Jon-Emile S. Kenny MD [@heart_lung] with illustrations by Carla M. Canepa MD [@_carlemd_]

“…fires had been put out by volunteers using brickmason’s ladders and buckets of water carried in from wherever it could be found, and methods so disorderly that they sometimes caused more damage than the fires.”

- Gabriel García Márquez

In this second primer on COVID-19 therapy [see part 1], some of the lesser known management approaches are briefly discussed followed by a concise review of traditional supportive measures in the intensive care unit [ICU]. This is especially important in light of the recently-released Surviving Sepsis Campaign [SSC] guidelines on COVID-19.

Importantly, there are many more potential therapies for COVID-19 than are described in this brief, two-part primer [e.g. Vitamin C, various antibodies, ECMO etc.]; these posts quickly sketch some of the more commonly contemplated approaches.

Convalescent Plasma

Convalescent plasma from patients who have recovered from viral infections [i.e. immunoglobulins] may be a consideration in COVID-19 because of previous clinical success without severe adverse events. Indeed, immunoglobulins do have precedent with betacoronavirus outbreaks including SARS-CoV and MERS-CoV. Further, in a meta-analysis, convalescent plasma was associated with shorter hospital stay and lower mortality in those previous outbreaks, though many of the studies were of low quality. As viremia typically peaks within the first 7-10 days of infection, the administration of convalescent plasma is likely most effective when administered early. For example, when given within the first 14 days of SARS symptoms, convalescent plasma was most effective.

While, the SSC guidelines suggest not routinely using convalescent plasma in SARS-CoV-2, physicians can apply for convalescent plasma through the Food and Drug Administration [FDA] via an emergency Investigational New Drug Application [eIND]. To qualify, the patient must have severe or life-threatening COVID-19, defined here by the FDA.

Tocilizumab

Tocilizumab is a very expensive IL-6 inhibitor, ostensibly advantageous for ‘cytokine storm’ observed in severe COVID-19 disease. This monoclonal antibody should be reserved for critically-ill patients with significant, bilateral lung disease and elevated IL-6 levels. There is essentially no data for this drug in severe COVID-19, but there are clinical trials evaluating its efficacy.

The cytokine cyclone noted in severe COVID-19 may be secondary hemophagocytic lymphohistiocytosis [i.e. sHLH – an overlooked, hyperinflammatory syndrome exemplified by overwhelming multiorgan failure secondary to explosive cytokine elaboration]. Classically, sHLH presents with cytopenias, elevated ferritin, unrelenting fever and ARDS in roughly 50%. One potential way to screen for severe COVID-19 patients in whom anti-inflammation is warranted is to evaluate for rising ferritin, cytopenias and/or calculate the HScore. An HScore of 170 or greater has a very good sensitivity and specificity for diagnosing sHLH [see figure 1]

Therapeutic options for those with severe COVID-19 and sHLF include corticosteroids [see controversy in part 1], intravenous immunoglobulin, selective cytokine blockade [e.g. tocilizumab, others] and Janus Kinase inhibition.

Figure 1: Illustration of the HScore for predicting sHLH. Immunosuppression is defined as: HIV positive or receiving long-term immunosuppressive therapy [e.g. glucocorticoids, cyclosporine, azathioprine]. See text for details. By @_carlemd_Inhaled Interferon

The use of inhaled interferons is extrapolated completely from the SARS-CoV experience; its use has been recommended in China during the SARS-CoV-2 pandemic. Inhaled interferons [i.e. alpha and beta] reduced SARS-CoV replication in vitro and IFN-gamma probably also has some in vitro efficacy. Importantly, in a review of clinical trials, their use was deemed 'inconclusive.' Despite the above, there was a weak recommendation made in China for atomization of α-interferon in severe COVID-19. The SSC guidelines declare that there is insufficient evidence to issue a recommendation on the use of recombinant interferons, alone or in combination with antivirals, in critically-ill adults with COVID-19.

