By Kathryn Radigan, MD, MSc

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

Dr. Radigan reports no financial relationships relevant to this field of study.

SYNOPSIS: COVID-19 is a systemic disease that primarily injures the vascular endothelium, causing a unique lung injury in which different management strategies may need to be considered to address the specific physiology of each patient.

SOURCE: Marini JJ, Gattinoni L. Management of COVID-19 respiratory distress. JAMA 2020; April 24. doi: 10.1001/jama.2020.6825. [Epub ahead of print].

Although patients with COVID-19 respiratory failure meet acute respiratory distress syndrome (ARDS) criteria, these patients may fail to qualify as the typical ARDS patient. Marini and Gattinoni believe that the primary goal prior to intubation for COVID-19 respiratory failure patients should be adequate gas exchange and avoiding patient self-induced lung injury (P-SILI). They support the use of supplemental oxygen, continuous positive airway pressure (CPAP), noninvasive ventilation (NIV), and high-flow nasal cannula (HFNC) as indicated to attain the goal of adequate oxygenation and non-vigorous breathing. In addition to these strategies, they also support awake prone positioning to reduce respiratory effort, which can worsen both lung and vascular stress. If, at any point, strong inspiratory efforts persist despite these strategies, they believe in early intubation.

Once intubated, Marini and Gattinoni described COVID-19 respiratory failure patients as “type L” and “type H” patients. Typically, type L respiratory failure patients are those with scattered ground glass on imaging along with well-preserved compliance and typically are not positive end-expiratory pressure (PEEP)-responsive. The objective in these patients is to minimize pulmonary stress, optimize oxygenation, and avoid ventilator-induced lung injury (VILI). The clinicians favor treating these patients with minimal PEEP (< 10 cm H2O) and more liberal tidal volumes (Vt), such as 7-8 mL/kg, if indicated. They aim to reduce oxygen demand and consider prone positioning. The rationale for these ideals is that the higher PEEP may be ineffective, adding to dead space and adversely redirecting blood flow. The stricter, lower Vt may be unnecessary for these patients, especially if their plateau and driving pressures are well below 30 and 15 cm H2O, respectively.

On the other hand, the type H respiratory failure patients are those with extensive infiltrates, with both atelectasis and edema adding to the disease process. These patients have lower compliance and are PEEP-responsive more often, but also often appear much more dyspneic. The objective in these patients is to reduce and evenly distribute lung and vascular stresses, optimize oxygen, and avoid VILI. The clinicians favor treating these patients with higher PEEP (< 15 cm H2O) and lower Vt (5-7 mL/kg), similar to typical ARDS patients, to reduce oxygen demand. The rationale for these treatment strategies is that this disease process more closely behaves like ARDS and responds to typical ARDS treatment. Implementation of prone positioning should be strongly considered. The clinicians also stressed that the weaning phase may be a dangerous time in which VILI may occur. They warned that it is profoundly important to make transitions cautiously, avoid abrupt changes, and use spontaneous trials only at the very end of the weaning process.

Marini and Gattinoni admitted that type L and type H patients are theoretical extremes of a spectrum that includes intermediary stages in which the characteristics may overlap. Overall, they stressed that COVID-19 causes unique lung injury in which different management strategies may need to be considered to address the specific physiology of each patient.

COMMENTARY

Although most COVID-19 patients with respiratory failure meet the criteria for ARDS, some clinicians have noted profound differences in some COVID-19 patients when compared to typical ARDS patients. It is important to stress that even though the portal for COVID-19 is inhalational, which obviously affects the alveoli, there also is a profound vascular defect that contributes not only to disease pathophysiology but also to disease severity.

As opposed to typical ARDS, Marini and Gattinoni believe COVID-19 ARDS (CARDS) may be associated with substantial differences in pathophysiology. In the early phases of respiratory failure, they believe the disease process typically is complicated by pulmonary vascular dysregulation rather than alveolar edema. This often is followed by extreme hypoxemia and air hunger with high minute ventilation, but without respiratory distress. The pulmonary vascular dysregulation is thought to be the result of vasoplegia in which the lung cannot regulate perfusion to keep up with the ventilation. The net effect is not only profound hypoxia but also profound hypercapnia and dead-space ventilation. Often, these patients, identified as type L, are noted to have hypoxia out of proportion to lung infiltrates, along with relatively well-maintained compliance and a subsequently low response to PEEP. Higher than necessary PEEP levels may create dead space and redirect blood flow. In treating these patients, who maintain good lung compliance, it may be appropriate to accept slightly higher Vt at 7-8 mL/kg ideal body weight without worsening VILI as long as the plateau pressures are acceptable (i.e., plateau pressures and driving pressures well below 30 and 15 cm H2O, respectively). Marini and Gattinoni stressed that these goals should be maintained and not ignored. The higher Vt with still well-maintained plateau pressures will help to avoid reabsorption atelectasis and hypercapnia.

