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.].

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.

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, 8 GPs, 15 patients, and 8 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.

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.

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).

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.

Fragmentation of care between intensive and primary care settings and opportunities for improvement.

PURPOSE: To explore the gaps in care provided across the transitions from the intensive care unit (ICU) to primary care, in order to improve post-ICU care. METHODS: Semistructured interviews with three participant groups: intensivists, general practitioners (GPs) and patients and carers with framework analysis of textual data were used to investigate experiences of transitions of care post-ICU. Participants were purposively sampled for diversity. Eligible patients were adults, mechanically ventilated for >24 hours, with access to a video-enabled device. Exclusion criteria were non-English speaking and any cognitive/neurological limitation precluding interview participation. RESULTS: A total of 46 interviews (15 patients, 8 caregivers, 15 intensivists and 8 GPs) were completed. Eight themes were identified, and categorised into three healthcare tiers. Tier 1, health system factors: (1) fragmentation of care; (2) communication gaps; (3) limited awareness and recognition of issues beyond the ICU; (4) lack of a specialised ICU follow-up pathway; Tier 2, clinician factors: (5) relationships among ICU, hospitals, GPs and patients and carers; (6) need for clinician role definition and clarity in ICU follow-up; Tier 3, patient and carer factors: (7) patient autonomy and self-actualisation and (8) the evolving caregiver role. A conceptual model was developed, highlighting bidirectional feedback loops between hospital and primary care. CONCLUSION: This study identified gaps in care between ICU discharge and reintegration with primary care from the lived experience of patients, caregivers, intensivists and GPs. These data provide foci for future interventional research to improve the integration of care for this vulnerable and underserved cohort.

Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest: A Predefined Analysis of the TTM2 Randomized Clinical Trial.

Importance: The Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens. Objectives: To investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA. Design, Setting, and Participants: This study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing. Interventions: Randomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher). Main outcomes and measures: Functional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes. Results: At 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P = .46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,-0.33 to 1.05; P = .37) and SDMT (mean difference, 0.06; 95% CI,-0.16 to 0.27; P = .62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%). Conclusions: In this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common. Trial Registration: ClinicalTrials.gov Identifier: NCT02908308.

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

BACKGROUND: Self-reported penicillin allergies are highly prevalent in hospitalised patients and are associated with poor health and health service outcomes. Critically ill patients have historically been underrepresented in prospective delabelling studies in part due to concerns around clinical stability and reliability of penicillin skin testing. Allergy assessment tools exist to identify low-risk penicillin allergy phenotypes and facilitate direct oral challenge delabelling. PEN-FAST is a clinical decision rule that has been validated to predict true penicillin allergy in a cohort of non-critically ill patients. There is however limited evidence regarding the feasibility, safety and efficacy of direct oral challenges and the use of delabelling clinical decisions rules in the intensive care setting. METHODS: Critically ill patients in the intensive care unit (ICU) with low-risk penicillin allergy phenotypes (PEN-FAST score < 3) will be randomised 1:1 to direct oral penicillin challenge (single dose 250 mg oral amoxicillin or implicated penicillin) or routine care, followed by a 2-h observation period. Patients will receive a second oral challenge/observation prior to hospital discharge (with subsequent observation for 2 h). An assessment for antibiotic-associated adverse events will also be undertaken at 24 h and 5 days post each challenge/observation and again at 90 days post-randomisation. The primary outcome measures are feasibility (proportion of eligible patients recruited and protocol compliance) and safety (proportion of patients who experience an antibiotic-associated immune-mediated adverse event or serious adverse event). DISCUSSION: We will report the feasibility and safety of point-of-care penicillin direct oral challenge in this first randomised controlled trial of low-risk penicillin allergy in critically ill hospitalised patients. Upon completion of the project, important findings will inform the design of planned large prospective multi-centre clinical trials in Australian and international ICUs, further examining safety and efficacy and exploring antimicrobial prescribing-related outcomes following penicillin oral challenge. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Registration Number: ACTRN12621000051842 Date registered: 20/01/2021 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379735&isReview=true.

