CaCl2-citrate regional anticoagulation with CVVHD leads to unwanted chloride loading compared to CVVH with systemic anticoagulation.

INTRODUCTION: Chloride transfers during continuous renal replacement therapy (CRRT) have not been adequately described and may differ based on CRRT technique. We aimed to measure chloride mass transfer (JS,Cl) during CRRT and identify associated determinants. METHODS: We performed a two-center, prospective, observational study in France and Australia in ICU patients with CRRT initiated for < 24h. Patients received continuous veno-venous hemofiltration (CVVH) or continuous veno-venous hemodialysis (CVVHD, with citrate-CaCl2 regional anticoagulation). Over a 24h period, plasma and effluent chloride concentrations were measured every 4h to compute chloride mass transfer (JS,Cl, in mmol.min-1) using a modality-specific model, with negative value indicating chloride transfer towards the patient. Secondary outcomes were the identification of CRRT settings associated with JS,Cl (using multivariate mixed effects regression). Results are presented with median [interquartile range]. RESULTS: Between February 2021 and August 2022, we enrolled 37 patients (64 [56-71] years, 67% male), for a total of 20 CVVHD and 20 CVVH sessions. Over 24h, plasma chloride concentrations were significantly higher, and JS,Cl significantly lower during CVVHD, compared to CVVH (-0.10 [-0.33-0.15] vs. 0.01 [-0.10-0.13] mmol.min-1, P<0.05). With both modalities, net ultrafiltration (QUFNET) and plasma chloride concentrations were the principal determinants of JS,Cl, with higher QUFNET being associated with an increase in JS,Cl during CVVHD. Also, CVVHD sessions demonstrated a concentration gradient between the plasma and the effluent chamber of -6 [-9- -4] mmol.L-1. Finally, CaCl2 reinjection during CVVHD accounted for 35% [32%-60%] of total JS,Cl in sessions with a negative JS,Cl. CONCLUSION: Compared to CVVH, CVVHD with regional citrate anticoagulation was associated with greater chloride mass transfer to the patient and higher plasma chloride concentrations. This was due to high dialysate chloride concentrations and CaCl2 reinjection. This effect could only be controlled by high net ultrafiltration flow rates.

Conservative or liberal oxygen targets in patients on venoarterial extracorporeal membrane oxygenation.

PURPOSE: Patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) frequently develop arterial hyperoxaemia, which may be harmful. However, lower oxygen saturation targets may also lead to harmful episodes of hypoxaemia. METHODS: In this registry-embedded, multicentre trial, we randomly assigned adult patients receiving VA-ECMO in an intensive care unit (ICU) to either a conservative (target SaO2 92-96%) or to a liberal oxygen strategy (target SaO2 97-100%) through controlled oxygen administration via the ventilator and ECMO gas blender. The primary outcome was the number of ICU-free days to day 28. Secondary outcomes included ICU-free days to day 60, mortality, ECMO and ventilation duration, ICU and hospital lengths of stay, and functional outcomes at 6 months. RESULTS: From September 2019 through June 2023, 934 patients who received VA-ECMO were reported to the EXCEL registry, of whom 300 (192 cardiogenic shock, 108 refractory cardiac arrest) were recruited. We randomised 149 to a conservative and 151 to a liberal oxygen strategy. The median number of ICU-free days to day 28 was similar in both groups (conservative: 0 days [interquartile range (IQR) 0-13.7] versus liberal: 0 days [IQR 0-13.7], median treatment effect: 0 days [95% confidence interval (CI) - 3.1 to 3.1]). Mortality at day 28 (59/159 [39.6%] vs 59/151 [39.1%]) and at day 60 (64/149 [43%] vs 62/151 [41.1%] were similar in conservative and liberal groups, as were all other secondary outcomes and adverse events. The conservative group experienced 44 (29.5%) major protocol deviations compared to 2 (1.3%) in the liberal oxygen group (P < 0.001). CONCLUSIONS: In adults receiving VA-ECMO in ICU, a conservative compared to a liberal oxygen strategy, did not affect the number of ICU-free days to day 28.

Carboxyhemoglobin as Potential Biomarker for Cardiac Surgery Associated Acute Kidney Injury.

