key: cord-0803714-aty50muh
authors: Paternoster, Gianluca; Bertini, Pietro; Belletti, Alessandro; Landoni, Giovanni; Gallotta, Serena; Palumbo, Diego; Isirdi, Alessandro; Guarracino, Fabio
title: Veno-Venous Extracorporeal Membrane Oxygenation in Awake Non-Intubated Patients with COVID-19 ARDS at High Risk for Barotrauma
date: 2022-03-17
journal: J Cardiothorac Vasc Anesth
DOI: 10.1053/j.jvca.2022.03.011
sha: 18d5c40c218e669426cbd68ad264d43e4b176b6f
doc_id: 803714
cord_uid: aty50muh

Objective : To assess the efficacy of an awake veno-venous extracorporeal membrane oxygenation (VV-ECMO) management strategy in preventing clinically relevant barotrauma in coronavirus disease 2019 (COVID-19) patients with severe acute respiratory distress syndrome (ARDS) at high risk for pneumothorax (PNX)/pneumomediastinum (PMD), defined as detection of the Macklin-like sign on chest computed tomography (CT) scan. Design : Case series Setting : Intensive Care Unit of tertiary-care institution Participants : Seven patients with COVID-19-associated severe ARDS and Macklin-like radiological sign on baseline chest CT. Interventions : Primary VV-ECMO under spontaneous breathing instead of invasive mechanical ventilation (IMV). All patients received non-invasive ventilation or oxygen through high-flow nasal cannula before and during ECMO support. We collected data on cannulation strategy, clinical management, and outcome. Failure of awake VV-ECMO strategy was defined as the need for IMV due to worsening respiratory failure or delirium/agitation. The primary outcome was the development of PNX/PMD. Measurements and Main Results : No patient developed PNX/PMD. The awake VV-ECMO strategy failed in one patient (14.3%). Severe complications were observed in four (57.1%) patients and were: intracranial bleeding in one patient (14.3%); septic shock in two patients (28.6%); and secondary pulmonary infections in three patients (42.8%). Two patients died (28.6%), while five were successfully weaned off VV-ECMO and discharged home from the hospital. Conclusions : VV-ECMO in awake and spontaneously breathing patients with severe COVID-19 ARDS may be a feasible and safe strategy to prevent the development of PNX/PMD in patients at high risk for this complication.

Patients with coronavirus disease 2019 (COVID-19) frequently develop acute respiratory distress syndrome (ARDS), with admission to an intensive care unit (ICU) and institution of mechanical ventilation. [1] [2] [3] Several studies suggest that pneumomediastinum (PMD) and pneumothorax (PNX) occur frequently in mechanically ventilated patients with COVID-19-related ARDS, with a reported rate of 12 to 20%. 4-6 COVID-19 ARDS patients are at higher risk for PMD/PNX occurrence as compared with patients with ARDS due to other than COVID-19 causes. 6, 7 A higher than expected incidence of PMD/PNX was also observed in COVID-19 patients not requiring invasive mechanical ventilation. [8] [9] [10] Notably, PNX/PMD has been reported to occur despite the use of lung-protective mechanical ventilation strategies. 4, 6, 7, 11 Unfortunately, PNX/PMD have difficult, non-standardized management. 4, 11, 12 , and mortality rates for COVID-19 ARDS patients who develop PNX/PMD may be higher than 60%. 4, 6, 13 Macklin-like radiological sign on chest computed tomography (CT) scan (i.e. linear collection of air contiguous to the bronchovascular sheath on lung parenchyma windowed CT images 14, 15 ) ( Figure   1 ) is a consistent, highly reproducible predictor of barotrauma in mechanically ventilated COVID-19 ARDS patients 8 to 12 days before overt PNX/PMD development (reported sensitivity: 89.2%, specificity: 95.6%, overall accuracy: 94.2%). 4, 16 Of note, Palumbo et al. 16 reported an almost perfect inter reader agreement for the detection of this radiological sign.

Extracorporeal membrane oxygenation (ECMO) is an extracorporeal life support technique that is used to support or replace lung function in case of severe respiratory failure refractory to conventional strategies. 17 Accordingly, ECMO is generally instituted in patients already receiving invasive mechanical ventilation, although cases of "awake" ECMO for non-intubated patients have been described. [18] [19] [20] [21] We, therefore, hypothesized that non-intubated COVID-19 patients with severe ARDS and at high risk for barotrauma (i.e. patients already with Macklin sign on CT scan) may benefit from early, awake ECMO and avoidance of invasive mechanical ventilation (IMV).

