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Invited Commentary

Is It the Missing Piece for Coronavirus Disease 2019, Acute Respiratory Distress Syndrome, and Venovenous Extracorporeal Membrane Oxygenation?

Ritchie, Michael K.; Fox, Matthew P.

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doi: 10.1097/MAT.0000000000001313
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Acute respiratory distress syndrome (ARDS) is an end-point for multiple heterogeneous disease processes. Most current treatment strategies have focused on minimizing the harm placed on the patient by mechanical ventilation (Table 1). Today, the mainstay of treatment for ARDS has been reduced to treating the underlying condition and maintaining lung protective mechanical ventilation. Unfortunately, even with these protective measures, there is still ventilator-induced lung injury. Ventilator-induced lung injury is a well described, multifactorial phenomenon experienced by the patient during ventilation that encompasses barotrauma, volutrauma, atelectrauma, biotrauma, and newly described energy trauma.1,5,9,10

Table 1. - The History and Management of ARDS1–11
1967: ARDS was first described by Ashbaugh et al.1
1975: Suter et al. found that the optimum PEEP for optimizing oxygen delivery was the PEEP that achieved the best compliance.1
1975: Kirby et al. described a high PEEP strategy to minimize shunting.1
1979: NIH did the first trial looking at ECMO for ARDS.1
1981: Lemaire et al. found that the minimal PEEP for the patient should be 2 cm H2O above the lower inflection point.1
1987: Gattinoni et al. described the concept of “baby lung” and that the lungs were not stiff, but the size of the usable lung was that of a child’s lung.2
1990: Hickling et al. described lung rest with low tidal volume ventilation.1
1994: NIH-NHLBI ARDSNet was created.3
1999: Ranieri et al. published a paper showing reduced inflammatory markers when using lung protective strategies.4
1999: Slutsky described the four accepted ventilator-induced lung injuries.5
2000: ARMA trial was published which showed that 6 ml/kg is better than 12 ml/kg.6
2009: CESAR trial showed improved outcomes in patients who went to an ECMO center.7
2011: The Berlin definition of ARDS was described.8
2015: Amato et al. described ΔP. A ΔP ≤ 15 cm H2O reduced mortality.9
2016: Energy trauma, based on ΔP, was described as a new type of VILI.10
2019: Rozencwajg et al.8 described ultra-lung protection ventilation on ECMO was shown to reduce biotrauma.11
ΔP, driving pressure; ARDS, acute respiratory distress syndrome; ARDSNet, Acute Respiratory Distress Syndrome Network; ARMA, lower tidal volume ventilation in ALI/ARDS; CESAR, efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure; ECMO, extracorporeal membrane oxygenation; NHLBI, National Heart, Lung, and Blood Institute; NIH, National Institute of Health; PEEP, positive end-expiratory pressure; VILI, ventilator-induced lung injury.

Over the past 2 decades, extracorporeal membrane oxygenation (ECMO) has gained popularity as a life-sustaining modality for patients who cannot be adequately oxygenated or ventilated using more conventional means. Using ECMO, in conjunction with ultraprotective lung ventilation (UPLV), has been shown to reduce barotrauma, volutrauma, atelectrauma, and energy trauma.11 Additionally, the ability to reduce the fraction of inspired oxygen on ECMO decreases oxygen free radicals. This reduction, and the reduction in injurious ventilator settings, reduces inflammation and cytokine production which decreases biotrauma.11–13

Despite these advantages of ECMO, several problems remain. Notably, while ECMO/UPLV can reduce the iatrogenic inflammation from mechanical ventilation, it does not address the underlying inflammatory insult of the disease. Furthermore, the ECMO circuit itself is a pro-inflammatory. The artificial surface of the circuit initiates several inflammatory cascades which contribute to biotrauma, end-organ damage, and coagulopathies.12,13

The coronavirus disease 2019 (COVID-19) epidemic has brought biotrauma to the forefront as a major contributor to mortality in ARDS. Coronavirus disease 2019 is extremely pro-inflammatory and can spiral into cytokine storm, which carries a high mortality rate. Cytokines are released when the body recognizes an infection and are responsible for the immune response mounted to fight off the invading organism. Cytokines are responsible for their own regulation which allows it to help specify the pathogen, limit itself to an appropriate response level, and downregulate during the resolution phase. Cytokine storms occur when the immune system either does not regulate its response, leading to inappropriately elevated levels, or does not appropriately enter the resolution phase, leading to prolonged inflammation. When there is an inappropriate response or prolonged response, the result is collateral damage to the body. It is unclear the exact mechanism of how COVID-19 infections cause cytokine storm, but the end result is supratherapeutic cytokine levels. When the cytokine levels reach hyperactive response level, it causes a more systemic response by activating the release and mobilization of neutrophils and monocytes to the infected site. This response inappropriately activates the coagulation, fibrinolytic, and complement cascades out of proportion to the infection causing shock, thromboembolic disease, and organ failure, especially lung damage. Interleukin (IL)–6 and tumor necrosis factor (TNF)–α are two of the pro-inflammatory cytokines most associated with cytokine storm and the resulting biotrauma leading to lung injury. Increased IL-2 levels are associated with capillary leak which causes the breakdown of cell bridges and increases the vascular permeability leading to pulmonary edema, kidney injury, and third-spacing. Capillary leak, with the addition of inflammatory vasodilation, is a major cause of the severe hypotension/shock also seen in these critically ill patients. Interleukin-10 is an anti-inflammatory cytokine and part of the Compensatory Anti-inflammatory Response Syndrome.14 Interleukin-10 downregulates the immune response and helps to keep the inflammatory response at an appropriate level. In cytokine storm, the IL-10 levels are also inappropriately elevated since it is trying to decrease the response.15 In 2007, Kellum et al.14 looked at the inflammatory markers in patients with pneumonia and sepsis. Cytokine levels were the highest in patients with the worst outcomes. The highest risk of death was in patients with high levels of both pro-inflammatory (IL-6) and anti-inflammatory markers (IL-10).16