Changes in SedLine-derived processed electroencephalographic parameters during hypothermia in patients undergoing cardiac surgery with cardiopulmonary bypass.

Objective: Processed electroencephalography (pEEG) is used to monitor depth-of-anesthesia during cardiopulmonary bypass (CPB). The SedLine device has been recently introduced for pEEG monitoring. However, the effect of hypothermia on its parameters during CPB is unknown. Accordingly, we aimed to investigate temperature-induced changes in SedLine-derived pEEG parameters during CPB. Design: Prospective observational study. Setting: Cardiac surgery operating theatre. Participants: 28 patients undergoing elective cardiac surgery with CPB. Interventions: We continuously measured patient state index (PSI), suppression ratio (SR), bilateral spectral edge frequency (SEF) and temperature. We used linear mixed modelling with fixed and random effects to study the interactions between pEEG parameters and core temperature. Measurements and main results: During CPB maintenance, the median temperature was 32.1°C [interquartile range (IQR): 29.8-33.6] at the end of cooling and 32.8°C (IQR: 30.1-34.0) at rewarming initiation. For each degree Celsius change in temperature during cooling and rewarming the PSI either decreased by 0.8 points [95% confidence interval (CI): 0.7-1.0; p < 0.001] or increased by 0.7 points (95% CI: 0.6-0.8; p < 0.001). The SR increased by 2.9 (95% CI: 2.3-3.4); p < 0.001) during cooling and decreased by 2.2 (95% CI: 1.7-2.7; p < 0.001) during rewarming. Changes in the SEF were not related to changes in temperature. Conclusions: During hypothermic CPB, temperature changes led to concordant changes in the PSI. The SR increased during cooling and decreased during rewarming. Clinicians using SedLine for depth-of-anesthesia monitoring should be aware of these effects when interpreting the PSI and SR values.

Mild Hypercapnia or Normocapnia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Guidelines recommend normocapnia for adults with coma who are resuscitated after out-of-hospital cardiac arrest. However, mild hypercapnia increases cerebral blood flow and may improve neurologic outcomes. METHODS: We randomly assigned adults with coma who had been resuscitated after out-of-hospital cardiac arrest of presumed cardiac or unknown cause and admitted to the intensive care unit (ICU) in a 1:1 ratio to either 24 hours of mild hypercapnia (target partial pressure of arterial carbon dioxide [Paco2], 50 to 55 mm Hg) or normocapnia (target Paco2, 35 to 45 mm Hg). The primary outcome was a favorable neurologic outcome, defined as a score of 5 (indicating lower moderate disability) or higher, as assessed with the use of the Glasgow Outcome Scale-Extended (range, 1 [death] to 8, with higher scores indicating better neurologic outcome) at 6 months. Secondary outcomes included death within 6 months. RESULTS: A total of 1700 patients from 63 ICUs in 17 countries were recruited, with 847 patients assigned to targeted mild hypercapnia and 853 to targeted normocapnia. A favorable neurologic outcome at 6 months occurred in 332 of 764 patients (43.5%) in the mild hypercapnia group and in 350 of 784 (44.6%) in the normocapnia group (relative risk, 0.98; 95% confidence interval [CI], 0.87 to 1.11; P = 0.76). Death within 6 months after randomization occurred in 393 of 816 patients (48.2%) in the mild hypercapnia group and in 382 of 832 (45.9%) in the normocapnia group (relative risk, 1.05; 95% CI, 0.94 to 1.16). The incidence of adverse events did not differ significantly between groups. CONCLUSIONS: In patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not lead to better neurologic outcomes at 6 months than targeted normocapnia. (Funded by the National Health and Medical Research Council of Australia and others; TAME ClinicalTrials.gov number, NCT03114033.).