key: cord-0871798-i90wpioc
authors: Ball, Lorenzo; Robba, Chiara; Herrmann, Jacob; Gerard, Sarah E; ME, Yi Xin; Pigati, Maria; Berardino, Andrea; Iannuzzi, Francesca; Battaglini, Denise; Brunetti, Iole; Minetti, Giuseppe; Seitun, Sara; Vena, Antonio; Giacobbe, Daniele Roberto; Bassetti, Matteo; Rocco, Patricia RM; Cereda, Maurizio; Castellan, Lucio; Patroniti, Nicolò; FESAIC, Paolo Pelosi FERS
title: Early versus late intubation in COVID-19 patients failing helmet CPAP: a quantitative computed tomography study
date: 2022-03-17
journal: Respir Physiol Neurobiol
DOI: 10.1016/j.resp.2022.103889
sha: 5321baff1c8a98657be9ac6ac4831c2a9bc1c70a
doc_id: 871798
cord_uid: i90wpioc

Purpose To describe the effects of timing of intubation in COVID-19 patients that fail helmet continuous positive airway pressure (h-CPAP) on progression and severity of disease. Methods COVID-19 patients that failed h-CPAP, required intubation, and underwent chest computed tomography (CT) at two levels of positive end-expiratory pressure (PEEP, 8 and 16 cmH2O) were included in this retrospective study. Patients were divided in two groups (early versus late) based on the duration of h-CPAP before intubation. Endpoints included percentage of non-aerated lung tissue at PEEP of 8 cmH2O, respiratory system compliance and oxygenation. Results Fifty-two patients were included and classified in early (h-CPAP for ≤2 days, N=26) and late groups (h-CPAP for >2 days, N=26). Patients in the late compared to early intubation group presented: 1) lower respiratory system compliance (median difference, MD -7 mL/cmH2O, p=0.044) and PaO2/FiO2 (MD -29 mmHg, p=0.047), 2) higher percentage of non-aerated lung tissue (MD 7.2%, p=0.023) and 3) similar lung recruitment increasing PEEP from 8 to 16 cmH2O (MD 0.1%, p=0.964). Conclusions In COVID-19 patients receiving h-CPAP, late intubation was associated with worse clinical presentation at ICU admission and more advanced disease. The possible detrimental effects of delaying intubation should be carefully considered in these patients.

The coronavirus disease 2019 has posed unprecedented challenges to intensive care unit (ICU) physicians Zhu et al., 2020) . Clinical manifestations range from asymptomatic to acute hypoxemic respiratory failure requiring invasive mechanical ventilation and admission to the ICU Ren et al., 2020) . Early intubation has been recommended in patients with signs of respiratory distress to prevent progression from moderate to severe lung injury (Marini and Gattinoni, 2020) due to increased respiratory drive and risk of patient self-inflicted lung injury (P-SILI) . However, there are controversies regarding this approach (Marini and Gattinoni, 2020; Tobin et al., 2020) which might result in higher incidence of ventilator-associated pneumonia and ventilator-induced lung injury (Tobin et al., 2020) , as reflected by an increased use of non-invasive respiratory support during the evolution of the pandemic (Doidge et al., 2021) . Among the different types of non-invasive respiratory support, continuous positive airway pressure (CPAP) delivered through an helmet (h-CPAP) has been widely applied especially in the European countries, since it is easy to use and for its potential of reducing environmental dispersion of droplets (Amirfarzan et al., 2021) .

Because of the shortage of critical care resources and number of ICU beds, most centers extensively employed non-invasive respiratory support strategies even in patients with radiological and functional (respiratory mechanics and gas exchange parameter) parameters that indicate the need for invasive mechanical ventilation (Franco et al., 2020) .

The effects of delaying intubation in COVID-19 patients on clinical outcome are matter of debate. In a recent meta-analysis, intubation within 24 h from ICU admission was not superior to intubation at any time after 24 h of ICU J o u r n a l P r e -p r o o f admission (Papoutsi et al., 2021) . Nevertheless, only observational trials were included, and the time spent under non-invasive respiratory support prior to ICU admission was not reported. Therefore, in COVID-19 patients that fail h-CPAP, the effects of timing of intubation on physiological parameters and severity of disease at ICU admission are still unknown. In our ICU, a large proportion of intubated patients was systematically assessed with chest computed tomography (CT) performed at two fixed levels of positive end-expiratory pressure (PEEP) to assess extension of disease and alveolar recruitment (Ball et al., 2021b) .

