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Severe Covid-19 | NEJM


Initial Steps

Patients with severe Covid-19 should be hospitalized for careful monitoring. Given the high risk of nosocomial spread,3 strict infection-control procedures are needed at all times. If able, the patient should wear a surgical mask to limit the dispersion of infectious droplets.15 Clinicians should don appropriate personal protective equipment (PPE) as defined by their local infection-prevention program, using particular caution when performing procedures that may increase the generation or dispersion of infectious aerosols. These include endotracheal intubation, extubation, bronchoscopy, airway suctioning, nebulization of medication, the use of high-flow nasal cannulae, noninvasive ventilation, and manual ventilation with a bag-mask device.16 Current guidelines recommend that clinicians wear gowns, gloves, N95 masks, and eye protection at the least and place patients in negative-pressure rooms whenever possible during aerosol-generating procedures.17

Patients with severe Covid-19 have a substantial risk of prolonged critical illness and death. Therefore, at the earliest opportunity, clinicians should partner with patients by reviewing advanced directives, identifying surrogate medical decision makers, and establishing appropriate goals of care. Because infection-control measures during the pandemic may prevent families from visiting seriously ill patients, care teams should develop plans to communicate with patients’ families and surrogate decision makers.

Basics of Respiratory Care

Invasive Mechanical Ventilation for Covid-19–Related Respiratory Failure.

As shown in Panel A, a life-threatening problem in the purple box or a combination of less severe problems in the purple and tan boxes determines the need for endotracheal intubation. In Panel B, “lung derecruitment” refers to the collapse of alveoli. All pressures are measured in the ventilator circuit and referenced to atmospheric pressure. ARDS denotes acute respiratory distress syndrome, and PEEP positive end-expiratory pressure.

Patients should be monitored carefully by direct observation and pulse oximetry. Oxygen should be supplemented by the use of a nasal cannula or Venturi mask to keep the oxygen saturation of hemoglobin between 90 and 96%.17 Deciding whether or not to intubate is a critical aspect of caring for seriously ill patients with Covid-19. Clinicians must weigh the risks of premature intubation against the risk of sudden respiratory arrest with a chaotic emergency intubation, which exposes staff to a greater risk of infection. Signs of excessive effort in breathing, hypoxemia that is refractory to oxygen supplementation, and encephalopathy herald impending respiratory arrest and the need for urgent endotracheal intubation and mechanical ventilation. There is no single number or algorithm that determines the need for intubation, and clinicians must consider a variety of factors (Figure 3A).

If the patient does not require intubation but remains hypoxemic, a high-flow nasal cannula can improve oxygenation and may prevent intubation in selected patients.17,18 The use of noninvasive positive-pressure ventilation should probably be restricted to patients with Covid-19 who have respiratory insufficiency due to chronic obstructive pulmonary disease, cardiogenic pulmonary edema, or obstructive sleep apnea rather than ARDS. Patients treated with a high-flow nasal cannula or noninvasive ventilation require careful monitoring for deterioration that would indicate the need for invasive mechanical ventilation.18

Having awake patients turn to the prone position while they breathe high concentrations of supplemental oxygen may improve oxygenation in patients with severe Covid-19. This approach is supported by data from prospective cohorts describing its use in nonintubated patients with severe hypoxemia.19 However, whether prone positioning can prevent intubation in patients with severe Covid-19 is unclear. Because it is difficult to provide rescue ventilation to patients who are prone, this position should be avoided in patients whose condition is rapidly deteriorating.

