Neurological outcomes and mortality of hyperoxaemia in patients with acute brain injury: protocol for a systematic review and meta-analysis.

INTRODUCTION: Oxygen is frequently prescribed in neurocritical care units. Avoiding hypoxaemia is a key objective in patients with acute brain injury (ABI). However, several studies suggest that hyperoxaemia may also be related to higher mortality and poor neurological outcomes in these patients. The evidence in this direction is still controversial due to the limited number of prospective studies, the lack of a common definition for hyperoxaemia, the heterogeneity in experimental designs and the different causes of ABI. To explore the correlation between hyperoxaemia and poor neurological outcomes and mortality in hospitalised adult patients with ABI, we will conduct a systematic review and meta-analysis of observational studies and RCTs. METHODS AND ANALYSIS: The systematic review methods have been defined according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and follow the PRISMA-Protocols structure. Studies published until June 2024 will be identified in the electronic databases MEDLINE, Embase, Scopus, Web of Science, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature and ClinicalTrials.gov. Retrieved records will be independently screened by four authors working in pairs, and the selected variables will be extracted from studies reporting data on the effect of 'hyperoxaemia' versus 'no hyperoxaemia on neurological outcomes and mortality in hospitalised patients with ABI. We will use covariate-adjusted ORs as outcome measures when reported since they account for potential cofounders and provide a more accurate estimate of the association between hyperoxaemia and outcomes; when not available, we will use univariate ORs. If the study presents the results as relative risks, it will be considered equivalent to the OR as long as the prevalence of the condition is close to 10%. Pooled estimates of both outcomes will be calculated applying random-effects meta-analysis. Interstudy heterogeneity will be assessed using the I2 statistic; risk of bias will be assessed through Risk Of Bias In Non-Randomised Studies of Interventions, Newcastle-Ottawa or RoB2 tools. Depending on data availability, we plan to conduct subgroup analyses by ABI type (traumatic brain injury, postcardiac arrest, subarachnoid haemorrhage, intracerebral haemorrhage and ischaemic stroke), arterial partial pressure of oxygen values, study quality, study time, neurological scores and other selected clinical variables of interest. ETHICS AND DISSEMINATION: Specific ethics approval consent is not required as this is a review of previously published anonymised data. Results of the study will be shared with the scientific community via publication in a peer-reviewed journal and presentation at relevant conferences and workshops. It will also be shared key stakeholders, such as national or international health authorities, healthcare professionals and the general population, via scientific outreach journals and research institutes' newsletters.

Stroke in critically ill patients with respiratory failure due to COVID-19: Disparities between low-middle and high-income countries.

PURPOSE: We aimed to compare the incidence of stroke in low-and middle-income countries (LMICs) versus high-income countries (HICs) in critically ill patients with COVID-19 and its impact on in-hospital mortality. METHODS: International observational study conducted in 43 countries. Stroke and mortality incidence rates and rate ratios (IRR) were calculated per admitted days using Poisson regression. Inverse probability weighting (IPW) was used to address the HICs vs. LMICs imbalance for confounders. RESULTS: 23,738 patients [20,511(86.4 %) HICs vs. 3,227(13.6 %) LMICs] were included. The incidence stroke/1000 admitted-days was 35.7 (95 %CI = 28.4-44.9) LMICs and 17.6 (95 %CI = 15.8-19.7) HICs; ischemic 9.47 (95 %CI = 6.57-13.7) LMICs, 1.97 (95 %CI = 1.53, 2.55) HICs; hemorrhagic, 7.18 (95 %CI = 4.73-10.9) LMICs, and 2.52 (95 %CI = 2.00-3.16) HICs; unspecified stroke type 11.6 (95 %CI = 7.75-17.3) LMICs, 8.99 (95 %CI = 7.70-10.5) HICs. In regression with IPW, LMICs vs. HICs had IRR = 1.78 (95 %CI = 1.31-2.42, p < 0.001). Patients from LMICs were more likely to die than those from HICs [43.6% vs 29.2 %; Relative Risk (RR) = 2.59 (95 %CI = 2.29-2.93), p < 0.001)]. Patients with stroke were more likely to die than those without stroke [RR = 1.43 (95 %CI = 1.19-1.72), p < 0.001)]. CONCLUSIONS: Stroke incidence was low in HICs and LMICs although the stroke risk was higher in LMICs. Both LMIC status and stroke increased the risk of death. Improving early diagnosis of stroke and redistribution of healthcare resources should be a priority. TRIAL REGISTRATION: ACTRN12620000421932 registered on 30/03/2020.