Oxygenation & Ventilation

Non-invasive Ventilation

Last, and certainly not least, are the tried-and-true supportive ICU interventions. For direction here, one can turn to the WHO guidelines; further, the Surviving Sepsis Campaign [SSC] guidelines on COVID-19 are newly-minted.

Regarding hypoxemic respiratory failure consequent to COVID-19, the SSC panel recommends titrating supplemental oxygen therapy to achieve a saturation of 92% to 96% based on a recent meta-analysis of non-COVID-19 patients showing that liberal oxygen therapy is associated with increased mortality. However, the authors also highlight the new LOCO2 trial which showed potential harm in ARDS patients managed with conservative oxygen therapy [i.e. saturation target of 88% to 92%].

When there is hypoxemic respiratory failure despite conventional oxygen therapy, high flow nasal cannula [HFNC] should be considered because of data illustrating that HFNC likely reduces the risk of intubation compared to conventional oxygen therapy. Additionally, as mechanical ventilation is a limited resource in pandemics, therapies that reduce intubation are desired. The FLORALI trial provides some data for selecting HFNC before NIPPV in addition to this meta-analysis showing that compared with NIPPV, HFNC reduces the need for intubation and mechanical ventilation.

Finally, with regards to infection control, there is data that the transmission rate of SARS-CoV was increased with NIPPV; however, for HFNC, environmental contamination was not greater than conventional oxygen mask in vitro and in a small cohort of critically-ill patients. Yet, in a recent, brief letter, four out of five healthy volunteers had cough droplet dispersion greater than 2 metres at baseline; the addition of HFNC increased droplet dispersion by 42 cm, on average, in these 5 volunteers.

Invasive Ventilation

Management of invasive mechanical ventilation should follow classical ARDS guidelines; that is, employing lower tidal volumes [i.e. 4–8 mL/kg predicted body weight, PBW] and lower inspiratory pressures [i.e. plateau pressure < 30 cmH2O]; targeting a driving pressure of less than 15 cm H2O is also reasonable. Higher positive end-expiratory pressure without stairway recruitment maneuvers is probably the best strategy – also endorsed by the SSC guidelines.

While some have advocated for airway pressure release ventilation [APRV], I am personally skeptical that one mode of ventilation will be truly superior to another. Further, the ‘pulmonary ARDS’ of COVID-19 may result in high trans-pulmonary pressures, and therefore increased mechanical driving power. Theoretically, APRV might elevate pulmonary ergotrauma and titrating T-low based solely on flow decay may not adequately individualize therapy. Nevertheless, I know extremely smart people who regularly use APRV [e.g. Dr. Spiegel], so local knowledge and comfort with a particular mode of ventilation is probably most important.

Prone Position

Prone position for patients with severe ARDS is recommended by both the World Health Organization [WHO] and SSC guidelines for COVID-19 while the latter also suggests prone for moderate ARDS. Both organizations declare that the prone position should be engaged for 12-16 hours per day to achieve maximal benefit. While prone position has the best evidence for mechanically-ventilated patients with moderate-to-severe ARDS, Dr. Farkas has had success in non-intubated patients. The respiratory and cardiovascular physiologies of the prone position are fascinating and improvements in both can, in theory, be multiplicative [see lecture 5, here].

Conservative Fluids

With respect to fluid therapy, the initial WHO management guidelines were decidedly fluid-forward, recommending upfront crystalloid loading of 30 mL/kg in patients with shock and COVID-19. Appropriately, Josh Farkas called this strategy ‘dangerously misguided’ and it appears that the WHO may have listened. In updated WHO guidelines, the recommendation is to give fluid challenges no more than 250-500 mL with reassessment of the patient’s physiology. Similarly, the SSC guidelines endorse a ‘fluid conservative’ approach given the absence of benefit for liberal fluid administration in sepsis and the risk of ARDS in COVID-19; thus, there is no mandated fluid challenge and the authors recommend following a resuscitation strategy similar to ANDROMEDA-SHOCK.

Best,

JE

Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he also the creator and author of a free hemodynamic curriculum at heart-lung.org

An Illustrated Primer on COVID-19 Therapy…