefit and low risk in life-threatening COVID-19, albeit in a small pilot study.

Reverse takotsubo cardiomyopathy in fulminant COVID-19 associated with cytokine release syndrome and resolution following therapeutic plasma exchange: a case-report.

BACKGROUND: Fulminant (life-threatening) COVID-19 can be associated with acute respiratory failure (ARF), multi-system organ failure and cytokine release syndrome (CRS). We present a rare case of fulminant COVID-19 associated with reverse-takotsubo-cardiomyopathy (RTCC) that improved with therapeutic plasma exchange (TPE). CASE PRESENTATION: A 40 year old previous healthy male presented in the emergency room with 4 days of dry cough, chest pain, myalgias and fatigue. He progressed to ARF requiring high-flow-nasal-cannula (flow: 60 L/minute, fraction of inspired oxygen: 40%). Real-Time-Polymerase-Chain-Reaction (RT-PCR) assay confirmed COVID-19 and chest X-ray showed interstitial infiltrates. Biochemistry suggested CRS: increased C-reactive protein, lactate dehydrogenase, ferritin and interleukin-6. Renal function was normal but lactate levels were elevated. Electrocardiogram demonstrated non-specific changes and troponin-I levels were slightly elevated. Echocardiography revealed left ventricular (LV) basal and midventricular akinesia with apex sparing (LV ejection fraction: 30%) and depressed cardiac output (2.8 L/min) consistent with a rare variant of stress-related cardiomyopathy: RTCC. His ratio of partial arterial pressure of oxygen to fractional inspired concentration of oxygen was < 120. He was admitted to the intensive care unit (ICU) for mechanical ventilation and vasopressors, plus antivirals (lopinavir/ritonavir), and prophylactic anticoagulation. Infusion of milrinone failed to improve his cardiogenic shock (day-1). Thus, rescue TPE was performed using the Spectra Optia™ Apheresis System equipped with the Depuro D2000 Adsorption Cartridge (Terumo BCT Inc., USA) without protective antibodies. Over 5 days he received daily TPE (each lasting 4 hours). His lactate levels, oxygenation, and LV function normalized and he was weaned off vasopressors. His inflammation markers improved, and he was extubated on day-7. RT-PCR was negative on day-17. He was discharged to home isolation in good condition. CONCLUSION: Stress-cardiomyopathy may complicate the course of fulminant COVID-19 with associated CRS. If inotropic therapy fails, TPE without protective antibodies may help rescue the critically ill patient.

A pilot study of therapeutic plasma exchange for serious SARS CoV-2 disease (COVID-19): A structured summary of a randomized controlled trial study protocol.