How to Define and Meet Blood Pressure Targets After Traumatic Brain Injury: A Narrative Review.

BACKGROUND: Traumatic brain injury (TBI) poses a significant challenge to healthcare providers, necessitating meticulous management of hemodynamic parameters to optimize patient outcomes. This article delves into the critical task of defining and meeting continuous arterial blood pressure (ABP) and cerebral perfusion pressure (CPP) targets in the context of severe TBI in neurocritical care settings. METHODS: We narratively reviewed existing literature, clinical guidelines, and emerging technologies to propose a comprehensive approach that integrates real-time monitoring, individualized cerebral perfusion target setting, and dynamic interventions. RESULTS: Our findings emphasize the need for personalized hemodynamic management, considering the heterogeneity of patients with TBI and the evolving nature of their condition. We describe the latest advancements in monitoring technologies, such as autoregulation-guided ABP/CPP treatment, which enable a more nuanced understanding of cerebral perfusion dynamics. By incorporating these tools into a proactive monitoring strategy, clinicians can tailor interventions to optimize ABP/CPP and mitigate secondary brain injury. DISCUSSION: Challenges in this field include the lack of standardized protocols for interpreting multimodal neuromonitoring data, potential variability in clinical decision-making, understanding the role of cardiac output, and the need for specialized expertise and customized software to have individualized ABP/CPP targets regularly available. The patient outcome benefit of monitoring-guided ABP/CPP target definitions still needs to be proven in patients with TBI. CONCLUSIONS: We recommend that the TBI community take proactive steps to translate the potential benefits of personalized ABP/CPP targets, which have been implemented in certain centers, into a standardized and clinically validated reality through randomized controlled trials.

Optic Nerve Sheath Diameter Point-of-Care Ultrasonography Quality Criteria Checklist: An International Consensus Statement on Optic Nerve Sheath Diameter Imaging and Measurement.

OBJECTIVES: To standardize optic nerve sheath diameter (ONSD) point-of-care ultrasonography (POCUS) and improve its research and clinical utility by developing the ONSD POCUS Quality Criteria Checklist (ONSD POCUS QCC). DESIGN: Three rounds of modified Delphi consensus process and three rounds of asynchronous discussions. SETTING: Online surveys and anonymous asynchronous discussion. SUBJECTS: Expert panelists were identified according to their expertise in ONSD research, publication records, education, and clinical use. A total of 52 panelists participated in the Delphi process. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three Delphi rounds and three asynchronous discussion rounds generated consensus on quality criteria (QC). This started with 29 QC in addition to other QC proposed by expert panelists. The QC items were categorized into probe selection, safety, body position, imaging, measurement, and research considerations. At the conclusion of the study, 28 QC reached consensus to include in the final ONSD POCUS QCC. These QC were then reorganized, edited, and consolidated into 23 QC that were reviewed and approved by the panelists. CONCLUSIONS: ONSD POCUS QCC standardizes ONSD ultrasound imaging and measurement based on international consensus. This can establish ONSD ultrasound in clinical research and improve its utility in clinical practice.

Predicting short-term outcomes in brain-injured patients: a comprehensive approach with transcranial Doppler and intracranial compliance assessment.