The present study was performed to describe the physiologic effects of early versus late intubation in COVID-19 patients previously receiving h-CPAP. We hypothesized that, in COVID-19 patients treated with h-CPAP, late compared to early intubation may be associated with higher amounts of non-aerated tissue, greater alveolar recruitment, as well as worse gas-exchange and lower respiratory system compliance.

This retrospective cohort study was conducted in a tertiary care hospital in Genoa, Northern Italy from March to December 2020, covering two pandemic surges. The protocol of the study was approved by the ethical review board (Comitato Etico Regione Liguria, protocol n. 163/2020) and the need for written informed consent was waived for retrospectively collected data; consent was delayed after discharge for prospectively collected data in unconscious patients. The study is reported in accordance with the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) (von Elm et al., 2007) and J o u r n a l P r e -p r o o f REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) (Benchimol et al., 2015) recommendations.

At our institution, starting from March 20 th 2020, a standardized protocol was introduced to acquire chest CT scans obtained at two fixed PEEP levels of 8 and 16 cmH 2 O (Ball et al., 2021b) . During the pandemic surges, ICU admission was limited to intubated patients, while in low and intermediate-care settings patients were managed using conventional oxygen therapy or h-CPAP. The decision to intubate was performed by a dedicated team of intensivists and main criteria were inability to maintain oxygenation with h-CPAP, respiratory rate above 28 min -1 , decline of consciousness and signs of respiratory distress (Robba et al., 2020) . A trial of h-CPAP was used in patients receiving conventional oxygen therapy in case of clinical deterioration, before considering intubation. Unavailability of ICU beds was the leading reason for delaying intubation in the context of pandemic surges. Once intubated and admitted to the ICU, all patients with an indication for CT underwent two-PEEP CT scan to assess disease severity and response to PEEP.

This study included all consecutive patients that received at least 2 hours of h-CPAP prior to intubation and ICU admission and that underwent a two-PEEP CT scan during their ICU stay. In patients with more than one two-PEEP CT available, the scan closest to intubation was chosen. Reasons for not performing two-PEEP scan and therefore exclusion criteria were: clinical instability hampering transport to the CT facility, absence of a clinical indication for chest CT, need for contrastenhanced CT, contraindications to high PEEP (e.g., undrained pneumothorax).

Patients were ventilated using a tidal volume of 6 mL per kg of predicted body weight with tolerance of higher values if the driving pressure was below 15 cmH 2 O. Part of the patients were included in another study (Ball et al., 2021b) . However, in the present study the effects of timing of intubation in COVID-19 patients that fail h-CPAP treatment on the progression and severity of disease were investigated. The respiratory rate was set targeting pH above 7.25 tolerating moderate hypercapnia, the clinical PEEP level was set by the treating physician to maintain the PaO 2 above 60 mmHg and limiting the plateau pressure below 27 cmH 2 O, if feasible. Clinical data were gathered from the electronic clinical record on the day of intubation and ICU admission and on the day of the two-PEEP CT scan, survival was assessed at ICU discharge. The ventilatory ratio (Sinha et al., 2009) , an estimator of ventilation impairment correlated with dead-space in COVID-19 (Diehl et al., 2020) , was computed as:

All chest two-PEEP CT scans were performed using a Somatom Definition Flash scanner (Siemens, Erlangen, Germany), operated at 140 kVp with dose modulation.