OBJECTIVES: Carboxyhemoglobin (CO-Hb) is a marker of hemolysis and inflammation, both risk factors for cardiac surgery-associated AKI (CSA-AKI). However, the association between CO-Hb and CSA-AKI remains unknown. DESIGN: A retrospective cohort study. SETTING: Tertiary university-affiliated metropolitan hospital: single center. PARTICIPANTS: Adult on-pump cardiac surgery patients from July 2014 to June 2022 (N = 1,698). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were stratified into quartiles based on CO-Hb levels at intensive care unit (ICU) admission. A progressive increased risk of CSA-AKI was observed with higher CO-Hb levels at ICU admission. On multivariable logistic regression analysis, the highest quartile (CO-Hb ≥ 1.4%) showed an independent association with the occurrence of CSA-AKI (odds ratio 1.45 compared to the lowest quartile [CO-Hb < 1.0%], 95% CI 1.023-2.071; p = 0.038). Compared to patients with CO-Hb <1.4%, patients with CO-Hb ≥ 1.4% at ICU admission had significantly higher postoperative creatinine (135 vs 116 µmol/L, p < 0.001), higher rates of postoperative RRT (6.7% vs 2.3%, p < 0.001) and AKI (p < 0.001) on univariable analysis and shorter time to event for AKI or death (p < 0.001). CONCLUSIONS: CO-Hb ≥ 1.4% at ICU admission is an independent risk factor for CSA-AKI, which is easily obtainable and available on routine arterial blood gas measurements. Thus, CO-Hb may serve as a practical and biologically logical biomarker for risk stratification and population enrichment in trials of CSA-AKI prevention.

Twenty percent human albumin solution fluid bolus administration therapy in patients after cardiac surgery-II: a multicentre randomised controlled trial.

PURPOSE: After cardiac surgery, fluid bolus therapy (FBT) with 20% human albumin may facilitate less fluid and vasopressor administration than FBT with crystalloids. We aimed to determine whether, after cardiac surgery, FBT with 20% albumin reduces the duration of vasopressor therapy compared with crystalloid FBT. METHODS: We conducted a multicentre, parallel-group, open-label, randomised clinical trial in six intensive care units (ICUs) involving cardiac surgery patients deemed to require FBT. We randomised 240 patients to receive up to 400 mL of 20% albumin/day as FBT, followed by 4% albumin for any subsequent FBT on that day, or to crystalloid FBT for at least the first 1000 mL, with use of crystalloid or 4% albumin FBT thereafter. The primary outcome was the cumulative duration of vasopressor therapy. Secondary outcomes included fluid balance. RESULTS: Of 480 randomised patients, 466 provided consent and contributed to the primary outcome (mean age 65 years; median EuroSCORE II 1.4). The cumulative median duration of vasopressor therapy was 7 (interquartile range [IQR] 0-19.6) hours with 20% albumin and 10.8 (IQR 0-22.8) hours with crystalloids (difference - 3.8 h, 95% confidence interval [CI] - 8 to 0.4; P = 0.08). Day one fluid balance was less with 20% albumin FBT (mean difference - 701 mL, 95% CI - 872 to - 530). CONCLUSIONS: In patients after cardiac surgery, when compared to a crystalloid-based FBT, 20% albumin FBT was associated with a reduced positive fluid balance but did not significantly reduce the duration of vasopressor therapy.

Effects of mild hypercapnia on myocardial injury after out-of-hospital cardiac arrest. A sub-study of the TAME trial.