In this case series, we present characteristics, management and outcome of the first seven patients managed according to this strategy. 22 Documented infection was defined as SARS-CoV-2 RNA detection on nose and throat swabs or bronchoalveolar lavage (BAL) using multiplexed-tandem PCR technology.

Patients who were already under IMV at the time of VV-ECMO implantation were excluded from the study.

General management of patients with COVID-19 patients at our institution follows international guidelines and recommendations regarding the institution of non-invasive and invasive ventilation, and consideration for ECMO support. 18, [23] [24] [25] [26] Awake pronation for non-intubated COVID-19 ARDS patients, with or without CPAP, is also used at our institution. 27, 28 All patients with moderate-to-severe (as defined by the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO 2 /FiO 2 ≤ 200 mmHg) 22 COVID-19 related ARDS receive chest CT at the discretion of attending clinicians. Patients were considered for IMV according to criteria suggested by Pisano et al. 29 However, in case of detection of Macklin-like radiological sign on the first chest CT scan performed in the emergency department in non-intubated patients with severe COVID-19 ARDS, we decided to avoid intubation and proceed directly with VV-ECMO implantation. Macklin-like radiological sign effectively predicts subsequent development of PNX/PMD in mechanically ventilated COVID-19 ARDS patients. 4, 16 We, therefore, decided to proceed directly with ECMO to maintain spontaneous ventilation and avoid further barotrauma in patients already at risk for severe complications such as PNX and/or PMD. (Figure 2) The decision to proceed with VV-ECMO as the initial strategy instead of IMV, including potential advantages and risks, was discussed with each patient, and each patient provided consent.

Cannulation was performed using transthoracic echocardiography (TTE)-guided approach. The decision to use a femoro-jugular, femoro-femoral, or a single, double-lumen, internal jugular cannula 30 configuration was at the discretion of attending clinicians.

Before site cannulation, in all patients ultrasound color Doppler was performed to assess dimension and patency of target vessels, and exclude the presence of thrombi.

During cannulation, patients were placed in the supine position and, after local anesthesia and mild sedation, cannulation was performed. During the cannulation maneuvers, five patients received oxygen through a high-flow nasal cannula (HFNC), and two patients (previously on helmet continuous positive airway pressure [CPAP]) through a non-rebreathing mask with an oxygen reservoir.

The decision to proceed with tracheal intubation after ECMO initiation was individualized and based on clinical signs of persistent respiratory distress despite optimization of NIV and ECMO support, marked agitation requiring deep sedation, cardiovascular failure, or inability to protect airways.

Anticoagulation during ECMO was maintained with a continuous infusion of unfractionated heparin, titrated to achieve an Antifactor Xa activity of 0.2 to 0.4. Antifactor Xa monitoring represents the institutional preference, since assessing the common pathway of the coagulation cascade may be the most reliable measure of the anticoagulation status. 31 An heparin bolus (5000 international units) was administered before cannulation.

The ECMO machines used in our case series were Cardiohelp HLS 7.0 (Getinge AB, Göteborg, Sweden) in five patients e Rotaflow PLS (Getinge AB, Göteborg, Sweden) in two patients. CMO flow was 2.5 l/min to 5 l/min.

This study aimed to assess the efficacy of awake ECMO management in preventing clinically relevant barotrauma in Covid 19 patients with severe ARDS and at high risk for pneumothorax/pneumomediastinum based on CT scan evaluation if treated with invasive mechanical ventilation.

The primary outcome was the development of PNX and/or PMD after the institution of VV-ECMO.

Along with baseline characteristics, data collection included comorbidities, chronic medications, COVID-19 specific data, concomitant medical treatment, ECMO settings, and outcome data (occurrence of PNX/PMD, hospital survival, awake ECMO strategy failure [defined as the need for intubation for worsening respiratory failure or agitation after ECMO initiation], duration of ECMO support, length of ICU and hospital stay, and adverse events during support).