The first scan was acquired at PEEP 8 cmH 2 O during expiratory breath-hold, then PEEP was increased to 16 cmH 2 O and the scan was repeated after one minute. This resulted in a ventilation reaching plateau pressures from 25 to 35 cmH 2 O between the two scans. The range of pressures reached and the time spent between the two J o u r n a l P r e -p r o o f scan was sufficient to recruit most respiratory units susceptible to the PEEP effect (Crotti et al., 2001; Katz et al., 1981) . Images were reconstructed with a slice thickness of 0.75 mm or 1.25 mm and a sharp convolution kernel (B80f). Lung parenchyma segmentation was performed using an automated multi-resolution convolutional neural network with automated airway exclusion (Gerard et al., 2020) followed by manual refinement using ITKSnap (http://www.itksnap.org). Images were analyzed with Matlab (Mathworks, Massachussetts, US) using custom-made scripts based on established quantitative analysis methods, assuming density proportional to the gas and tissue fraction contained within each voxel and approximating tissue density to 1 g per mL (Protti et al., 2014) . We defined hyper-aerated, normal, poorly aerated, and non-aerated lung regions based on Hounsfield Units (HU) thresholds (below -900 HU, -900 HU to -500 HU, -500 HU to -100 HU and above -100 HU, respectively) . Three regions of interest (ROI) of equal lung weight (Güldner et al., 2016; Scaramuzzo et al., 2020) were defined along the ventral-dorsal and cranio-caudal axes. Lung recruitment was defined as the proportion of total lung weight accounted for non-aerated tissue at PEEP 8 cmH 2 O that was re-aerated at PEEP of 16 cmH 2 O, as previously described (Gattinoni et al., 2006) : 

The primary endpoint of the study was the percent amount of non-aerated lung tissue. Among patients included in a previous study (Ball et al., 2021b) , those that received less than 2 days of h-CPAP before intubation had 36%±8% non-aerated lung tissue mass. Accounting for the use of non-parametric statistics, we needed to analyze at least 50 patients divided in two equally sized groups to achieve 80%

power ( 

As illustrated in Figure 1 , of 162 patients admitted to the ICU in the study period, 52 received at least 2 hours of h-CPAP before intubation and underwent chest CT scan at two PEEP levels and were therefore analyzed. Of these, 26 patients were included in a previous unrelated study on alveolar recruitment in COVID-19 (Ball et al., 2021b) . The median [interquartile range] duration of h-CPAP before intubation was 2 [1 -7] days: 26 patients were classified in the early group (duration of h-CPAP ≤ 2 days) and 26 in the late group (h-CPAP for more than 2 days before intubation).

The ICU mortality was 12/26 (46%) in the early group and 16/26 (62%) in the late group (p=0.404). Characteristics of patients in the two groups at ICU admission are described in Table 1 . Patients in the late group, compared to the early intubation group, had a longer time elapsed from symptoms onset and hospital admission to ICU admission, but similar comorbidities and sequential organ failure assessment (SOFA) score. At ICU admission, in the late compared to the early group, the respiratory system compliance was lower (median difference -7 mL/cmH 2 O, 95% CI from -14 to -1 mL/cmH 2 O, p=0.044), the respiratory rate was higher (median difference 3 min -1 , 95% CI from 1 to 6 min -1 , p=0.016) and the PaO 2 /FiO 2 was lower (median difference -29 mmHg, 95% CI from -73 to -1 mmHg, p=0.047). Plateau pressure was similar in the two groups, but patients in the late intubation group were J o u r n a l P r e -p r o o f ventilated at lower PEEP level, reflecting the need of limiting PEEP to maintain plateau pressure below a safety threshold value ( Table 1) .

Clinical and quantitative chest CT parameters in the two groups are reported in Figure 2) , less normally aerated tissue (median difference -11.2%, 95% CI from -15.8% to 3.2%, p=0.004, Figure 2 ) and higher percentage of excess lung tissue mass (median difference 22%, 95% CI from 1% to 42%, p=0.048, Table 3 ). In both groups, the amount of non-aerated and poorly aerated tissue was modestly reduced increasing PEEP from 8 to 16 cmH 2 O (Figure 2 and Table 3) .

Lung recruitment was similar in the two groups (median difference 0.1%, 95% CI from -1.8% to 2.0%, p=0.964, Table 3 ). The effects of PEEP increase according to J o u r n a l P r e -p r o o f lung density are depicted in Figure 3 . Loss of aeration was distributed along a ventral to dorsal and a cranial to caudal gradients (eFigure 1 and eFigure 2). 

In patients with severe COVID-19 pneumonia receiving h-CPAP prior to intubation, late versus early intubation resulted in: 1) higher amount of non-aerated lung tissue; 2) comparable lung recruitment after PEEP increase from 8 cmH 2 O to 16 cmH 2 O; and 3) worse respiratory mechanics and gas exchange at ICU admission and during ICU stay.