PURPOSE: Mild hypercapnia did not improve neurological outcomes for resuscitated out-of-hospital cardiac arrest (OHCA) patients in the Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME) trial. However, the effects of hypercapnic acidosis on myocardial injury in patients with cardiac arrest is unexplored. We investigated whether mild hypercapnia compared to normocapnia, following emergency coronary intervention, increased myocardial injury in comatose OHCA-patients with AMI. METHODS: Single-centre, prospective, pre-planned sub-study of the TAME trial. Patients were randomised to targeted mild hypercapnia (PaCO2 = 6.7-7.3 kPa) or normocapnia (PaCO2 = 4.7-6.0 kPa) for 24 h. Myocardial injury was assessed with high-sensitive cardiac troponin T (hs-cTnT) measured at baseline, 24, 48 and 72 h. Haemodynamics were assessed with right heart catheterisation and blood-gas analyses every 4th hour for 48 h. RESULTS: We included 125 OHCA-patients. 57 (46%) had an AMI, with 31 and 26 patients randomised to hypercapnia and normocapnia, respectively. Median peak hs-cTnT in AMI-patients was 58% lower in the hypercapnia-group: 2136 (IQR: 861-4462) versus 5165 ng/L (IQR: 2773-7519), p = 0.007. Lower average area under the hs-cTnT curve was observed in the hypercapnia-group: 2353 (95% CI 1388-3319) versus 4953 ng/L (95% CI 3566-6341), P-group = 0.002. Hypercapnia was associated with increased cardiac power output (CPO) and lower lactate levels in patients with AMI (P-group < 0.05). hs-cTnT, lactate and CPO were not significantly different between intervention groups in OHCA-patients without AMI (p > 0.05). CONCLUSIONS: Mild hypercapnia was not associated with increased myocardial injury in resuscitated OHCA-patients. In AMI-patients, mild hypercapnia was associated with lower hs-cTnT and lactate, and improved cardiac performance. TRIAL REGISTRATION NUMBER: NCT03114033.

Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot safety and feasibility randomised controlled trial.

PURPOSE: Critically ill patients are vulnerable to penicillin allergy labels that may be incorrect. The validity of skin testing in intensive care units (ICUs) is uncertain. Many penicillin allergy labels are low risk, and validated tools exist to identify those amenable to direct oral challenge. This pilot randomised controlled trial explored the feasibility, safety, and validity of direct enteral challenge for low-risk penicillin allergy labels in critical illness. METHODS: Consenting patients with a low-risk penicillin allergy label (PAL) (PEN-FAST risk assessment score < 3) in four ICUs (Melbourne, Australia) were randomised 1:1 to penicillin (250 mg amoxicillin or implicated penicillin) direct enteral challenge versus routine care (2-h post-randomisation observation for each arm). Repeat challenge was performed post -ICU in the intervention arm. Patients were reviewed at 24 h and 5 days after each challenge/observation. RESULTS: We screened 533 patients. 130 (24.4%) were eligible and 80/130 (61.5%) enrolled (age median 64.5 years (interquartile range, IQR 53.5, 74), PEN-FAST median 1 (IQR 0,1)), with 40 (50%) randomised to direct enteral challenge. A positive challenge rate of 2.5% was identified. No antibiotic-associated serious adverse events were identified. 32/40 (80%) received a repeat challenge (zero positive). Post-randomisation, 13 (32%) of the intervention arm and 4 (10%) of the control arm received penicillin (odds ratio, OR 4.33 [1.27, 14.78] p = 0.019). CONCLUSION: These findings support the safety, validity, and feasibility of direct enteral challenge for critically ill patients with PEN-FAST assessed low-risk penicillin allergy. The absence of false negative results was confirmed by subsequent negative repeat challenges. A relatively low recruitment to screened ratio suggests that more inclusive eligibility criteria and integration of allergy assessment into routine ICU processes are needed to optimise allergy delabelling in critical illness.

Corrigendum to "Blend to Limit OxygEN in ECMO: A RanDomised ControllEd Registry (BLENDER) trial: Study protocol and statistical analysis plan" [Crit Care Resuscit 25 (2023) 118-125].

[This corrects the article DOI: 10.1016/j.ccrj.2023.06.001.].

Renin Levels and Angiotensin II Responsiveness in Vasopressor-Dependent Hypotension.