Endotracheal Intubation

A skilled operator should perform endotracheal intubation in patients with severe Covid-19. The use of unfamiliar PPE, the risk of infection to staff, and the presence of severe hypoxemia in patients all increase the difficulty of intubation. If possible, intubation should be performed after preoxygenation and rapid-sequence induction of sedation and neuromuscular blockade. An antiviral filter should be placed in line with the airway circuit at all times. Video laryngoscopy may allow the operator to have a good view of the airway from a greater distance.20 However, operators should choose the technique that is most likely to be successful on the first attempt. Continuous-wave capnography is the best method to confirm tracheal intubation.20 Patients with severe Covid-19 often become hypotensive soon after intubation owing to positive-pressure ventilation and systemic vasodilation from sedatives.20 Therefore, intravenous fluids and vasopressors should be immediately available at the time of intubation, and careful hemodynamic monitoring is essential.20

Ventilator Management

It is unclear whether Covid-19 is associated with a distinct form of ARDS that would benefit from a new strategy of mechanical ventilation. However, most autopsies performed on patients with severe Covid-19 reveal the presence of diffuse alveolar damage, which is the hallmark of ARDS.21 Moreover, respiratory-system compliance and gas exchange in patients with respiratory failure from severe Covid-19 are similar to those in populations enrolled in previous therapeutic trials for ARDS.22 Therefore, clinicians should follow the treatment paradigm developed during the past two decades for ARDS (Figure 3B).17,18 This strategy aims to prevent ventilator-induced lung injury by avoiding alveolar overdistention, hyperoxia, and cyclical alveolar collapse.

To prevent alveolar overdistention, clinicians should limit both the tidal volume delivered by the ventilator and the maximum pressure in the alveoli at the end of inspiration. To do this, clinicians should set the ventilator to deliver a tidal volume of 6 ml per kilogram of predicted body weight; this approach is termed “lung-protective ventilation.” A tidal volume up to 8 ml per kilogram of predicted body weight is allowed if the patient becomes distressed and attempts to take larger tidal volumes. A few times each day, clinicians should initiate a half-second end-inspiratory pause, which allows the pressure in the airway circuit to equilibrate between the patient and the ventilator. The pressure in the airway circuit at the end of the pause — “the plateau pressure” — approximates the alveolar pressure (relative to atmospheric pressure). To prevent alveolar overdistention, the plateau pressure should not exceed 30 cm of water.23 A higher plateau pressure without the development of ventilator-induced lung injury may be possible in patients with central obesity or noncompliant chest walls.

For patients with Covid-19–related ARDS, setting sufficient positive end-expiratory pressure (PEEP) on the ventilator may prevent alveolar collapse and facilitate the recruitment of unstable lung regions. As a result, PEEP can improve respiratory-system compliance and allow for a reduction in the Fio2. However, PEEP can reduce venous return to the heart and cause hemodynamic instability. Moreover, excessive PEEP can lead to alveolar overdistention and reduce respiratory-system compliance. No particular method of determining the appropriate level of PEEP has been shown to be superior to other methods.17

Sedatives and analgesics should be targeted to prevent pain, distress, and dyspnea. They can also be used to blunt the patient’s respiratory drive, which improves patient synchrony with mechanical ventilation. Sedation is especially important in febrile patients with high metabolic rates who are treated with lung-protective ventilation. Neuromuscular blocking agents can be used in deeply sedated patients who continue to use their accessory muscles of ventilation and have refractory hypoxemia.17 These agents can reduce the work of breathing, which reduces oxygen consumption and carbon dioxide production.24 Moreover, sedatives and neuromuscular blocking agents may help reduce the risk of lung injury that may occur when patients generate strong spontaneous respiratory efforts.

Refractory Hypoxemia

Clinicians should consider prone positioning during mechanical ventilation in patients with refractory hypoxemia (Pao2:Fio2 of <150 mm Hg during respiration and Fio2 of 0.6 despite appropriate PEEP). In randomized trials involving intubated patients with ARDS (not associated with Covid-19), placing the patient in the prone position for 16 hours per day has improved oxygenation and reduced mortality.18,25 However, prone positioning of patients requires a team of at least three trained clinicians, all of whom require full PPE.17 Inhaled pulmonary vasodilators (e.g., inhaled nitric oxide) can also improve oxygenation in refractory respiratory failure, although they do not improve survival in ARDS not associated with Covid-19.17 Extracorporeal membrane oxygenation (ECMO) is a potential rescue strategy in patients with refractory respiratory failure. Clinicians should carefully balance possible benefits with risks (e.g., bleeding) as well as the resources available during the pandemic.26

Therapy

A large, randomized clinical trial involving more than 6400 hospitalized patients with Covid-19 showed that dexamethasone significantly reduced 30-day mortality (17% reduction); benefit was limited to patients who required oxygen supplementation and appeared greater in patients receiving mechanical ventilation.27 Consequently, dexamethasone (or potentially other glucocorticoids) is now considered the standard of care for patients with severe Covid-19.