OBJECTIVES: To evaluate the safety of therapeutic plasma exchange (TPE) in adult patients with serious/life-threatening COVID-19 requiring intensive care unit (ICU) admission, and associated 28-day mortality. Serious and life threatening COVID-19 are defined as per published literature (please, refer to the full protocol, Additional file 1). The rationale is that TPE can remove interleukins-3, 6, 8, 10, interferon-gamma and tumor necrosis factor-alpha. Thus, it may reduce the cytokine release syndrome associated with fulminant COVID-19 disease. TRIAL DESIGN: Pilot, interventional, open-label, randomized controlled multicenter trial. PARTICIPANTS: Inclusion criteria are: 1) age ≥ 18 years old; 2) intubation and intensive care unit (ICU) admission; 3) serious and/or life-threatening COVID-19 (please, refer to the full protocol, Additional file 1). SARS-CoV-2 infection is confirmed by Real-Time-Polymerase-Chain-Reaction (RT-PCR) assays using QuantiNova Probe RT-PCR kit (Qiagen) in a Light-Cycler 480 real-time PCR system (Roche, Basel, Switzerland). Exclusion criteria are: 1) previous allergic reaction to plasma exchange or its ingredients (i.e., sodium citrate), 2) two consecutive negative RT-PCR tests for SARS-CoV-2 at least 24 hours apart, 3) mild COVID-19 not requiring ICU admission and 4) terminally ill patients receiving palliative care. The primary site will be King Saud Medical City (KSMC), Riyadh, Kingdom of Saudi Arabia (KSA). Also, the study will run in ICUs (Ministry of Health Cluster 1; Riyadh) and other centers in KSA pending their institutional review board (IRB) approval. INTERVENTIONS AND COMPARATOR: The intervention group will receive TPE, plus empiric treatment for COVID-19. TPE is administered using the Spectra Optia TM Apheresis System equipped with the Depuro D2000 Adsorption Cartridge (Terumo BCT Inc., USA). The first dose is 1.5 plasma volumes, followed by one plasma volume on alternate days or daily for five to seven total treatments. Spectra Optia TM Apheresis System operates with acid-citrate dextrose anticoagulant (ACDA) as per Kidney Disease Improving Global Outcomes (KDIGO) 2019 guidelines. Plasma is replaced with albumin 5% or fresh frozen plasma in patients with coagulopathy (prothrombin time >37 seconds; international normalized ratio >3; activated partial thromboplastin time >100 or fibrinogen level <100 mg/d). TPE sessions are performed daily over four hours and laboratory markers measured daily. The comparators are controls not receiving TPE but usual empiric treatment for COVID-19 as per institutional, national and international recommendations. Both groups will receive standard ICU supportive care. MAIN OUTCOMES: Primary study end-point is 28-day mortality and safety of TPE in serious and/or life-threatening COVID-19. Safety will be evaluated by the documentation of any pertinent adverse and/or serious adverse effects related to TPE as per institutional, national and international (Food and Drug Administration) guidelines. Secondary outcomes are: i) improvement in Sequential Organ Function Assessment (SOFA) score ; ii) changes in inflammatory markers: serum C-reactive protein, lactate dehydrogenase, ferritin, d-dimers and interleukin-6; iii) days on mechanical ventilation and ICU length of stay. RANDOMIZATION: Eligible consented patients are randomized (1:1 allocation) after stratification by ICU center and two PaO2/FIO2 ratio categories (> 150 and ≤ 150). Randomization occurs in variable block sizes of four to eight patients. A web-based randomization service, randomize.net, is used to allocate patients to their respective strata prior to the intervention or control therapy. BLINDING (MASKING): Given the visibility of TPE machinery, the intervention will be unblinded; hence, no enrollment concealment will be expedited. The lack of allocation concealment will be mitigated by several measures (please, refer to the full protocol, Additional file 1). NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): This pilot randomized trial aims to recruit a convenience sample of patients with serious and/or life-threatening COVID-19. Therefore, at least 20 patients are to be randomized to each group per participating center. We are hoping to consent and randomize approximately 60 patients in each group over a 3 to 6 months period giving a total of 120 participants. TRIAL STATUS: The protocol version 1 was approved 29/04/2020. Recruitment is ongoing, and began on 01/05/2020. We estimate completion by 29/10/2020. TRIAL REGISTRATION: Registered at ISRCTN on 18/05/2020 (ISRCTN21363594; doi.10.1186/ ISRCTN21363594). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol.

Donation after circulatory determination of death in western Canada: a multicentre study of donor characteristics and critical care practices.

PURPOSE: Donation after circulatory determination of death (DCD) has been performed in Canada since 2006. Numerous aspects of donor management remain controversial. METHODS: We performed a multicentre cohort study involving potential DCD donors in western Canada (2008-2017), as well as recipients of their organs, to describe donor characteristics and critical care practices, and their relation to one-year recipient and graft survival. RESULTS: There were 257 patients in four provinces that underwent withdrawal of life-sustaining therapies (WLST) in anticipation of possible DCD. The proportion of patients that died within two hours of WLST ranged from 67% to 88% across provinces (P = 0.06), and was predicted by deeper coma (P = 0.01), loss of pupillary light or corneal reflexes (P = 0.02), and vasopressor use (P = 0.01). There were significant differences between provinces in time intervals from onset of hypotension to death (9-11 min; P = 0.02) and death to vascular cannulation (7-10 min; P < 0.001). There was inconsistency in pre-mortem heparin administration (82-96%; P = 0.03), including timing (before vs after WLST; P < 0.001) and dose (≥ 300 vs < 300 units·kg-1; P < 0.001). Donation after circulatory death provided organs for 321 kidney, 81 liver, and 50 lung transplants. One-year recipient and graft survival did not differ among provinces (range 85-90%, P = 0.45). Predictors of death or graft failure included older recipient age (odds ratio [OR] per year, 1.04; 95% confidence interval [CI],1.01 to 1.07) and male donor sex (OR, 3.35; 95% CI, 1.39 to 8.09), but not time intervals between WLST and cannulation or practices related to heparin use. CONCLUSION: There is significant variability in critical care DCD practices in western Canada, but this has not resulted in significant differences in recipient or graft survival. Further research is required to guide optimal management of potential DCD donors.

