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Oxygenation and Ventilation

Last Updated: December 17, 2020

The COVID-19 Treatment Guidelines Panel’s (the Panel’s) recommendations below emphasize recommendations from the Surviving Sepsis Campaign Guidelines for adult sepsis, pediatric sepsis, and COVID-19.

Nonmechanically Ventilated Adults With Hypoxemic Respiratory Failure

Recommendations

  • For adults with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy, the Panel recommends high-flow nasal cannula (HFNC) oxygen over noninvasive positive pressure ventilation (NIPPV) (BIIa).
  • In the absence of an indication for endotracheal intubation, the Panel recommends a closely monitored trial of NIPPV for adults with COVID-19 and acute hypoxemic respiratory failure and for whom HFNC is not available (BIIa).
  • For patients with persistent hypoxemia despite increasing supplemental oxygen requirements in whom endotracheal intubation is not otherwise indicated, the Panel recommends considering a trial of awake prone positioning to improve oxygenation (CIIa).
  • The Panel recommends against using awake prone positioning as a rescue therapy for refractory hypoxemia to avoid intubation in patients who otherwise meet the indications for intubation and mechanical ventilation (AIII).
  • If intubation becomes necessary, the procedure should be performed by an experienced practitioner in a controlled setting due to the enhanced risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure to health care practitioners during intubation (AIII).

Rationale

Severe illness in COVID-19 typically occurs approximately 1 week after the onset of symptoms. The most common symptom is dyspnea, which is often accompanied by hypoxemia. Patients with severe disease typically require supplemental oxygen and should be monitored closely for worsening respiratory status because some patients may progress to acute respiratory distress syndrome (ARDS).

Goal of Oxygenation

The optimal oxygen saturation (SpO2) in adults with COVID-19 is uncertain. However, a target SpO2 of 92% to 96% seems logical considering that indirect evidence from experience in patients without COVID-19 suggests that an SpO2 <92% or >96% may be harmful.

Regarding the potential harm of maintaining an SpO2 <92%, a trial randomly assigned ARDS patients without COVID-19 to either a conservative oxygen strategy (target SpO2 of 88% to 92%) or a liberal oxygen strategy (target SpO2 ≥96%). The trial was stopped early due to futility after enrolling 205 patients, but in the conservative oxygen group there was increased mortality at 90 days (between-group risk difference of 14%; 95% CI, 0.7% to 27%) and a trend toward increased mortality at 28-days (between-group risk difference of 8%; 95% CI, -5% to 21%).1

Regarding the potential harm of maintaining an SpO2 >96%, a meta-analysis of 25 randomized trials involving patients without COVID-19 found that a liberal oxygen strategy (median SpO2 of 96%) was associated with an increased risk of in-hospital mortality compared to a lower SpO2 comparator (relative risk 1.21; 95% CI, 1.03–1.43).2

Acute Hypoxemic Respiratory Failure

In adults with COVID-19 and acute hypoxemic respiratory failure, conventional oxygen therapy may be insufficient to meet the oxygen needs of the patient. Options for providing enhanced respiratory support include HFNC, NIPPV, intubation and invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

High-Flow Nasal Cannula and Noninvasive Positive Pressure Ventilation

HFNC is preferred over NIPPV in patients with acute hypoxemic respiratory failure based on data from an unblinded clinical trial in patients without COVID-19 who had acute hypoxemic respiratory failure. Study participants were randomized to HFNC, conventional oxygen therapy, or NIPPV. The patients in the HFNC group had more ventilator-free days (24 days) than those in the conventional oxygen therapy group (22 days) or NIPPV group (19 days) (P = 0.02), and 90-day mortality was lower in the HFNC group than in either the conventional oxygen therapy group (HR 2.01; 95% CI, 1.01–3.99) or the NIPPV group (HR 2.50; 95% CI, 1.31–4.78).3 In the subgroup of more severely hypoxemic patients (PaO2/FiO2 mm Hg ≤200), the intubation rate was lower for HFNC than for conventional oxygen therapy or NIPPV (HR 2.07 and 2.57, respectively).

The trial’s findings were corroborated by a meta-analysis of eight trials with 1,084 patients conducted to assess the effectiveness of oxygenation strategies prior to intubation. Compared to NIPPV, HFNC reduced the rate of intubation (OR 0.48; 95% CI, 0.31–0.73) and ICU mortality (OR 0.36; 95% CI, 0.20–0.63).4

NIPPV may generate aerosol spread of SARS-CoV-2 and thus increase nosocomial transmission of the infection.5,6 It remains unclear whether HFNC results in a lower risk of nosocomial SARS-CoV-2 transmission than NIPPV.

