Management of Respiratory Distress Syndrome due to COVID-19 infection

The proposed models of the underlying pathophysiology of COVID-19 associated acute respiratory distress syndrome (CARDS) are continuously investigated. Whether patients with CARDS present a similar pathophysiology for “typical” ARDS and match the Berlin Criteria definition remains a subject of debate. Based on current available clinical data the following components have been described in these patients:

Fever has been reported with variable incidence among case series, ranging between 43 and 98% of the patients, hence the absence of fever does not exclude COVID-19 infection [15‐17]. Cough is the second most common symptom (59–72%), followed by myalgia (15%) and fatigue (23%). Gastrointestinal symptoms (diarrhea, nausea and vomiting) has been reported in 10% of the patients usually preceding the onset of fever and dyspnea [17]. ARDS has been described to be present in 17–41% of these patients, with a median time from first symptom to progression to ARDS of 8 days [4, 17, 18].

In regard to initial laboratory findings, white blood cell count tends to be normal and lymphopenia is present in 80% of the patients [19]. CRP has been found to be consistently elevated in patients with COVID-19 infection and shares an inverse relationship with oxygen requirement levels, and may be used for mortality prognostication [20, 21]. Other prognostic laboratory values sharing a direct relationship with mortality in COVID-19 infection are IL-6, LDH and serum ferritin and D-dimer [22]. Procalcitonin levels are moderately elevated in these patients and have not been consistently associated to predict mortality of the disease [19]. In addition to the reverse-transcription polymerase chain reaction (RT-PCR) for COVID-19, routine blood cultures and viral panel should be sent to rule out the presence of any other microorganism as a main culprit or as co-infection [23].

Chest radiograph demonstrates the typical patchy ground glass opacities, which tends to be towards the periphery and basal fields of the lungs, and its sensitivity has been reported around 59% [19, 24]. In regards to Computerized Tomography (CT) findings, its sensitivity seems to be related to the symptomatology of the patient at the moment the test is performed: 86–97% in patients with respiratory symptoms and 50% in patients with constitutional symptoms only [19, 25, 26].

Zhou et al. in a cohort of 100 COVID-19 patients who underwent 272 CT of the chest, demonstrated a predominant peripheral distribution (62%), followed by a combined peripheral plus central distribution (38%). The vast majority had a bilateral lung compromise (92%), and a significantly involvement of the middle, lower and posterior zones [27]. Not all patients suspected for COVID-19 pneumonia require CT imaging. The decision of requesting this exam should be made in a case-by-case basis based on the clinician’s judgement, given the potential risk for pathogen dissemination during the patient transportation and the consequent exposure to the healthcare personnel.

Lung ultrasound in patients with COVID-19 pneumonia has also been described and its findings appear to correlate satisfactorily with the CT findings. Peng et al. described the presence of scattered B-lines which tends to coalesce as the disease progresses. Thickening of the pleural line as well as pleural effusions have been described [28].

Environmental control is paramount to be considered in the initial approach to patients with COVID-19 pneumonia. Droplet precautions have been advocated by multiple organizations. The World Health Organization and the Australian and New Zealand Intensive Care Society recommend airborne precautions when aerosol-generating procedures are expected in COVID-19 patients, including: face mask ventilation, non-invasive ventilation, endotracheal intubation, open airway suctioning, aerosolized medications, bronchoscopy, disconnection of the patient from the ventilator and cardiopulmonary resuscitation. Despite the high risk of contamination during these procedures, current evidence suggests that meticulous use of personal protective equipment is effective to prevent infection among healthcare personnel [29‐31].

Gattinoni et al. proposed tailored modifications to the usual ARDS principles based on the phenotype of the COVID-19 pneumonia. In intubated type 1 phenotype patients, the management of hypoxemia should be directed to improve the ventilation/perfusion mismatch by liberalized tidal volumes (7-8 ml/kg ideal body weight, to avoid resorption atelectasis), limited PEEP levels (8-10cmH2O) and keeping the respiratory rate < 20 breaths per minute [6, 7, 32].

As lung damage progresses, type 2 phenotype arises following a similar pattern of a “typical” ARDS (bilateral infiltrates, decreased respiratory system compliance and increased lung weight) [6]. The standard approach of lung protective ventilation through low tidal volumes (6 ml/kg ideal body weight), PEEP levels (<10cmH2O), FiO2 levels as tolerated to avoid poor tissue perfusion, plateau pressures <30cmH2O, lower driving pressures (target of 13–15 cmH2O) and permissive hypercapnia have consistently demonstrated to be an accepted intervention for CARDS [38]. The aim is to avoid ventilator-induced lung injury by reducing lung and vascular stress [32]. While some authors advocate for high levels of PEEP (<15cmH2O) in phenotype 2 patients, based on the high lung elastance and increased non-aerated lung tissue [8], a single-center observational study demonstrated poor lung recruitability in spite of high PEEP levels. Lung recruitment was more evident after prone positioning in the population analyzed [39].

Airway pressure release ventilation (APRV) may be considered early in the course of intubated patients with moderate to severe ARDS, in order to provide adequate alveolar recruitment. The application of APRV continues to be limited, given that many providers are not familiar with this ventilation mode or its titration methodology [40]. No data has been published yet regarding APRV utility in patients with CARDS.