Neurocritical patients frequently exhibit abnormalities in cerebral hemodynamics (CH) and/or intracranial compliance (ICC), all of which significantly impact their clinical outcomes. Transcranial Doppler (TCD) and the cranial micro-deformation sensor (B4C) are valuable techniques for assessing CH and ICC, respectively. However, there is a scarcity of data regarding the predictive value of these techniques in determining patient outcomes. We prospectively included neurocritical patients undergoing intracranial pressure (ICP) monitoring within the first 5 days of hospital admission for TCD and B4C assessments. Comprehensive clinical data were collected alongside parameters obtained from TCD (including the estimated ICP [eICP] and estimated cerebral perfusion pressure [eCPP]) and B4C (measured as the P2/P1 ratio). These parameters were evaluated individually as well as in combination. The short-term outcomes (STO) of interest were the therapy intensity levels (TIL) for ICP management recommended by the Seattle International Brain Injury Consensus Conference, as TIL 0 (STO 1), TIL 1-3 (STO 2) and death (STO 3), at the seventh day after last data collection. The dataset was randomly separated in test and training samples, area under the curve (AUC) was used to represent the noninvasive techniques ability on the STO prediction and association with ICP. A total of 98 patients were included, with 67% having experienced severe traumatic brain injury and 15% subarachnoid hemorrhage, whilst the remaining patients had ischemic or hemorrhagic stroke. ICP, P2/P1, and eCPP demonstrated the highest ability to predict early mortality (p = 0.02, p = 0.02, and p = 0.006, respectively). P2/P1 was the only parameter significant for the prediction of STO 1 (p = 0.03). Combining B4C and TCD parameters, the highest AUC was 0.85 to predict death (STO 3), using P2/P1 + eCPP, whereas AUC was 0.72 to identify ICP > 20 mmHg using P2/P1 + eICP. The combined noninvasive neuromonitoring approach using eCPP and P2/P1 ratio demonstrated improved performance in predicting outcomes during the early phase after acute brain injury. The correlation with intracranial hypertension was moderate, by means of eICP and P2/P1 ratio. These results support the need for interpretation of this information in the ICU and warrant further investigations for the definition of therapy strategies using ancillary tests.

Towards the automatic calculation of the EQUAL Candida Score: Extraction of CVC-related information from EMRs of critically ill patients with candidemia in Intensive Care Units.

OBJECTIVES: Candidemia is the most frequent invasive fungal disease and the fourth most frequent bloodstream infection in hospitalized patients. Its optimal management is crucial for improving patients' survival. The quality of candidemia management can be assessed with the EQUAL Candida Score. The objective of this work is to support its automatic calculation by extracting central venous catheter-related information from Italian text in clinical notes of electronic medical records. MATERIALS AND METHODS: The sample includes 4,787 clinical notes of 108 patients hospitalized between January 2018 to December 2020 in the Intensive Care Units of the IRCCS San Martino Polyclinic Hospital in Genoa (Italy). The devised pipeline exploits natural language processing (NLP) to produce numerical representations of clinical notes used as input of machine learning (ML) algorithms to identify CVC presence and removal. It compares the performances of (i) rule-based method, (ii) count-based method together with a ML algorithm, and (iii) a transformers-based model. RESULTS: Results, obtained with three different approaches, were evaluated in terms of weighted F1 Score. The random forest classifier showed the higher performance in both tasks reaching 82.35%. CONCLUSION: The present work constitutes a first step towards the automatic calculation of the EQUAL Candida Score from unstructured daily collected data by combining ML and NLP methods. The automatic calculation of the EQUAL Candida Score could provide crucial real-time feedback on the quality of candidemia management, aimed at further improving patients' health.

Targeted temperature control following traumatic brain injury: ESICM/NACCS best practice consensus recommendations.

AIMS AND SCOPE: The aim of this panel was to develop consensus recommendations on targeted temperature control (TTC) in patients with severe traumatic brain injury (TBI) and in patients with moderate TBI who deteriorate and require admission to the intensive care unit for intracranial pressure (ICP) management. METHODS: A group of 18 international neuro-intensive care experts in the acute management of TBI participated in a modified Delphi process. An online anonymised survey based on a systematic literature review was completed ahead of the meeting, before the group convened to explore the level of consensus on TTC following TBI. Outputs from the meeting were combined into a further anonymous online survey round to finalise recommendations. Thresholds of ≥ 16 out of 18 panel members in agreement (≥ 88%) for strong consensus and ≥ 14 out of 18 (≥ 78%) for moderate consensus were prospectively set for all statements. RESULTS: Strong consensus was reached on TTC being essential for high-quality TBI care. It was recommended that temperature should be monitored continuously, and that fever should be promptly identified and managed in patients perceived to be at risk of secondary brain injury. Controlled normothermia (36.0-37.5 °C) was strongly recommended as a therapeutic option to be considered in tier 1 and 2 of the Seattle International Severe Traumatic Brain Injury Consensus Conference ICP management protocol. Temperature control targets should be individualised based on the perceived risk of secondary brain injury and fever aetiology. CONCLUSIONS: Based on a modified Delphi expert consensus process, this report aims to inform on best practices for TTC delivery for patients following TBI, and to highlight areas of need for further research to improve clinical guidelines in this setting.