RéSUMé: OBJECTIF: Le don d'organes après décès cardiocirculatoire (DDC) est pratiqué au Canada depuis 2006. De nombreux aspects touchant à la prise en charge des donneurs demeurent controversés. MéTHODE: Nous avons réalisé une étude de cohorte multicentrique auprès de donneurs potentiels de DDC dans l'Ouest canadien (2008­2017), ainsi qu'auprès des récipiendaires de leurs organes, afin de décrire les caractéristiques des donneurs et les pratiques de soins intensifs, ainsi que la relation entre ces éléments et la survie à un an des récipiendaires et des organes greffés. RéSULTATS: Au total, 257 patients provenant de quatre provinces ont subi une interruption des traitements de survie en vue d'un possible DDC. La proportion de patients décédés dans les deux heures suivant l'interruption des traitements de survie allait de 67 % à 88 % dans toutes les provinces à l'étude (P = 0,06) et pouvait être prédite par une profondeur du coma plus importante (P = 0,01), la perte de la réaction pupillaire à la lumière ou des réflexes cornéens (P = 0,02), et l'utilisation de vasopresseurs (P = 0,01). Des différences significatives ont été observées entre les différentes provinces dans les intervalles de temps entre le début de l'hypotension et le décès (9­11 min; P = 0,02) et entre le décès et la canulation vasculaire (7­10 min; P < 0,001). Il y avait divergence dans l'administration d'héparine avant le décès (82-96 %; P = 0,03), notamment en ce qui concerne le moment d'administration (avant vs après l'interruption des traitements de survie; P < 0,001) et la posologie (≥ 300 vs < 300 unités·kg−1; P < 0,001). Le don après décès cardiocirculatoire a permis de procurer des organes pour 321 greffes rénales, 81 greffes hépatiques et 50 greffes pulmonaires. La survie à un an du récipiendaire et du greffon ne différait pas d'une province à l'autre (allant de 85 à 90 %, P = 0,45). Les prédicteurs de décès ou de la défaillance du greffon incluaient l'âge plus avancé du récipiendaire (rapport de cotes [RC] par année, 1,04; intervalle de confiance [IC] 95 %, 1,01 à 1,07) et un donneur de sexe masculin (RC, 3,35; IC 95 %, 1,39 à 8,09), mais pas les intervalles de temps entre l'interruption des traitements de survie et la canulation, ni les pratiques liées à l'utilisation d'héparine. CONCLUSION: Il existe une importante variabilité dans les pratiques de soins intensifs pour le DDC dans l'Ouest canadien, mais cette variabilité n'a pas résulté en différences significatives en matière de survie des récipiendaires ou des greffons. Des recherches supplémentaires sont nécessaires afin d'aiguiller la prise en charge optimale des donneurs potentiels de DDC.