Prone positioning leads to a relieve of severe hypoxemia due to reduction of overinflated lung areas, promoting of alveolar recruitment and decreasing ventilation/perfusion mismatch [39]. The Proning Severe ARDS Patients (PROSEVA) trial, performed by Guerin et al. demonstrated a significant decrease in 28-day and 90-day mortality in patients with severe ARDS [41]. Prone positioning has been advocated in intubated patients with CARDS. Pan et al. demonstrated increased lung recruitability and PaO2/FiO2 improvement after prone positioning in patients with moderate CARDS [39]. The main obstacle continues to be its implementation and generalization among each institution. Trained and qualified nursing and respiratory therapy staff is the most important factor to obtain successful results, as severe life-threatening events may occur at any given time (self-extubation, hemodynamic instability, lack of adequate sedation, pressure ulcers) [29, 30].

In regards to neuromuscular blockade, in an effort to avoid ventilator dyssynchrony, adjust tidal volumes and decrease airway resistance with the goal to decrease lung parenchyma inflammation, neuromuscular blocking agents were introduced as part of the alternative therapies for severe ARDS [42]. No formal clinical trial or body of evidence has been published yet regarding the use of neuromuscular blockade in patients with CARDS. The Surviving Sepsis Campaign recommends the use of intermittent doses of neuromuscular blocking agents to facilitate lung protective ventilation in COVID-19 patients [29].

In regards to inflammatory attenuators for patients with CARDS, the RECOVERY trial, a large multicenter, randomized controlled trial, demonstrated that patients in the intervention group (receiving Dexamethasone 6 mg for 10 days, either enterally or intravenously) reduced death by up to one-third in hospitalized patients with severe respiratory complications from COVID-19. The effect seemed to be more prominent in patients on mechanical ventilation (number needed to treat: 8) and intermediate in those who required supplemental oxygen only (number needed to treat: 25). The trial did not show any benefit from Dexamethasone in patients who did not required respiratory support [43].

Selective pulmonary vasodilation is thought to improve ARDS secondary to redistribution of blood from poorly ventilated areas to those with higher ventilation, thereby decreasing the shunt fraction and correcting hypoxemia. Nitric Oxide and Prostaglandins (e.g. PGI₂ [epoprostenol]), despite its pulmonary vasodilatory properties have failed to demonstrate a mortality benefit in ARDS [44]. Nitric Oxide use during the COVID-19 patients is controversial [45]. Some authors advocate for its potential anti-viral activity following the results of a study performed during the SARS-CoV outbreak in 2004 [46]. Currently there is no recommendation for the use of pulmonary vasodilators in patients with ARDS due to COVID-19, other than a last resource (rescue therapy) for refractory hypoxemia [29].

When refractory hypoxemia ensues and alternative therapies fail, the use of extracorporeal maneuvers becomes appropriate. Despite that the use of ECMO has increased substantially in the past decades, its use still remains controversial. Two large multi-center RCT have offered a contradictory view regarding the use of ECMO in ARDS. CESAR trial (Conventional ventilatory support versus ECMO for severe ARDS) performed by Peek et al. (2009), introduced encouraging results demonstrating a significant improvement in survival without severe disability at 6 months. The authors of this trial concluded that for patients with severe ARDS with potentially reversible causes not responsive to conventional management ECMO should be instituted. On the other hand, the EOLIA trial (ECMO to Rescue Lung Injury in ARDS) performed by Combes et al. (2018), concluded that 60-day mortality was not significantly lower within patients in the ECMO group and therefore the trial was stopped given pre-specified rules, although a post-hoc bayesian analysis of this trial demonstrated a posterior probability of mortality benefit from ECMO in the population analyzed with very severe ARDS [47, 48].

In light of these controversial results and in the midst of a worldwide pandemic caused by the COVID-19, with multiple patients expected to develop severe ARDS, the Extracorporeal Life Support Organization (ELSO) emitted a consensus guideline for the use of ECMO in these patients. The ELSO emphasizes that center experience as well as provider and team training are the most prominent factors to determine the use of extracorporeal techniques in patients with COVID-19. In regards to patient prioritization, the consensus guideline recommends highest priority to younger patients with minor or no co-morbidities as well as healthcare providers, highlighting that patients with poor prognosis, advanced age with multiple co-morbidities, do-not-resuscitate status, terminal disease or severe central nervous system damage should be excluded.

In order to determine patient eligibility, the ELSO consensus on CARDS provides a forthright algorithm centered in providing conservative management (prone positioning, neuromuscular blockade, pulmonary vasodilators, high PEEP, recruitment maneuvers) for patients with PaO2/FiO2 ratio < 150 mmHg. If the patient develops worsening refractory hypoxemia (PaO2/FiO2 ratio < 80 mmHg for > 6 h, or PaO2/FiO2 ratio < 50 mmHg for > 3 h) or signs of poor tissue perfusion and hypercarbia (pH < 7.25 with partial pressure of arterial carbon dioxide [PaCO2] > 60 mmHg), then the patient should be considered for ECMO, assuming no contraindications are present. Also, for patients with PaO2/FiO2 ratio > 150 mmHg, but with signs of poor tissue perfusion and hypercarbia, ECMO should be considered as well [49].