A Comprehensive Perspective on Intracranial Pressure Monitoring and Individualized Management in Neurocritical Care: Results of a Survey with Global Experts.

BACKGROUND: Numerous trials have addressed intracranial pressure (ICP) management in neurocritical care. However, identifying its harmful thresholds and controlling ICP remain challenging in terms of improving outcomes. Evidence suggests that an individualized approach is necessary for establishing tolerance limits for ICP, incorporating factors such as ICP waveform (ICPW) or pulse morphology along with additional data provided by other invasive (e.g., brain oximetry) and noninvasive monitoring (NIM) methods (e.g., transcranial Doppler, optic nerve sheath diameter ultrasound, and pupillometry). This study aims to assess current ICP monitoring practices among experienced clinicians and explore whether guidelines should incorporate ancillary parameters from NIM and ICPW in future updates. METHODS: We conducted a survey among experienced professionals involved in researching and managing patients with severe injury across low-middle-income countries (LMICs) and high-income countries (HICs). We sought their insights on ICP monitoring, particularly focusing on the impact of NIM and ICPW in various clinical scenarios. RESULTS: From October to December 2023, 109 professionals from the Americas and Europe participated in the survey, evenly distributed between LMIC and HIC. When ICP ranged from 22 to 25 mm Hg, 62.3% of respondents were open to considering additional information, such as ICPW and other monitoring techniques, before adjusting therapy intensity levels. Moreover, 77% of respondents were inclined to reassess patients with ICP in the 18-22 mm Hg range, potentially escalating therapy intensity levels with the support of ICPW and NIM. Differences emerged between LMIC and HIC participants, with more LMIC respondents preferring arterial blood pressure transducer leveling at the heart and endorsing the use of NIM techniques and ICPW as ancillary information. CONCLUSIONS: Experienced clinicians tend to personalize ICP management, emphasizing the importance of considering various monitoring techniques. ICPW and noninvasive techniques, particularly in LMIC settings, warrant further exploration and could potentially enhance individualized patient care. The study suggests updating guidelines to include these additional components for a more personalized approach to ICP management.

Inferior vena cava distensibility during pressure support ventilation: a prospective study evaluating interchangeability of subcostal and trans­hepatic views, with both M­mode and automatic border tracing.

The Inferior Vena Cava (IVC) is commonly utilized to evaluate fluid status in the Intensive Care Unit (ICU),with more recent emphasis on the study of venous congestion. It is predominantly measured via subcostal approach (SC) or trans-hepatic (TH) views, and automated border tracking (ABT) software has been introduced to facilitate its assessment. Prospective observational study on patients ventilated in pressure support ventilation (PSV) with 2 × 2 factorial design. Primary outcome was to evaluate interchangeability of measurements of the IVC and the distensibility index (DI) obtained using both M-mode and ABT, across both SC and TH. Statistical analyses comprised Bland-Altman assessments for mean bias, limits of agreement (LoA), and the Spearman correlation coefficients. IVC visualization was 100% successful via SC, while TH view was unattainable in 17.4% of cases. As compared to the M-mode, the IVC-DI obtained through ABT approach showed divergences in both SC (mean bias 5.9%, LoA -18.4% to 30.2%, ICC = 0.52) and TH window (mean bias 6.2%, LoA -8.0% to 20.4%, ICC = 0.67). When comparing the IVC-DI measures obtained in the two anatomical sites, accuracy improved with a mean bias of 1.9% (M-mode) and 1.1% (ABT), but LoA remained wide (M-mode: -13.7% to 17.5%; AI: -19.6% to 21.9%). Correlation was generally suboptimal (r = 0.43 to 0.60). In PSV ventilated patients, we found that IVC-DI calculated with M-mode is not interchangeable with ABT measurements. Moreover, the IVC-DI gathered from SC or TH view produces not comparable results, mainly in terms of precision.

Modelling midline shift and ventricle collapse in cerebral oedema following acute ischaemic stroke.