Sepsis in Traumatic Brain Injury: Epidemiology and Outcomes.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability. Risk factors for in-hospital mortality include older age, co-morbidity, and TBI severity. Few studies have investigated the role of sepsis in individuals with TBI. METHODS: We studied adult patients with TBI admitted to intensive care over a 5-year period. Patient characteristics were identified by linking clinical and administrative databases. Charts of individuals with TBI and sepsis were manually reviewed. Predictors of ICU and hospital mortality were identified using logistic regression modeling. RESULTS: Four hundred eighty-six individuals with TBI were admitted to intensive care. Sixteen (3.3%) developed sepsis. Pneumonia was the most common source (94%). Staphylococcus aureus was the most common pathogen (75%). ICU lengths of stay (LOS) (12.2 days [interquartile range (IQR) 4.4-23.5] versus 3.7 days [IQR 1.7-8.2]; p < 0.001) and hospital LOS (28.0 days [IQR 11.8-41.4] versus 15.3 days [IQR 5.0-30.9]; p = 0.017) were longer in patients with TBI and sepsis. Sepsis was not associated with ICU (adjusted odds ratio [aOR] 0.51; 95%CI 0.12-2.27; p = 0.38) or hospital (aOR 0.78; 95% CI 0.21-2.96; p = 0.78) mortality, though age (aOR 1.02; 95% CI 1.00-1.04; p = 0.014 for hospital mortality), severe TBI (aOR 3.71; 95% CI 1.52-9.08; p = 0.004 for ICU mortality and 4.10; 95% CI 1.95-8.65; p < 0.001 for hospital mortality), and APACHE II score (aOR 1.19; 95% CI 1.11-1.28; p < 0.001 for ICU mortality and 1.22; 95% CI 1.14-1.31; p < 0.001 for hospital mortality) were. CONCLUSION: Sepsis in patients with TBI was not associated with mortality; however, sepsis was associated with increased health care utilization (ICU and hospital LOS).

The impact of cirrhosis in patients undergoing cardiac surgery: a retrospective observational cohort study.

PURPOSE: Patients with cirrhosis and concomitant coronary/valvular heart disease present a clinical dilemma. The therapeutic outcome of major cardiac surgery is significantly poorer in patients with cirrhosis compared with patients without cirrhosis. To address this, we aimed to identify associations between the severity of cirrhosis and post-cardiac surgical outcomes. METHODS: A historical cohort analysis of patients undergoing cardiac surgery at the University of Alberta Hospital from January 2004 to December 2014 was used to identify and propensity score-match 60 patients with cirrhosis to 310 patients without cirrhosis. The relationships between cirrhosis and i) mortality, ii) postoperative complications, and iii) requirement of healthcare resources were evaluated. RESULTS: Ten-year mortality was significantly higher in cirrhotic patients compared with propensity score-matched non-cirrhotic patients (40% vs 20%; relative risk [RR], 2.0; 95% confidence interval [CI], 1.3 to 2.9; P = 0.001). Cirrhotic patients had more complications (63% vs 48%; RR, 1.3; 95% CI, 1.05 to 1.7; P = 0.02), longer median [interquartile range (IQR)] intensive care unit stays (5 [3-11] vs 2 [1-4] days; P < 0.001), time on mechanical ventilation (median [IQR] 2 [1-5] vs 1 [0.5-1.2] days; P < 0.001) and more frequently required renal replacement therapy (15% vs 6%; RR, 2.5; 95% CI, 1.2 to 5.2; P = 0.02) postoperatively. After adjusting for other covariates, presence of cirrhosis (adjusted odds ratio, 2.2; 95% CI, 1.1 to 4.1) and intraoperative transfusion (adjusted odds ratio, 3.2; 95% CI, 1.6 to 6.3) were independently associated with increased mortality. CONCLUSION: Despite having low median model for end-stage liver disease scores, this small series of cirrhotic patients undergoing cardiac surgery had significantly higher mortality rates and required more organ support postoperatively than propensity score-matched non-cirrhotic patients. Impact de la cirrhose chez les patients subissant une chirurgie cardiaque : une étude de cohorte observationnelle et rétrospective.

Deceased organ donation potential in Canada: a review of consecutive deaths in Alberta.