Prone Positioning for Nonintubated Patients

Although prone positioning has been shown to improve oxygenation and outcomes in patients with moderate-to-severe ARDS who are receiving mechanical ventilation,7,8 there is less evidence regarding the benefit of prone positioning in awake patients who require supplemental oxygen without mechanical ventilation. In a case series of 50 patients with COVID-19 pneumonia who required supplemental oxygen upon presentation to a New York City emergency department, awake prone positioning improved the overall median oxygen saturation of the patients. However, 13 patients still required intubation due to respiratory failure within 24 hours of presentation to the emergency department.9 Other case series of patients with COVID-19 requiring oxygen or NIPPV have similarly reported that awake prone positioning is well-tolerated and improves oxygenation,10-12 with some series also reporting low intubation rates after proning.10,12

A prospective feasibility study of awake prone positioning in 56 patients with COVID-19 receiving HFNC or NIPPV in a single Italian hospital found that prone positioning for ≤3 hours was feasible in 84% of the patients. There was a significant improvement in oxygenation during prone positioning (PaO2/FiO2 181 mm Hg in supine position vs. PaO2/FiO2 286 mm Hg in prone position). However, when compared with baseline oxygenation before initiation of prone positioning, this improvement in oxygenation was not sustained (PaO2/FiO2 of 181 mm Hg and 192 mm Hg at baseline and 1 hour after resupination, respectively). Among patients put in the prone position, there was no difference in intubation rate between patients who maintained improved oxygenation (i.e., responders) and nonresponders.9

A prospective, multicenter observational cohort study in Spain and Andorra evaluated the effect of prone positioning on the rate of intubation in COVID-19 patients with acute respiratory failure receiving HFNC. Of the 199 patients requiring HFNC, 55 (27.6%) were treated with prone positioning. Although the time to intubation was 1 day (IQR 1.0–2.5) in patients receiving HFNC and prone positioning versus 2 days [IQR 1.0–3.0] in patients receiving only HFNC (P = 0.055), the use of awake prone positioning did not reduce the risk of intubation (RR 0.87; 95% CI, 0.53–1.43; P = 0.60).13

Overall, despite promising data, it is unclear which hypoxemic, nonintubated patients with COVID-19 pneumonia benefit from prone positioning, how long prone positioning should be continued, or whether the technique prevents the need for intubation or improves survival.10

Appropriate candidates for awake prone positioning are those who can adjust their position independently and tolerate lying prone. Awake prone positioning is contraindicated in patients who are in respiratory distress and who require immediate intubation. Awake prone positioning is also contraindicated in patients who are hemodynamically unstable, patients who recently had abdominal surgery, and patients who have an unstable spine.14 Awake prone positioning is acceptable and feasible for pregnant patients and can be performed in the left lateral decubitus position or the fully prone position.15

Intubation for Invasive Mechanical Ventilation

It is essential to monitor hypoxemic patients with COVID-19 closely for signs of respiratory decompensation. To ensure the safety of both patients and health care workers, intubation should be performed in a controlled setting by an experienced practitioner.

Mechanically Ventilated Adults

Recommendations

For mechanically ventilated adults with COVID-19 and ARDS:

  • The Panel recommends using low tidal volume (VT) ventilation (VT 4–8 mL/kg of predicted body weight) over higher VT ventilation (VT >8 mL/kg) (AI).
  • The Panel recommends targeting plateau pressures of <30 cm H2O (AIIa).
  • The Panel recommends using a conservative fluid strategy over a liberal fluid strategy (BIIa).
  • The Panel recommends against the routine use of inhaled nitric oxide (AIIa).

Rationale

There is no evidence that ventilator management of patients with hypoxemic respiratory failure due to COVID-19 should differ from ventilator management of patients with hypoxemic respiratory failure due to other causes.

Positive End-Expiratory Pressure and Prone Positioning in Mechanically Ventilated Adults With Moderate to Severe Acute Respiratory Distress Syndrome

Recommendations

For mechanically ventilated adults with COVID-19 and moderate-to-severe ARDS:

  • The Panel recommends using a higher positive end-expiratory pressure (PEEP) strategy over a lower PEEP strategy (BIIa).
  • For mechanically ventilated adults with COVID-19 and refractory hypoxemia despite optimized ventilation, the Panel recommends prone ventilation for 12 to 16 hours per day over no prone ventilation (BIIa).