OBJECTIVES: The relationship between renin levels, exposure to renin-angiotensin system (RAS) inhibitors, angiotensin II (ANGII) responsiveness, and outcome in patients with vasopressor-dependent vasodilatory hypotension is unknown. DESIGN: We conducted a single-center prospective observational study to explore whether recent RAS inhibitor exposure affected baseline renin levels, whether baseline renin levels predicted ANGII responsiveness, and whether renin levels at 24 hours were associated with clinical outcomes. SETTING: An academic ICU in Melbourne, VIC, Australia. PATIENTS: Forty critically ill adults who received ANGII as the primary agent for vasopressor-dependent vasodilatory hypotension who were included in the Acute Renal effects of Angiotensin II Management in Shock study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After multivariable adjustment, recent exposure to a RAS inhibitor was independently associated with a relative increase in baseline renin levels by 198% (95% CI, 36-552%). The peak amount of ANGII required to achieve target mean arterial pressure was independently associated with baseline renin level (increase by 46% per ten-fold increase; 95% CI, 8-98%). Higher renin levels at 24 hours after ANGII initiation were independently associated with fewer days alive and free of continuous renal replacement therapy (CRRT) (-7 d per ten-fold increase; 95% CI, -12 to -1). CONCLUSIONS: In patients with vasopressor-dependent vasodilatory hypotension, recent RAS inhibitor exposure was associated with higher baseline renin levels. Such higher renin levels were then associated with decreased ANGII responsiveness. Higher renin levels at 24 hours despite ANGII infusion were associated with fewer days alive and CRRT-free. These preliminary findings emphasize the importance of the RAS and the role of renin as a biomarker in patients with vasopressor-dependent vasodilatory hypotension.

Carboxyhemoglobin in Cardiac Surgery Patients and Its Association with Risk Factors and Biomarkers of Hemolysis.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with hemolysis. Yet, there is no easily available and frequently measured marker to monitor this hemolysis. However, carboxyhemoglobin (CO-Hb), formed by the binding of carbon monoxide (a product of heme breakdown) to hemoglobin, may reflect such hemolysis. We hypothesized that CO-Hb might increase after cardiac surgery and show associations with operative risk factors and indirect markers for hemolysis. METHODS: We conducted a retrospective descriptive cohort study of data from on-pump cardiac surgery patients. We analyzed temporal changes in CO-Hb levels and applied a generalized linear model to assess patient characteristics associated with peak CO-Hb levels. Additionally, we examined their relationship with red blood cell (RBC) transfusion and bilirubin levels. RESULTS: We studied 38,487 CO-Hb measurements in 1735 patients. CO-Hb levels increased significantly after cardiac surgery, reaching a peak CO-Hb level 2.1 times higher than baseline (P < .001) at a median of 17 hours after the initiation of surgery. Several factors were independently associated with higher peak CO-Hb, including age (P < .001), preoperative respiratory disease (P = .001), New York Heart Association Class IV (P = .019), the number of packed RBC transfused (P < .001), and the duration of CPB (P = .002). Peak CO-Hb levels also significantly correlated with postoperative total bilirubin levels (Rho = 0.27, P < .001). CONCLUSIONS: CO-Hb may represent a readily obtainable and frequently measured biomarker that has a moderate association with known biomarkers of and risk factors for hemolysis in on-pump cardiac surgery patients. These findings have potential clinical implications and warrant further investigation.

Clinician- and Patient-Identified Solutions to Reduce the Fragmentation of Post-ICU Care in Australia.

BACKGROUND: Critical care survivors experience multiple care transitions, with no formal follow-up care pathway. RESEARCH QUESTION: What are the potential solutions to improve the communication between treating teams and integration of care following an ICU admission, from the perspective of patients, their caregivers, intensivists, and general practitioners (GPs) from diverse socioeconomic areas? STUDY DESIGN AND METHODS: This study included a qualitative design using semi-structured interviews with intensivists, GPs, and patients and caregivers. Framework analysis was used to analyze data and to identify solutions to improve the integration of care following hospital discharge. Patients were previously mechanically ventilated for > 24 h in the ICU and had access to a video-enabled device. Clinicians were recruited from hospital networks and a state-wide GP network. RESULTS: Forty-six interviews with clinicians, patients, and caregivers were completed (15 intensivists, eight GPs, 15 patients, and eight caregivers). Three higher level feedback loops were identified that comprised 10 themes. Feedback loop 1 was an ICU and primary care collaboration. It included the following: (1) developing collaborative relationships between the ICU and primary care; (2) providing interprofessional education and resources to support primary care; and (3) improving role clarity for patient follow-up care. Feedback loop 2 was developing mechanisms for improved communication across the care continuum. It included: (4) timely, concise information-sharing with primary care on post-ICU recovery; (5) survivorship-focused information-sharing across the continuum of care; (6) empowering patients and caregivers in self-management; and (7) creation of a care coordinator role for survivors. Feedback loop 3 was learning from post-ICU outcomes to improve future care. It included: (8) developing comprehensive post-ICU care pathways; (9) enhancing support for patients following a hospital stay; and (10) integration of post-ICU outcomes within the ICU to improve clinician morale and understanding. INTERPRETATION: Practical solutions to enhance the quality of survivorship for critical care survivors and their caregivers were identified. These themes are mapped to a novel conceptual model that includes key feedback loops for health system improvements and foci for future interventional trials to improve ICU survivorship outcomes.