Data from a randomized, placebo-controlled trial involving more than 1000 patients with severe Covid-19 showed that the antiviral agent remdesivir reduced time to clinical recovery; the benefit appeared greatest in patients who were receiving supplemental oxygen but were not intubated.28 The 29-day mortality in that trial was 11.4% with remdesivir and 15.2% with placebo (hazard ratio for death, 0.73; 95% confidence interval, 0.52 to 1.03). These data support the Food and Drug Administration (FDA) approval of remdesivir for the treatment of hospitalized patients with Covid-19 in October 2020. Recent preliminary results of a large, multinational, open-label, randomized trial did not show a reduction in in-hospital mortality with use of remdesivir.29 The combination of dexamethasone and remdesivir is increasingly used clinically, but its benefit has not been shown in randomized clinical trials. Tocilizumab, an interleukin-6 inhibitor, did not significantly reduce disease progression30 or death in small randomized trials involving patients with severe Covid-19.31,32

Supportive Care

Patients with Covid-19 often present with volume depletion and receive isotonic-fluid resuscitation. Volume repletion helps maintain blood pressure and cardiac output during intubation and positive-pressure ventilation. After the first few days of mechanical ventilation, the goal should be to avoid hypervolemia.33 Fever and tachypnea in patients with severe Covid-19 often increase insensible water loss, and careful attention must be paid to water balance. If the patient is hypotensive, the dose of vasopressor can be adjusted to maintain a mean arterial pressure of 60 to 65 mm Hg.17 Norepinephrine is the preferred vasopressor. The presence of unexplained hemodynamic instability should prompt consideration of myocardial ischemia, myocarditis, or pulmonary embolism.

In case series, approximately 5% of patients with severe Covid-19 have received renal-replacement therapy34; the pathophysiology of the renal failure is currently unclear but is probably multifactorial. Because blood clotting in the circuit is common in patients with severe Covid-19,6 the efficacy of continuous renal-replacement therapy is uncertain.

Abnormalities of the clotting cascade, such as thrombocytopenia and elevation of d-dimer levels, are common in patients with severe Covid-19 and are associated with increased mortality.3If there are no contraindications, patients should receive standard thromboprophylaxis (e.g., subcutaneous low-molecular-weight heparin).35 Some case series of patients with severe Covid-19 have shown clinically significant thrombosis despite the use of thromboprophylaxis.6 However, the benefits and risks of the routine use of more intense prophylactic anticoagulation in patients are unknown.35

Patients hospitalized with severe Covid-19 are often treated empirically with antibiotics.3,9 However, bacterial coinfection is rare when immunocompetent patients first present to the hospital.36 Antibiotics can be discontinued after a short course if signs of bacterial coinfection, such as leukocytosis and focal pulmonary infiltrates, are absent.18 Although Covid-19 itself can cause prolonged fever,2 clinicians should be vigilant for nosocomial infections.

Performing cardiopulmonary resuscitation in patients with Covid-19 may expose health care workers to infectious droplets and aerosols. Therefore, all the members of the resuscitation team should wear appropriate PPE before performing rescue ventilation, chest compressions, or defibrillation.37

Patients with Covid-19 who are receiving mechanical ventilation should receive appropriate nutrition and care to prevent constipation and injury to the skin and corneas. If the condition of a patient has stabilized, clinicians should attempt to withhold continuous sedation each day.38 Daily awakening may be challenging because an increase in the work of breathing and the loss of synchrony with mechanical ventilation may result in distress and hypoxemia.

During the Covid-19 pandemic, an overwhelming surge of patients presenting to a hospital may temporarily require the rationing of health care resources. Local guidelines and medical ethics consultation can help clinicians navigate these difficult decisions with patients and their families.



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