BACKGROUND: Transplantation is the most effective treatment for many patients with end-stage organ failure. There is a gap between the number of patients who would benefit from transplantation and availability of organs. We assessed maximum potential for deceased donation in Alberta and barriers to increasing the donation rate. METHODS: All deaths that occurred in Alberta in 2015 in areas where mechanical ventilation could be provided were retrospectively identified using administrative data. Medical records were reviewed by donation coordinators and critical care physicians with expertise in donation, using a standardized tool to determine whether deceased patients could potentially have been organ donors. RESULTS: There were 2,706 deaths occurring in either an intensive care unit or emergency department, of which 1,252 were attributable to a non-neurologic cause: 946 involved cardiac arrests with unsuccessful resuscitation, and 57 were not mechanically ventilated. Of the remaining 451 deaths, 117 (28 donors per million population [dpmp]) either were, or could potentially have been, organ donors after neurologic determination of death (NDD). Of these, 19 (4.5 dpmp) were not appropriately identified or referred, and 45 approached families (10.8 dpmp) did not provide consent. Non-identified NDD cases accounted for a larger proportion of deaths due to neurologic causes in emergency departments (18%) than in intensive care units (2%) (P < 0.0001) and in rural (9%) compared with urban centres (3%) (P = 0.05). If routinely available, donation after circulatory death (DCD) could potentially have been possible in as many as 113 (27 dpmp) cases. CONCLUSIONS: Maximum deceased organ donation potential in Alberta is approximately 55 dpmp. The current donation rate has potential to increase with more widespread availability of DCD and a higher consent rate.

Relaxation for Critically ill Patient Outcomes and Stress-coping Enhancement (REPOSE): a protocol for a pilot randomised trial of an integrative intervention to improve critically ill patients' delirium and related outcomes.

INTRODUCTION: Delirium is a common complication of critical illness, associated with negative patient outcomes. Preventive or therapeutic interventions are mostly ineffective. Although relaxation-inducing approaches may benefit critically ill patients, no well-designed studies target delirium prevention as a primary outcome. The objective of this study is to assess feasibility and treatment effect estimates of a multimodal integrative intervention incorporating relaxation, guided imagery and moderate pressure touch massage for prevention of critical illness delirium and for related outcomes. METHODS AND ANALYSIS: Randomised, controlled, single-blinded trial with two parallel groups (1:1 allocation: intervention and standard care) and stratified randomisation (age (18-64 years and ≥65 years) and presence of trauma) with blocking, involving 104 patients with Intensive Care Delirium Screening Checklist (ICDSC): 0-3 recruited from two academic intensive care units (ICUs). Intervention group participants receive the intervention in addition to standard care for up to five consecutive days (or until transfer/discharge); control group participants receive standard care and a sham intervention. We will assess predefined feasibility outcomes, that is, recruitment rates and protocol adherence. The primary clinical outcome is incidence of delirium (ICDSC ≥4). Secondary outcomes include pain scores, inflammatory biomarkers, heart rate variability, stress and quality of life (6 weeks and 4 months) post-ICU discharge. Feasibility measures will be analysed descriptively, and outcomes will be analysed longitudinally. Estimates of effects will be calculated. ETHICS AND DISSEMINATION: The study has received approval from the Human Research Ethics Board, University of Alberta. Results will inform the design of a future multicentre trial. TRIAL REGISTRATION NUMBER: NCT02905812; Pre-results.

Transplantation of Hearts Donated after Circulatory Death.

Cardiac transplantation has become limited by a critical shortage of suitable organs from brain-dead donors. Reports describing the successful clinical transplantation of hearts donated after circulatory death (DCD) have recently emerged. Hearts from DCD donors suffer significant ischemic injury prior to organ procurement; therefore, the traditional approach to the transplantation of hearts from brain-dead donors is not applicable to the DCD context. Advances in our understanding of ischemic post-conditioning have facilitated the development of DCD heart resuscitation strategies that can be used to minimize ischemia-reperfusion injury at the time of organ procurement. The availability of a clinically approved ex situ heart perfusion device now allows DCD heart preservation in a normothermic beating state and minimizes exposure to incremental cold ischemia. This technology also facilitates assessments of organ viability to be undertaken prior to transplantation, thereby minimizing the risk of primary graft dysfunction. The application of a tailored approach to DCD heart transplantation that focuses on organ resuscitation at the time of procurement, ex situ preservation, and pre-transplant assessments of organ viability has facilitated the successful clinical application of DCD heart transplantation. The transplantation of hearts from DCD donors is now a clinical reality. Investigating ways to optimize the resuscitation, preservation, evaluation, and long-term outcomes is vital to ensure a broader application of DCD heart transplantation in the future.