The effect of age on clinical dose equivalency of fentanyl and morphine analgosedation in mechanically ventilated patients: Findings from the ANALGESIC trial.

BACKGROUND: The dose equivalency of fentanyl vs. morphine is widely considered to be approximately 1:100. However, little is known about the effect of age on this ratio when these agents are used as infusions for analgosedation. OBJECTIVES: To assess the impact of age on the clinical dose equivalency of fentanyl and morphine when used as infusions for analgosedation in mechanically ventilated intensive care unit patients. METHODS: We performed a post hoc analysis of the Assessment of Opioid Administration to Lead to Analgesic Effects and Sedation in Intensive Care (ANALGESIC) cluster randomised crossover trial of fentanyl and morphine infusions for analgosedation. Dose and analgosedative clinical equivalency of fentanyl and morphine were assessed by age and by using different body-size descriptors. RESULTS: We studied 663 patients (338 fentanyl, 325 morphine). Median (interquartile range) hourly dose of fentanyl and morphine were 58.1 (40.0-89.2) mcg and 3400 (2200-5000) mcg, respectively. The ratio of total dose of fentanyl:morphine was 1:93 in the 18- to 29-year-old group and 1:25 in the ≥80-year-old group (p = 0.015), respectively, with fentanyl becoming relatively less clinically effective as age increased. This effect was also seen when comparing dosing by different body-size descriptors with the strongest age-related change when using body surface area as body-size descriptor (p = 0.009). CONCLUSION: The analgosedative clinical dose equivalency of fentanyl vs. morphine is heterogeneous when used as infusions for analgosedation, with fentanyl becoming relatively less clinically effective as age increases. This information can help guide prescription of these agents during transition from one agent to the other in critically ill patients.

Renal medullary oxygenation during laparoscopic vs open surgery: the impact of blood pressure management-a pilot randomized controlled trial.

The impact of blood pressure targets and surgical approach (laparoscopic or open) on continuous urinary oxygenation (PuO2), a validated surrogate of renal medullary PO2, during general surgery, is unclear. We aimed to assess the effects of different blood pressure targets and surgical procedures on PuO2. We randomized patients receiving either laparoscopic or open surgery into two mean arterial pressure (MAP) target groups: usual MAP or a high MAP. We measured PuO2 in real-time and analyzed it according to the type of surgery and blood pressure target. The study was retrospectively registered on the 5th of July 2023 (ACTRN12623000726651). We included 43 participants who underwent either laparoscopic (n = 20) or open surgery (n = 23). We found that PuO2 significantly decreased during both laparoscopic and open surgery under a usual blood pressure target (- 51% and - 49%, respectively). However, there was a sharper fall with laparoscopic surgery resulting in a higher PuO2 with open surgery (mean difference: 11 ± 1 mmHg higher; p < 0.001). Targeting a higher MAP resulted in a higher PuO2 over time during laparoscopic surgery (mean difference: 7 ± 1 mmHg, p < 0.001). In contrast, targeting a usual MAP resulted in a higher PuO2 during open surgery (mean difference: 7 ± 1 mmHg, p < 0.001). Surgical approach and intraoperative blood pressure targets significantly impact urinary oxygenation. Further studies with larger sample sizes are needed to confirm these findings and understand their potential clinical implications.Registration number: ACTRN12623000726651; Date of registration: 05/07/2023 (retrospectively registered).