A convenience sample was considered for this analysis. All data were stored in an electronic database. Dichotomous and categorical variables were expressed as numbers and percentages, while continuous variables were expressed as means ± standard deviations (SD) in case of normal distribution, or median and interquartile range (IQR) in case of non-normal distribution. Given the small sample size and the study design, we performed only a descriptive analysis.

All analyses were performed with Stata (version 15, StataCorp, College Station, Texas, USA).

During the study period, we enrolled a total of seven consecutive patients with severe COVID-19 ARDS, PaO 2 /FiO 2 ratio < 70, and Macklin-like radiological sign at the baseline CT scan who underwent ECMO implantation instead of IMV. The topographical distribution of the Macklin-like radiological sign within the lungs was found to be peripheral (adjacent to segmental/subsegmental bronchial branches) in five out of seven cases (71.4%) and central (adjacent to lobar bronchial branches) in the remaining two (29.6%). Patients were followed up for a total of 117± 18 days.

The majority of patients were male (71%) with a mean age of 51,71 ± 12,46 (range 41-67) years.

All patients had at least one comorbidity (Table 1) .

All patients received steroids, and most patients were on antibiotics. Most patients received cardiovascular support with vasopressor or inotropes during ECMO support (Table 1) .

All patients received oxygen through HFNC and/or NIV before ECMO (Figure 3) , while all of them received oxygen through HFNC during ECMO. One patient underwent awake pronation on NIV before ECMO implantation.

The median time between the onset of symptoms and ICU admission and from ICU admission and the start of ECMO support are presented in Table 1 .

ECMO cannulation was femoro-femoral in four patients, femoro-jugular in two patients, while one patients received a single, double-lumen internal jugular cannula ( Table 2 ).

Blood gas analysis parameters at the time of ECMO implantation are presented in Table 2 . Notably, PaO 2 /FiO 2 ratio was 56 ± 8.9.

The median duration of the ECMO support was 15 (2-71) days.

Complications and outcomes are presented in Table 2 . No patient developed PNX, PMD, or other signs of barotrauma.

In one patient (14.2%) tracheal intubation was performed 18 hours after the start of ECMO support due to persistent hypoxemia and worsening respiratory mechanics. In this case, a third venous cannula was added to improve venous return, leading to restored ECMO efficacy. This patient survived hospital discharge. This patient was considered a case of awake ECMO failure ( Table 2) A total of two patients (28.6%) died because of multiorgan failure as a consequence of septic shock secondary to bacterial superinfection. One of the two patients was intubated three hours before death. We did not consider this as ECMO failure as the patient was intubated due to worsening of cognitive function and hemodynamics requiring high-dose inotropes and vasopressors, and not for worsening respiratory failure. The two patients who died received femoro-femoral cannulation.

One patient developed intracranial bleeding (subarachnoid hemorrhage), without indication to surgical treatment according to neurosurgeons. The patient ultimately recovered and was discharged home.

No pulmonary embolism was observed.

At the time of this report, all survived patients have been discharged home.

In this observational study, we found that early institution of VV-ECMO in COVID-19 patients with severe ARDS and at high risk for barotrauma is feasible and resulted in no barotrauma event.

These results are particularly encouraging considering the high risk of barotrauma in COVID-19 ARDS patients 4, 16 and the high mortality rates for patients who developed this complication. 6

The use of ECMO in awake spontaneously breathing patients has been previously described in several case series in patients with ARDS, 32 cardiogenic shock, 33 waiting for lung transplantation, 34 immunocompromised, 35 and in mixed respiratory failure populations, 36 including cases of ECMO before intubation. 19, 35, 37 In addition, the successful application of VV-ECMO approach instead of invasive mechanical ventilation has already been described in COVID-19 patients. 19, 20, 37, 38 Schmidt et al. report a successful case of awake VV-ECMO in a patient with severe ARDS who refused intubation. 19 Similarly, Azzam et al. reported the case of a patient with extensive surgical emphysema, PMD, and bilateral PNX in which ECMO was used instead of mechanical ventilation. 20 The patient survived and was discharged home. In a small case series of seven patients by Assanangkornchai et al, four patients ultimately required intubation, and one died. 37 Compared to all these studies, in our case series the decision to start awake VV-ECMO instead of invasive mechanical ventilation was undertaken after evaluation of chest CT scan that classified patients at high risk for subsequent barotrauma development. Our previous experience in COVID- 19 ARDS patients showed that Macklin-like radiological sign has an 89% sensitivity and a 95% specificity in predicting PNX/PMD development, i.e. 33 out of 39 Macklin-positive patients (84%) developed overt PNX/PMD within the following twelve days. 4, 16 On the contrary, in the present study we found zero cases of PNX/PMD out of seven Macklin-positive patients. To the best of our knowledge, this is the first description of ARDS management and extracorporeal life support algorithm including Macklin-like radiological sign to stratify patient's risk. Furthermore, this is also the first study in which early detection of Macklin-like radiological sign led to a change in clinical management. The use of awake VV-ECMO without invasive mechanical ventilation probably allowed us to avoid PNX or PMD development despite the high risk 4, 16 . Indeed, we believe that this is the most interesting finding of our study (Table 3) .