Rationale

PEEP is beneficial in patients with ARDS because it prevents alveolar collapse, improves oxygenation, and minimizes atelectotrauma, a source of ventilator-induced lung injury. A meta-analysis of individual patient data from the three largest trials that compared lower and higher levels of PEEP in patients without COVID-19 found lower rates of ICU mortality and in-hospital mortality with higher PEEP in those with moderate (PaO2/FiO2 100–200 mm Hg) and severe ARDS (PaO2/FiO2 <100 mm Hg).16

Although there is no clear standard as to what constitutes a high level of PEEP, one conventional threshold is >10 cm H2O.17 Recent reports have suggested that, in contrast to patients with non-COVID-19 causes of ARDS, some patients with moderate or severe ARDS due to COVID-19 have normal static lung compliance and thus, in these patients, higher PEEP levels may cause harm by compromising hemodynamics and cardiovascular performance.18,19 Other studies reported that patients with moderate to severe ARDS due to COVID-19 had low compliance, similar to the lung compliance seen in patients with conventional ARDS.20-23 These seemingly contradictory observations suggest that COVID-19 patients with ARDS are a heterogeneous population and assessment for responsiveness to higher PEEP should be individualized based on oxygenation and lung compliance. Clinicians should monitor patients for known side effects of higher PEEP, such as barotrauma and hypotension.

Neuromuscular Blockade in Mechanically Ventilated Adults With Moderate to Severe Acute Respiratory Distress Syndrome

Recommendations

For mechanically ventilated adults with COVID-19 and moderate-to-severe ARDS:

  • The Panel recommends using, as needed, intermittent boluses of neuromuscular blocking agents (NMBA) or continuous NMBA infusion to facilitate protective lung ventilation (BIIa).
  • In the event of persistent patient-ventilator dyssynchrony, or in cases where a patient requires ongoing deep sedation, prone ventilation, or persistently high plateau pressures, the Panel recommends using a continuous NMBA infusion for up to 48 hours as long as patient anxiety and pain can be adequately monitored and controlled (BIII).

Rationale

The recommendation for intermittent boluses of NMBA or continuous infusion of NMBA to facilitate lung protection may require a health care provider to enter the patient’s room frequently for close clinical monitoring. Therefore, in some situations, the risks of SARS-CoV-2 exposure and the need to use personal protective equipment for each entry into a patient’s room may outweigh the benefit of NMBA treatment.

Rescue Therapies for Mechanically Ventilated Adults With Acute Respiratory Distress Syndrome

Recommendations

For mechanically ventilated adults with COVID-19, severe ARDS, and hypoxemia despite optimized ventilation and other rescue strategies:

  • The Panel recommends using recruitment maneuvers rather than not using recruitment maneuvers (CIIa).
  • If recruitment maneuvers are used, the Panel recommends against using staircase (incremental PEEP) recruitment maneuvers (AIIa).
  • The Panel recommends using an inhaled pulmonary vasodilator as a rescue therapy; if no rapid improvement in oxygenation is observed, the treatment should be tapered off (CIII).

Rationale

There are no studies to date assessing the effect of recruitment maneuvers on oxygenation in severe ARDS due to COVID-19. However, a systematic review and meta-analysis of six trials of recruitment maneuvers in non-COVID-19 patients with ARDS found that recruitment maneuvers reduced mortality, improved oxygenation 24 hours after the maneuver, and decreased the need for rescue therapy.24 Because recruitment maneuvers can cause barotrauma or hypotension, patients should be closely monitored during recruitment maneuvers. If a patient decompensates during recruitment maneuvers, the maneuver should be stopped immediately. The importance of properly performing recruitment maneuvers was illustrated by an analysis of eight randomized controlled trials in non-COVID-19 patients (n = 2,544) which found that recruitment maneuvers did not reduce hospital mortality (RR 0.90; 95% CI, 0.78–1.04). Subgroup analysis found that traditional recruitment maneuvers significantly reduced hospital mortality (RR 0.85; 95% CI, 0.75–0.97), whereas incremental PEEP titration recruitment maneuvers increased mortality (RR 1.06; 95% CI, 0.97–1.17).25

Although there are no published studies of inhaled nitric oxide in patients with COVID-19, a Cochrane review of 13 trials of inhaled nitric oxide use in patients with ARDS found no mortality benefit.26 Because the review showed a transient benefit in oxygenation, it is reasonable to attempt inhaled nitric oxide as a rescue therapy in COVID patients with severe ARDS after other options have failed. However, if there is no benefit in oxygenation with inhaled nitric oxide, it should be tapered quickly to avoid rebound pulmonary vasoconstriction that may occur with discontinuation after prolonged use.

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  2. Chu DK, Kim LH, Young PJ, et al. Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet. 2018;391(10131):1693-1705. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29726345.
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  10. Sun Q, Qiu H, Huang M, Yang Y. Lower mortality of COVID-19 by early recognition and intervention: experience from Jiangsu Province. Ann Intensive Care. 2020;10(1):33. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32189136.
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