Magnitude and time to peak oxygenation effect of prone positioning in ventilated adults with COVID-19 related acute hypoxemic respiratory failure.

BACKGROUND: Prone positioning may improve oxygenation in acute hypoxemic respiratory failure and was widely adopted in COVID-19 patients. However, the magnitude and timing of its peak oxygenation effect remain uncertain with the optimum dosage unknown. Therefore, we aimed to investigate the magnitude of the peak effect of prone positioning on the PaO2 :FiO2 ratio during prone and secondly, the time to peak oxygenation. METHODS: Multi-centre, observational study of invasively ventilated adults with acute hypoxemic respiratory failure secondary to COVID-19 treated with prone positioning. Baseline characteristics, prone positioning and patient outcome data were collected. All arterial blood gas (ABG) data during supine, prone and after return to supine position were analysed. The magnitude of peak PaO2 :FiO2 ratio effect and time to peak PaO2 :FIO2 ratio effect was measured. RESULTS: We studied 220 patients (mean age 54 years) and 548 prone episodes. Prone positioning was applied for a mean (±SD) 3 (±2) times and 16 (±3) hours per episode. Pre-proning PaO2 :FIO2 ratio was 137 (±49) for all prone episodes. During the first episode. the mean PaO2 :FIO2 ratio increased from 125 to a peak of 196 (p < .001). Peak effect was achieved during the first episode, after 9 (±5) hours in prone position and maintained until return to supine position. CONCLUSIONS: In ventilated adults with COVID-19 acute hypoxemic respiratory failure, peak PaO2 :FIO2 ratio effect occurred during the first prone positioning episode and after 9 h. Subsequent episodes also improved oxygenation but with diminished effect on PaO2 :FIO2 ratio. This information can help guide the number and duration of prone positioning episodes.

Exploring the norepinephrine to angiotensin II conversion ratio in patients with vasodilatory hypotension: A post-hoc analysis of the ARAMIS trial.

PURPOSE: Angiotensin II is approved for catecholamine-refractory vasodilatory shock but the conversion dose ratio from norepinephrine to angiotensin II remains unclear. METHODS: We conducted a post-hoc analysis of the Acute Renal effects of Angiotensin II Management in Shock (ARAMIS) trial involving patients with vasodilatory hypotension. We determined the norepinephrine equivalent dose immediately prior to angiotensin II initiation and calculated the conversion dose ratio between norepinephrine and angiotensin II. We performed subgroup analyses based on recent exposure to angiotensin receptor blockers (ARBs) and renin levels at baseline. RESULTS: In 37 patients, the median conversion dose ratio between norepinephrine equivalent and angiotensin II was to 10:1 for norepinephrine bitartrate (5:1 for norepinephrine base). The conversion ratio was not affected by the baseline renin, with a median ratio of 10 (7-21) in the high renin group versus 12 (5-22) in the low renin group. Finally, exposure to ARBs prior admission appeared to diminish the conversion ratio with a median ratio of 7 (4-13) in ARB patients vs. 12 (7-22) in non-ARB patients. CONCLUSIONS: The norepinephrine to angiotensin II conversion dose ratio is 10:1 in a vasodilatory hypotension population. These findings can guide clinicians and researchers in the use, dosing, and study of angiotensin II in critical care.

Neuromuscular blockade and oxygenation changes during prone positioning in COVID-19.

PURPOSE: Neuromuscular blockers (NMBs) are often used during prone positioning to facilitate mechanical ventilation in COVID-19 related ARDS. However, their impact on oxygenation is uncertain. METHODS: Multi-centre observational study of invasively ventilated COVID-19 ARDS adults treated with prone positioning. We collected data on baseline characteristics, prone positioning, NMB use and patient outcome. We assessed arterial blood gas data during supine and prone positioning and after return to the supine position. RESULTS: We studied 548 prone episodes in 220 patients (mean age 54 years, 61% male) of whom 164 (75%) received NMBs. Mean PaO2:FiO2 (P/F ratio) during the first prone episode with NMBs reached 208 ± 63 mmHg compared with 161 ± 66 mmHg without NMBs (Δmean = 47 ± 5 mmHg) for an absolute increase from baseline of 76 ± 56 mmHg versus 55 ± 56 mmHg (padj < 0.001). The mean P/F ratio on return to the supine position was 190 ± 63 mmHg in the NMB group versus 141 ± 64 mmHg in the non-NMB group for an absolute increase from baseline of 59 ± 58 mmHg versus 34 ± 56 mmHg (padj < 0.001). CONCLUSION: During prone positioning, NMB is associated with increased oxygenation compared to non-NMB therapy, with a sustained effect on return to the supine position. These findings may help guide the use of NMB during prone positioning in COVID-19 ARDS.