In ischaemic stroke, a large reduction in blood supply can lead to the breakdown of the blood-brain barrier and to cerebral oedema after reperfusion therapy. The resulting fluid accumulation in the brain may contribute to a significant rise in intracranial pressure (ICP) and tissue deformation. Changes in the level of ICP are essential for clinical decision-making and therapeutic strategies. However, the measurement of ICP is constrained by clinical techniques and obtaining the exact values of the ICP has proven challenging. In this study, we propose the first computational model for the simulation of cerebral oedema following acute ischaemic stroke for the investigation of ICP and midline shift (MLS) relationship. The model consists of three components for the simulation of healthy blood flow, occluded blood flow and oedema, respectively. The healthy and occluded blood flow components are utilized to obtain oedema core geometry and then imported into the oedema model for the simulation of oedema growth. The simulation results of the model are compared with clinical data from 97 traumatic brain injury patients for the validation of major model parameters. Midline shift has been widely used for the diagnosis, clinical decision-making, and prognosis of oedema patients. Therefore, we focus on quantifying the relationship between ICP and midline shift (MLS) and identify the factors that can affect the ICP-MLS relationship. Three major factors are investigated, including the brain geometry, blood-brain barrier damage severity and the types of oedema (including rare types of oedema). Meanwhile, the two major types (stress and tension/compression) of mechanical brain damage are also presented and the differences in the stress, tension, and compression between the intraparenchymal and periventricular regions are discussed. This work helps to predict ICP precisely and therefore provides improved clinical guidance for the treatment of brain oedema.

Effects of mechanical ventilation on the interstitial extracellular matrix in healthy lungs and lungs affected by acute respiratory distress syndrome: a narrative review.

BACKGROUND: Mechanical ventilation, a lifesaving intervention in critical care, can lead to damage in the extracellular matrix (ECM), triggering inflammation and ventilator-induced lung injury (VILI), particularly in conditions such as acute respiratory distress syndrome (ARDS). This review discusses the detailed structure of the ECM in healthy and ARDS-affected lungs under mechanical ventilation, aiming to bridge the gap between experimental insights and clinical practice by offering a thorough understanding of lung ECM organization and the dynamics of its alteration during mechanical ventilation. MAIN TEXT: Focusing on the clinical implications, we explore the potential of precise interventions targeting the ECM and cellular signaling pathways to mitigate lung damage, reduce inflammation, and ultimately improve outcomes for critically ill patients. By analyzing a range of experimental studies and clinical papers, particular attention is paid to the roles of matrix metalloproteinases (MMPs), integrins, and other molecules in ECM damage and VILI. This synthesis not only sheds light on the structural changes induced by mechanical stress but also underscores the importance of cellular responses such as inflammation, fibrosis, and excessive activation of MMPs. CONCLUSIONS: This review emphasizes the significance of mechanical cues transduced by integrins and their impact on cellular behavior during ventilation, offering insights into the complex interactions between mechanical ventilation, ECM damage, and cellular signaling. By understanding these mechanisms, healthcare professionals in critical care can anticipate the consequences of mechanical ventilation and use targeted strategies to prevent or minimize ECM damage, ultimately leading to better patient management and outcomes in critical care settings.

Contemporary management of aneurysmal subarachnoid haemorrhage. An update for the intensivist.

Aneurysmal subarachnoid haemorrhage (aSAH) is a rare yet profoundly debilitating condition associated with high global case fatality and morbidity rates. The key determinants of functional outcome include early brain injury, rebleeding of the ruptured aneurysm and delayed cerebral ischaemia. The only effective way to reduce the risk of rebleeding is to secure the ruptured aneurysm quickly. Prompt diagnosis, transfer to specialized centers, and meticulous management in the intensive care unit (ICU) significantly improved the prognosis of aSAH. Recently, multimodality monitoring with specific interventions to correct pathophysiological imbalances has been proposed. Vigilance extends beyond intracranial concerns to encompass systemic respiratory and haemodynamic monitoring, as derangements in these systems can precipitate secondary brain damage. Challenges persist in treating aSAH patients, exacerbated by a paucity of robust clinical evidence, with many interventions showing no benefit when tested in rigorous clinical trials. Given the growing body of literature in this field and the issuance of contemporary guidelines, our objective is to furnish an updated review of essential principles of ICU management for this patient population. Our review will discuss the epidemiology, initial stabilization, treatment strategies, long-term prognostic factors, the identification and management of post-aSAH complications. We aim to offer practical clinical guidance to intensivists, grounded in current evidence and expert clinical experience, while adhering to a concise format.

The time constant of the cerebral arterial bed: exploring age-related implications.