They also believe prone positioning should be considered carefully. Since the key issue in this early stage is disrupted vasoregulation, the pathophysiology of the disease process for a particular patient may be different, and prone positioning may worsen dead space ventilation and must be considered cautiously. To balance the theories of Marini and Gattatoni, it also must be highlighted that managing patients with strict type L method may need to be approached with caution because it also may do harm if not applied in the appropriate setting with careful attention to specific responses to each intervention.

Although some of these type L patients stabilize and improve, the clinicians believe others will progress to the next stage, type H. The reason for progression is thought to be due to either disease severity or suboptimal management. Unfortunately, the spontaneous vigorous inspiratory effort, which may occur prior to fatigue or sedation, leads to high transpulmonary pressures and contributes to P-SILI, which also leads to increased blood flow and vascular pressures to the lung, eventually leading to vascular injury. If intubated, higher than needed PEEP in the early stages of disease also may hinder more than help. Clinicians now believe that the later stages of COVID-19 respiratory failure, or type H, may be more similar to typical ARDS.

It is well-described that ARDS is a disease process of non-cardiogenic pulmonary edema with low lung compliance associated with shunt-related hypoxia most often due to reduced lung size. The typical treatment of ARDS or type H patients includes increasing lung size by increasing the levels of PEEP along with other maneuvers, including prone positioning. To decrease VILI, which is caused by high transpulmonary pressure, patients are treated with low Vt.

According to the National Institutes of Health (NIH) expert panel, all patients with COVID-19 respiratory failure should be treated similarly to ARDS patients.1 In essence, the expert panel believes that all COVID-19 patients with respiratory failure should be treated like type H. Escalation to HFNC over noninvasive positive pressure ventilation (NIPPV) is preferred. If NIPPV is attempted in the absence of HFNC, they recommend a closely monitored trial. The NIH also recommends early intubation in a controlled setting. The panel recommends low Vt ventilation (Vt 4-8 mL/kg of predicted body weight) over higher Vt ventilation (Vt > 8 mL/kg). If the patient is mechanically ventilated with refractory hypoxemia despite optimized ventilation, the panel recommends prone ventilation for 12-16 hours a day. If patients have severe ARDS and hypoxemia despite optimized ventilation and other rescue strategies, the panel recommends a trial of inhaled pulmonary vasodilator as a rescue therapy. If no rapid improvement in oxygenation is observed, the patient should be tapered off treatment.

Shortly after the article by Marini and Gattinoni was released, Ziehr and colleagues published a manuscript reflecting their experience at Massachusetts General Hospital further supporting the recommendations made by the NIH expert panel. Patients in their cohort were managed with established ARDS therapies, including low Vt ventilation, conservative fluid administration, and, in many cases, prone ventilation. It must be highlighted that almost all patients were intubated on the day of admission. With a minimum follow-up of 30 days, overall mortality was 16.7%, and the majority of patients were extubated successfully and discharged from the intensive care unit (ICU).2 With their findings, Ziehr and colleagues provided a pathophysiologic justification for the use of early intubation and established ARDS therapies, including low Vt and early prone ventilation, for COVID-19 respiratory failure.

Overall, clinicians agree that COVID-19 respiratory failure is complex. Ziehr and colleagues, along with the NIH expert panel, provide evidence to support traditional ARDS strategies. Marini and Gattinoni support the principle of separating COVID-19 patients according to their specific clinical presentation and treating accordingly, but they also recognize that type L and type H patients are the extremes of a spectrum that includes intermediate stages in which their features may overlap. To complicate issues further, an additional feature of the disease process is a highly activated coagulation cascade with extensive micro- and macro-thromboses, not only in the lung, but also in other organs.3 Endothelial damage is a substantial issue that disrupts not only pulmonary vasoregulation, but also further impairs ventilation-perfusion mismatch and promotes thrombogenesis often leading to end-organ damage. Further studies are needed to delineate if alternative ventilator strategies are needed as well as to optimally manage the thrombogenic nature of the disease process, which many believe is a substantial aspect of this puzzle. Until then, the optimal management strategy is to do no harm following proven ARDS strategies, but also to balance the “one-size-fits-all” guidelines with the knowledge that these patients may have some distinct differences in clinical features and physiology that may need to be considered for optimal management.

REFERENCES

  1. National Institutes of Health. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. https://www.covid19treatmentguidelines.nih.gov
  2. Ziehr DR, Alladina J, Petri CR, et al. Respiratory pathophysiology of mechanically ventilated patients with COVID-19: A cohort study. Am J Respir Crit Care Med 2020; April 29. doi: 10.1164/rccm.202004-1163LE. [Epub ahead of print].
  3. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020;395:1054-1062.