Mortality and intubation rate in our study are comparable to a previous case series on awake VV-ECMO in COVID-19 and non-COVID ARDS patients. 32,37 , and lower as compared with case series on immunocompromised patients. 35 Comparison with data from other series is generally difficult, as in several cases awake ECMO was not the first strategy and patients underwent IMV first, 21,36 but our results are nevertheless encouraging. Interestingly, the mortality rate is lower as compared with large case series on VV-ECMO in COVID-19 ARDS patients. 39, 40 However, our study has a very small sample size and therefore comparison with large case series should be interpreted with caution.

There is a strong rationale for the use of VV-ECMO in the treatment of respiratory failure in awake, spontaneously breathing patients that has been thoughtfully previously reviewed. 18 In particular, awake ECMO allows to avoid several side effects related to prolonged sedation and paralysis, to reduce the risk of secondary infections related to prolonged invasive mechanical ventilation, and avoid possible complications of additional invasive procedures such as tracheostomy. Furthermore, patients on awake VV-ECMO may undergo early active physiotherapy, with potential long-term benefits and shorter recovery time in terms of functional capacity and neuropsychological recovery.

In addition to these potential advantages, our data suggest that awake VV-ECMO without intubation is feasible in severe COVID-19 ARDS and may have the additional advantage of preventing barotrauma-related complications.

Our management strategy is based on our observation that COVID-19 ARDS patients with Macklin-like radiological sign have a very high risk of developing barotrauma despite protective invasive mechanical ventilation, 4,16 that barotrauma is common in COVID-19 ARDS patients, 6 and the associated mortality rate is greater than 60%. 6, 13, 41 We, therefore, hypothesized that patients with severe COVID-19 ARDS and Macklin-like radiological sign on chest CT scan may benefit from the early application of awake VV-ECMO rather than invasive mechanical ventilation, considering that our preliminary results show halved mortality rate in these high patients.

Patients with COVID-19 ARDS may be the ideal candidate for such strategy, as dissociation between the degree of hypoxia and clinical signs of respiratory distress has been frequently reported in COVID-19 patients. 42 This may help in maintaining wakefulness with minimal anxiolysis and potentially reducing the risk of self-induced lung injury by avoiding excessive respiratory drive. 43, 44 We believe that our findings may have relevant clinical implications. Our data suggest for the first time that in COVID-19 severe ARDS progression of barotrauma from clinically silent (Macklin-like radiological sign) to overt PNX/PMD may be successfully avoided by early application of alternative strategies, such as VV-ECMO. While this might seem excessive, we should consider the 60% mortality rate for COVID-19 ARDS patients with barotrauma, which in our opinion justifies the application of a resource-consuming technology such as ECMO. Although we performed our studies in COVID-19 ARDS, our findings encourage exploring the clinical significance of Macklinlike radiological effect and alternative management strategies also in non-COVID-19 ARDS.

It might be argued whether early application of a risky procedure such as ECMO before conventional strategies (including rescue stratgies such as proning and inhaled nitric oxide) is justified. This remains a key issue to be determined, as complications of ECMO are well described 45 . Indeed, one patient enrolled in our study developed subarachnoid hemorrhage from which recovered. Nevertheless, major complications such as hemorrhagic stroke and massive bleeding were similar between ARDS patients treated with versus without ECMO in the recent ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial 46 , while ischemic stroke rate was even lower in the ECMO group. Furthermore, mechanical ventilation is associated with a relatively high rate of complications itself, including barotrauma (6 to 10% of ARDS patients receiving invasive ventilation), ventilator-associated pneumonia, and adverse effects of prolonged sedation and immobilization. Notably, with the exception of prone positioning, none of currently recommended rescue strategies for severe ARDS has been proven to be effective in improving outcome 47, 48 , and some (e.g. recruitment maneouvers, inhaled nitric oxide) may actually be harmful 49, 50 . On the contrary, there are some evidence that ECMO may ultimately improve survival in ARDS patients 51 .