The time constant of the cerebral arterial bed (τ) represents an estimation of the  transit time of flow from the point of insonation at the level of the middle cerebral artery to the arteriolar-capillary boundary, during a cardiac cycle. This study assessed differences in τ among healthy volunteers across different age groups. Simultaneous recordings of transcranial Doppler cerebral blood flow velocity (CBFV) and arterial blood pressure (ABP) were performed on two groups: young volunteers (below 30 years of age), and older volunteers (above 40 years of age). τ was estimated using mathematical transformation of ABP and CBFV pulse waveforms. 77 healthy volunteers [52 in the young group, and 25 in the old group] were included. Pulse amplitude of ABP was higher [16.7 (14.6-19.4) mmHg] in older volunteers as compared to younger ones [12.5 (10.9-14.4) mm Hg; p < 0.001]. CBFV was lower in older volunteers [59 (50-66) cm/s] as compared to younger ones [72 (63-78) cm/s p < 0.001]. τ was longer in the younger volunteers [217 (168-237) ms] as compared to the older volunteers [183 (149-211) ms; p = 0.004]. τ significantly decreased with age (rS = - 0.27; p = 0.018). τ is potentially an integrative marker of the changes occurring in cerebral vasculature, as it encompasses the interplay between changes in compliance and resistance that occur with age.

Comparison between high-flow nasal oxygen (HFNO) alternated with non-invasive ventilation (NIV) and HFNO and NIV alone in patients with COVID-19: a retrospective cohort study.

BACKGROUND: Non-invasive respiratory support (conventional oxygen therapy [COT], non-invasive ventilation [NIV], high-flow nasal oxygen [HFNO], and NIV alternated with HFNO [NIV + HFNO] may reduce the need for invasive mechanical ventilation (IMV) in patients with COVID-19. The outcome of patients treated non-invasively depends on clinical severity at admission. We assessed the need for IMV according to NIV, HFNO, and NIV + HFNO in patients with COVID-19 according to disease severity and evaluated in-hospital survival rates and hospital and intensive care unit (ICU) lengths of stay. METHODS: This cohort study was conducted using data collected between March 2020 and July 2021. Patients ≥ 18 years admitted to the ICU with a diagnosis of COVID-19 were included. Patients hospitalized for < 3 days, receiving therapy (COT, NIV, HFNO, or NIV + HFNO) for < 48 h, pregnant, and with no primary outcome data were excluded. The COT group was used as reference for multivariate Cox regression model adjustment. RESULTS: Of 1371 patients screened, 958 were eligible: 692 (72.2%) on COT, 92 (9.6%) on NIV, 31 (3.2%) on HFNO, and 143 (14.9%) on NIV + HFNO. The results for the patients in each group were as follows: median age (interquartile range): NIV (64 [49-79] years), HFNO (62 [55-70] years), NIV + HFNO (62 [48-72] years) (p = 0.615); heart failure: NIV (54.5%), HFNO (36.3%), NIV + HFNO (9%) (p = 0.003); diabetes mellitus: HFNO (17.6%), NIV + HFNO (44.7%) (p = 0.048). > 50% lung damage on chest computed tomography (CT): NIV (13.3%), HFNO (15%), NIV + HFNO (71.6%) (p = 0.038); SpO2/FiO2: NIV (271 [118-365] mmHg), HFNO (317 [254-420] mmHg), NIV + HFNO (229 [102-317] mmHg) (p = 0.001); rate of IMV: NIV (26.1%, p = 0.002), HFNO (22.6%, p = 0.023), NIV + HFNO (46.8%); survival rate: HFNO (83.9%), NIV + HFNO (63.6%) (p = 0.027); ICU length of stay: NIV (8.5 [5-14] days), NIV + HFNO (15 [10-25] days (p < 0.001); hospital length of stay: NIV (13 [10-21] days), NIV + HFNO (20 [15-30] days) (p < 0.001). After adjusting for comorbidities, chest CT score and SpO2/FiO2, the risk of IMV in patients on NIV + HFNO remained high (hazard ratio, 1.88; 95% confidence interval, 1.17-3.04). CONCLUSIONS: In patients with COVID-19, NIV alternating with HFNO was associated with a higher rate of IMV independent of the presence of comorbidities, chest CT score and SpO2/FiO2. Trial registration ClinicalTrials.gov identifier: NCT05579080.