Protocol summary and statistical analysis plan for the low oxygen intervention for cardiac arrest injury limitation (LOGICAL) trial.

Background: The effect of conservative vs. liberal oxygen therapy on outcomes of intensive care unit (ICU) patients with hypoxic ischaemic encephalopathy (HIE) is uncertain and will be evaluated in the Low Oxygen Intervention for Cardiac Arrest injury Limitation (LOGICAL) trial. Objective: The objective of this study was to summarise the protocol and statistical analysis plans for the LOGICAL trial. Design setting and participants: LOGICAL is a randomised clinical trial in adults in the ICU who are comatose with suspected HIE (i.e., those who have not obeyed commands following return of spontaneous circulation after a cardiac arrest where there is clinical concern about possible brain damage). The LOGICAL trial will include 1400 participants and is being conducted as a substudy of the Mega Randomised registry trial comparing conservative vs. liberal oxygenation targets in adults receiving unplanned invasive mechanical ventilation in the ICU (Mega-ROX). Main outcome measures: The primary outcome is survival with favourable neurological function at 180 days after randomisation as measured with the Extended Glasgow Outcome Scale (GOS-E). A favourable neurological outcome will be defined as a GOS-E score of lower moderate disability or better (i.e. a GOS-E score of 5-8). Secondary outcomes include survival time, day 180 mortality, duration of invasive mechanical ventilation, ICU length of stay, hospital length of stay, the proportion of patients discharged home, quality of life assessed at day 180 using the EQ-5D-5L, and cognitive function assessed at day 180 using the Montreal Cognitive Assessment (MoCA-blind). Conclusions: The LOGICAL trial will provide reliable data on the impact of conservative vs. liberal oxygen therapy in ICU patients with suspected HIE following resuscitation from a cardiac arrest. Prepublication of the LOGICAL protocol and statistical analysis plan prior to trial conclusion will reduce the potential for outcome-reporting or analysis bias. Trial registration: Australian and New Zealand Clinical Trials Registry (ACTRN12621000518864).

Blend to Limit OxygEN in ECMO: A RanDomised ControllEd Registry (BLENDER) Trial: Study Protocol and Statistical Analysis Plan.

Introduction: Critically ill patients supported with venoarterial extracorporeal membrane oxygenation (VA ECMO) are at risk of developing severe arterial hyperoxia, which has been associated with increased mortality. Lower saturation targets in this population may lead to deleterious episodes of severe hypoxia. This manuscript describes the protocol and statistical analysis plan for the Blend to Limit OxygEN in ECMO: A RanDomised ControllEd Registry (BLENDER) Trial. Design: The BLENDER trial is a pragmatic, multicentre, registry-embedded, randomised clinical trial., registered at ClinicalTrials.gov (NCT03841084) and approved by The Alfred Hospital Ethics Committee project ID HREC/50486/Alfred-2019. Participants and setting: Patients supported by VA ECMO for cardiogenic shock or cardiac arrest who are enrolled in the Australian national ECMO registry. Intervention: The study compares a conservative oxygenation strategy (target arterial saturations 92-96%) with a liberal oxygenation strategy (target 97-100%). Main Outcome Measures: The primary outcome is the number of intensive care unit (ICU)-free days for patients alive at day 60. Secondary outcomes include duration of mechanical ventilation, ICU and hospital mortality, the number of hypoxic episodes, neurocognitive outcomes, and health economic analyses. The 300-patient sample size enables us to detect a 3-day difference in ICU-free days at day 60, assuming a mean ICU-free days of 11 days, with a risk of type 1 error of 5% and power of 80%. Data will be analysed according to a predefined analysis plan. Findings will be disseminated in peer-reviewed publications. Conclusions: This paper details the protocol and statistical analysis plan for the BLENDER trial, a registry-embedded, multicentre interventional trial comparing liberal and conservative oxygenation strategies in VA ECMO.