Medications to target the cytokine cascades have always been of interest in research. If there was a way to prevent this inappropriate response, it could prevent the capillary leak, organ failure, and shock. Unfortunately, medications that target a specific part of a cascade have not been shown to be successful. Recombinant activated protein C was trialed to replete the reduced levels seen in septic shock. Initial studies were promising, but it was found to increase bleeding and not improve outcomes after further studies. Anti–TNF-α medications were also studied in patients with septic shock. The results are more controversial with heterogeneous studies but may have a positive role in patients in shock or with elevated IL-6 levels.17

Due to the poor results using medications, a variety of methods for extracorporeal blood purification have been explored to reduce the amount of circulating inflammatory markers in the body. Many modalities have been described in sepsis and ARDS, including continuous venovenous hemofiltration (CVVH), hemoperfusion, and plasma exchange. CVVH in ARDS was studied in the 2000s, and success with plasma exchange with H1N1 ARDS in 2009 was also described in a case series.18,19 The efficacy of these modalities has been controversial with conflicting trial results.20,21

In patients infected with COVID-19, immunomodulation has again become a major target for research and intervention. Currently, the standard of care for immunomodulator use is steroids and IL-6 inhibitors. Corticosteroids reduce the inflammatory response by binding to intracellular receptors that inhibit transcription factors, phospholipase A2, and cyclooxygenase 2, all of which reduce the production of pro-inflammatory cytokines. Dexamethasone was shown to reduce mortality in COVID-19 patients.22 Tocilizumab is an IL-6 receptor antibody that prevents IL-6 binding to the receptor which reduces the inflammatory response. Tocilizumab was initially shown in case reports and retrospective trials to reduce the need for mechanical ventilation and improve mortality. However, a recent prospective randomized controlled trial failed to repeat these results.23,24

Given the theoretical benefits, but mixed real-world efficacy of immunomodulation, the novel method of a selective cytopheretic device (SCD) presented by Yessayan et al.25 is intriguing. The device approaches the inflammatory cascade upstream of typical cytokine scavenging or inhibition methods by binding the most active neutrophils and monocytes. Through an unclear mechanism, the circulating neutrophils and monocytes are reduced to a less inflammatory state decreasing cytokine production. In this two-patient study, there was a clear reduction in inflammatory cytokine markers and improvement in the patient’s respiratory status after initiation of SCD. Other studies looking at the SCD in acute kidney injury have shown improvements and no side effects attributable to the device itself.26 One concern to consider is that looking at limited data can lead to misleading results. The inability to repeat a beneficial response to immunomodulation interventions has been seen over and over again. This study of two patients was limited and therefore has a high risk that similar results of improvement will not be seen when expanded to larger trials.

At our institution, we have currently managed nine COVID-19 patients on venovenous ECMO with results similar to the national average (Extracorporeal Life Support Organization Registry as of December 9, 2020: 989/1,846 [53%] discharged alive). We have had four survive to discharge, three were unable to be weaned, and two who are currently still on ECMO. When looking at our IL-6 data, the average level was 167 pg/mL, and we also saw a large distribution (37–519 pg/mL). We did have one patient with a level greater than 3,000 pg/mL that did not get tocilizumab. This level was a significant outlier and was not included in the average. Using the inclusion criteria of the SCD study, we would have had two patients qualify for the device, both which had prolonged courses and did not survive. Looking at these initial SCD results, this treatment option would be something we would want to have moving forward.

The limitations of needing an elevated IL-6 level and having not received Tocilizumab decreases the use of the SCD. Only 22% of our patients would have qualified for the study, which leaves a large population of critically ill patients excluded. As mentioned in the article, six patients with COVID-19 and ARDS were screened and did not have an IL-6 level elevated enough to meet criteria, and four of these patients were on ECMO at the time of screening. I think future trials would need to look at decreasing the limitations on SCD use to either mechanically ventilated COVID-19 patients with severe ARDS or any mechanically ventilated patients with elevated IL-6 levels. With such a small percentage of ECMO patients qualifying, small to medium centers for ECMO may not have enough patients meet the qualifications to be in a trial.

Finally, the use of steroids as an anti-inflammatory was not mentioned in the article. Dexamethasone was shown to decrease 28 day mortality in patients with COVID-19 who were receiving mechanical ventilation or supplemental oxygen.20 With steroids now being used early-on as an anti-inflammatory drug, it remains to be seen how the SCD would work as a supplement to steroid use and if it would reach statistical significance. Additionally, another consideration for future trials is that tocilizumab use is increasing, and if it prevents the use of SCD treatment, it could limit patient recruitment.

In conclusion, beyond treatment of the viral associated cytokine storms, the implications of being able to reduce inflammation and lung injury associated with ARDS and ECMO cannulation are intriguing. This has the potential to be the missing piece needed to address the nonventilator biotrauma that current management strategies for ARDS do not address. More trials need to be conducted to study the impact of the SCD for COVID-19 patients. Future trials are needed to look at the effectiveness of SCD in other patient populations. There is high potential for the SCD to be another treatment tool for ARDS, especially in COVID-19, and look forward to further studies.


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            coronavirus disease 2019; acute respiratory distress syndrome; extracorporeal membrane oxygenation; cytokine storm; selective cytopheretic device

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