We performed standardized acquisition of chest CT images at two fixed levels of PEEP, allowing a precise comparison between groups, independent of the J o u r n a l P r e -p r o o f ventilatory strategy adopted during the ICU stay. Moreover, the analysis of the effects of 16 versus 8 cmH 2 O of PEEP provided detailed information on the nature of lung lesions. Our cohort was characterized by a wide range of exposure time to noninvasive respiratory support prior to intubation, well representative of different clinical management strategies adopted during the pandemic. Since all the patients included ultimately failed h-CPAP and required intubation, the time spent under h-CPAP was considered as an objective marker of timeliness of intubation. The pre-intubation and ICU management of patients was standardized at our institution (Robba et al., , 2020 . We included only patients that received h-CPAP, which was the most commonly used non-invasive respiratory support in our center, reducing the possible confounding effect of different devices. Furthermore, the two groups were homogeneous according to comorbidities and non-respiratory disease severity at ICU admission and timing from intubation to chest CT scan.

Non-invasive respiratory support has been considered a bridge therapy to overcome gas exchange impairment. Patients with late intubation presented, at PEEP of 8 cmH 2 O, lower gas volume and normally aerated tissue, as well as higher poorly-and non-aerated tissue; this may be attributed to the duration of h-CPAP thus increasing the risk of P-SILI. In this line, during h-CPAP, high respiratory drive and transpulmonary pressure can promote progression of lung injury (Cruces et al., 2020) through increased trans-alveolar and trans-capillary pressure gradients, especially in juxta-diaphragmatic regions . Another possible mechanism explaining the worse lung injury observed in the CT analysis in the late intubation group is viral disease progression per se. Both disease progression and superimposed P-SILI could result in h-CPAP failure and need for intubation.

Additionally, late intubation was associated with worse oxygenation and respiratory J o u r n a l P r e -p r o o f mechanics parameters. The reduction in respiratory system compliance may be associated with the relevant loss of lung gas volume and normally aerated tissue, while oxygenation impairment may be explained by the higher proportion of nonaerated and poorly aerated tissue in the late intubation group. Other studies suggested a relevant role of perfusion abnormalities in the non-aerated (Ball et al., 2021a) and poorly aerated (Busana et al., 2021) regions in determining the severity of gas exchange impairment.

The non-aerated tissue may be caused by several mechanisms: 1) increased vascular permeability resulting in higher alveolar and interstitial oedema; 2) consolidation and/or 3) fibrosis. Increasing PEEP from 8 to 16 cmH 2 O resulted in minimal variations in the non-aerated tissue, showing a modest role of oedema in determining such alterations. Differently from conventional acute respiratory distress syndrome (ARDS), characterized by higher oedema and lung recruitability (Coppola et al., 2021; Gattinoni et al., 2006) at late phase of lung injury, COVID-19 patients in the late intubation group had a severe lung disease which was not associated with increased recruitability (increased response to PEEP). These findings suggest that the mechanisms leading to worsening of respiratory function ultimately resulting in h-CPAP failure might be related to more consolidation and fibrosis rather than atelectasis and interstitial oedema (Barisione et al., 2021; Grillo et al., 2020; Tonelli et al., 2021) . Another determinant of gas-exchange impairment in COVID-19 is the extension of ground glass opacities, corresponding to poorly aerated lung tissue (Busana et al., 2021) . The pathophysiological meaning of these lesions is under debate. Studies on lung perfusion showed that these regions might act both as areas of high or low ventilation/perfusion ratio (Ball et al., 2021a) , depending on the complex interaction of vasodilation, hypoxic or mechanical vasoconstriction and J o u r n a l P r e -p r o o f microthrombosis (Busana et al., 2021; Marini and Gattinoni, 2020) . This study has limitations that should be acknowledged. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

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FiO 2 , median

PaO 2 /FiO 2 , median [IQR], mmHg 129

Haemodynamics Heart rate, median [IQR], min -1 median [IQR], cmH 2 O 10

PaO 2 /FiO 2 , median [IQR], mmHg 111

Normally aerated mass, median [IQR], (g) in non-aerated)

Changes in poorly aerated

We are grateful for the efforts of the collaborators of the GECOVID (GEnoa COVID-