Mega-dose sodium ascorbate: a pilot, single-dose, physiological effect, double-blind, randomized, controlled trial.

BACKGROUND: Mega-dose sodium ascorbate (NaAscorbate) appears beneficial in experimental sepsis. However, its physiological effects in patients with septic shock are unknown. METHODS: We conducted a pilot, single-dose, double-blind, randomized controlled trial. We enrolled patients with septic shock within 24 h of diagnosis. We randomly assigned them to receive a single mega-dose of NaAscorbate (30 g over 1 h followed by 30 g over 5 h) or placebo (vehicle). The primary outcome was the total 24 h urine output (UO) from the beginning of the study treatment. Secondary outcomes included the time course of the progressive cumulative UO, vasopressor dose, and sequential organ failure assessment (SOFA) score. RESULTS: We enrolled 30 patients (15 patients in each arm). The mean (95% confidence interval) total 24-h UO was 2056 (1520-2593) ml with placebo and 2948 (2181-3715) ml with NaAscorbate (mean difference 891.5, 95% confidence interval [- 2.1 to 1785.2], P = 0.051). Moreover, the progressive cumulative UO was greater over time on linear mixed modelling with NaAscorbate (P < 0.001). Vasopressor dose and SOFA score changes over time showed faster reductions with NaAscorbate (P < 0.001 and P = 0.042). The sodium level, however, increased more over time with NaAscorbate (P < 0.001). There was no statistical difference in other clinical outcomes. CONCLUSION: In patients with septic shock, mega-dose NaAscorbate did not significantly increase cumulative 24-h UO. However, it induced a significantly greater increase in UO and a greater reduction in vasopressor dose and SOFA score over time. One episode of hypernatremia and one of hemolysis were observed in the NaAscorbate group. These findings support further cautious investigation of this novel intervention. Trial registration Australian New Zealand Clinical Trial Registry (ACTRN12620000651987), Date registered June/5/2020.

Cardiovascular changes induced by targeted mild hypercapnia after out of hospital cardiac arrest. A sub-study of the TAME cardiac arrest trial.

AIM: Hypercapnia may elicit detrimental haemodynamic effects in critically ill patients. We aimed to investigate the consequences of targeted mild hypercapnia versus targeted normocapnia on pulmonary vascular resistance and right ventricular function in patients resuscitated from out-of-hospital cardiac arrest (OHCA). METHODS: Pre-planned, single-centre, prospective, sub-study of the Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME) trial. Patients were randomised to mild hypercapnia (PaCO2 = 6.7-7.3 kPa) or normocapnia (PaCO2 = 4.7-6.0 kPa) for 24 hours. Haemodynamic assessment was performed with right heart catheterisation and serial blood-gas analyses every4th hour for 48 hours. RESULTS: We studied 84 patients. Mean pH was 7.24 (95% CI 7.22-7.30) and 7.32 (95% CI 7.31-7.34) with hypercapnia and normocapnia, respectively (P-group < 0.001). Pulmonary vascular resistance index (PVRI), pulmonary artery pulsatility index, and right atrial pressure did not differ between groups (P-group > 0.05). Mean cardiac index was higher with mild hypercapnia (P-group < 0.001): 2.0 (95% CI 1.85-2.1) vs 1.6 (95% CI 1.52-1.76) L/min/m2. Systemic vascular resistance index was 2579 dyne-sec/cm-5/ m2 (95% CI 2356-2830) with hypercapnia, and 3249 dyne-sec/cm-5/ m2 (95% CI 2930-3368) with normocapnia (P-group < 0.001). Stroke volumes (P-group = 0.013) and mixed venous oxygen saturation (P-group < 0.001) were higher in the hypercapnic group. CONCLUSION: In resuscitated OHCA patients, targeting mild hypercapnia did not increase PVRI or worsen right ventricular function compared to normocapnia. Mild hypercapnia comparatively improved cardiac performance and mixed venous oxygen saturation.