Accordingly, we do believe that early ECMO may be considered and justified in high-risk patients (such as those at high risk for barotrauma), and that future studies should be focused on identifying such patients.

An interesting and challenging aspect of our described approach regards the potential of patient self-induced lung injury (P-SILI). [52] [53] [54] The main mechanism leading to P-SILI is supposed to rely upon large inspiratory efforts imposed on severely injured lungs during mechanical, either invasive or non-invasive ventilation. 55 While not addressed yet, P-SILI remains a theoretical risk when keeping patients awake on ECMO, especially if they become agitated or when they do physical therapy. In such conditions, patients can induce wide swings in transpulmonary pressures despite breathing spontaneously. However, in our experience, the use of ECMO offered some advantages in this regard. Restoring the gas exchange by ECMO assistance contributed to blunting the major stimulus for a high respiratory drive and altered respiratory mechanics in ARDS patients, consisting in gas exchange impairment. In our series, the normalization of gas exchange by ECMO limited respiratory efforts significantly. We very closely clinically monitored the patients' spontaneous ventilation looking for signs of respiratory distress throughout the ICU stay. Any sign of increased effort was immediately managed through a fine modulation of the respiratory trigger by both regulating the sweep flow and titrating pharmacological effects of remifentanil and dexmedetomidine.

Our study has several strengths. Our management strategy is based on previous evidence showing the high accuracy and reproducibility of Macklin-like radiological sign in predicting PNX/PMD, the relatively high prevalence of this condition among COVID-19 ARDS patients, and the high mortality associated with this condition. The application of awake VV-ECMO and avoidance of invasive mechanical ventilation has a strong rationale and is increasingly suggested as an alternative strategy.

Our study has some limitations. The sample size is small, therefore we do acknowledge that our positive results may be a chance finding. However, the sample size is comparable to that of previous studies on awake VV-ECMO focused on ARDS patients. 35, 37 In our awake patients, we did not measure oesophageal pressure (Pes), so only clinical assessment of patients' respiratory effort was achieved. However, close clinical monitoring was effective to guide ECMO and anxiolysis management. Our study has all of the limitations of observational studies. However, this is the first description of this approach. We do not have a control group and the study is not randomized, therefore our findings can only be considered hypothesis-generating and no definitive conclusion can be drawn. In particular, efficacy of ECMO-first strategy in this setting requires to be tested in randomized trials. It is possible that the low mortality rate observed in our study was related to early institution of ECMO. However, this would further support an ECMO-first strategy in our patients, should our findings be confirmed.

We cannot exclude that application of ultraprotective mechanical ventilation instead of ECMO could also result in no barotrauma events. However, this would have required intubation anyway, and hence potentially expose patients to adverse effects of mechanical ventilation.

Future studies should confirm in broader populations and different settings the accuracy and clinical relevance of Macklin-like radiological sign in predicting barotrauma in patients with ARDS. In addition, future studies should aim to identify optimal timing (if any) of repeated chest CT scan for patients with ARDS and initial CT negative for Macklin-like radiological sign. Furthermore, future studies should confirm that the application of alternative management strategies such as early VV-ECMO in spontaneously ventilating patients can avoid the development of barotraumas in COVID-19 and non-COVID patients with ARDS, and improve outcome. Future studies should investigate whether ultraprotective mechanical ventilation could be also feasible and effective in preventing barotrauma in this high-risk patients. Finally, randomized controlled trials will be needed to confirm that prevention of barotrauma translates into improved outcome.

We found that early application of awake VV-ECMO without invasive mechanical ventilation in COVID-19 severe ARDS patients at high risk for barotrauma (defined as evidence of Macklin-like radiological sign on chest CT) resulted in no barotrauma events and low intubation and mortality rates. Future studies should confirm these findings in broader populations and different clinical settings (e.g. non-COVID-19 ARDS). 

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