Management of respiratory failure due to covid-19BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1786 (Published 04 May 2020) Cite this as: BMJ 2020;369:m1786
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The editorial on the management of respiratory failure due to COVID-19 is somewhat disappointing (1). Whilst it is sound and comprehensive in terms foundations of management of ARDS it adds little for the readers to address problems associated with entrenched respiratory failure associated specifically with COVID-19 infection.
The author states that from a pathological perspective we face a condition that is “very similar to established descriptions of ARDS” (1). A large series of post-mortem cases from Northern Italy suggest that pathophysiological process is perhaps somewhat different from the what we would expect from ARDS (2). The findings lend support to the hypothesis that the COVID-19 infection is associated with a thrombotic process. Endothelial infection (3) and activation (4) has been evidenced or suggested by other authors. This along with clear prognostic importance of d-dimers leads one to believe that there maybe a microangiopathic process occurring.
From a bedside perspective it has been known that anticoagulation is associated with better outcomes in the early descriptions of this illness (5). Those findings are now being replicated. Recent cases series demonstrated what has been described at pulmonary embolism in 23-30% of patients with COVID-19 (6,7). The author of the editorial does not entertain those possibilities, which given mounting evidence may prejudice patient outcomes.
A serious question for those managing respiratory failure due to COVID-19 infection remains whether it is truly ARDS? If the cause of ventilation perfusion mismatch is diffuse intravascular intrapulmonary thrombosis driven by infection or hyper-immunity then usual oxygenation strategies as described may only exacerbate the problem. Therapeutic anticoagulation or immunosuppression may be the answer.
1. Wilcox S.R. Management of respiratory failure due to covid-19. BMJ 2020;369:m1786.
2. Carsana L, Sonzogni A, Nasr A et al. Pulmonary pos-mortem findings in a large series of COVID-19 cases from Northern Italy. medRxiv 2020.04.19.20054262; doi: doi:https://doi.org/10.1101/2020.04.19.20054262. [Accessed 11.05.2020].
3. Varga Z, Flammer A.J. Steiger P et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. DOI:https://doi.org/10.1016/S0140-6736(20)30937-5. [Accessed 11.05.2020].
4. Escher R, Breakey N, Lämmle. Severe COVID-19 infection associated with endothelial activation. Thrombosis Research 2020 https://doi.org/10.1016/j.thromres.2020.04.014. [Accessed 11.05.2020].
5. Tang N, Bai H, Chen X et al. J Thromb Haemost 2020;18:1094-1099. doi: 10.1111/JTH.14817 . [Accessed 11.05.2020].
6. Grillet F, Behr J, Calame P et al. Acute Pulmonary Embolism Associated with COVID-19 Pneumonia Detected by Pulmonary CT Angiography. Radiology 2020; https://doi.org/10.1148/radiol.2020201544. [Accessed 11.05.2020].
7. Leonard-Lorant I, Delabranche X, Severac F et al. Acute Pulmonary Embolism in COVID-19 Patients on CT Angiography and Relationship to D- Dimer Levels. Radiology 2020; https://doi.org/10.1148/radiol.2020201561. [Accessed 11.05.2020].
Competing interests: No competing interests
we read with keen interest the Editorial by Susan R Wilcox. The author claimed that pathology and management of respiratory failure due to Covid-19 are similar to acute respiratory distress syndrome (ARDS).
However, Covid-19 pneumonia has some peculiarities compared to the “Typical” ARDS . Indeed, two disease types or stages have been identified: “non-ARDS” and “ARDS” . The key to treat patients in the right way is the prompt identification of the two stages of the disease, as they require different therapeutic approaches.
An important role in the transition from one stage to the other is the activation of the coagulative cascade triggered by inflammation and the pulmonary micro- and macro-thromboembolism, both contributing to the worsening evolution of the syndrome [3,4].
In the early stage (non-ARDS), lung parenchyma is characterized by high compliance. A mismatch between lung damage, P/F ratio and mild symptoms is observed. The clinician should evaluate the increase of PaO2, by boosting FIO2 (through Venturi mask, reservoir), since lungs promptly respond to oxygen therapy with PaO2 enhancement. In the advanced stage (ARDS), when pulmonary thrombosis occurs, clinician does not observe PaO2 increase despite boosting FIO2, since dead space and shunt fraction rise. In this context etCO2/PaCO2 relationship, evaluated by capnography, is useful to quantify the pulmonary exchange efficiency: a ratio < 1 indicates elevated shunt and dead space (areas of lung ventilated and not perfused). It is also important the increase in P/F ratio, as it rises with low PEEP in the early stage. The use of the lowest possible PEEP is important since high PEEP in presence of high lung compliance could be harmful both for the hemodynamic and ventilatory profile. Importantly, it can aggravate the shunt because the high pressures act on the more elastic alveoli, which compress the capillaries, worsening the Ventilation-Perfusion Ratio and then the shunt effect leading to hypoxia.
We believe that the aforementioned ventilatory parameters could be useful in understanding the exact stage or type of the disease and its differential treatment and could be more suitable than other blood chemistry parameters, such as D-Dimer (which specificity is too low, especially during inflammation), in guiding the choice of the antithrombotic strategy.
Covid-19 is a very complex disease that requires a different management depending on the stage or type. We have to understand when we act. This allows us to do the right thing at the right time.
1. Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. Covid-19 Does Not Lead to a “Typical” Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2020 Mar 30. doi: 10.1164/rccm.202003-0817LE.
2. Gattinoni L, Chiumello D, Rossi S. COVID-19 Pneumonia: ARDS or Not? Crit Care. 2020 Apr 16;24(1):154.
3. Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up. J Am Coll Cardiol 2020 Apr 15; S0735-1097(20)35008-7.
4. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical Course and Risk Factors for Mortality of Adult In patients With COVID-19 in Wuhan, China: A Retrospective Cohort Study. Lancet 2020 Mar 28;395(10229):1054-1062.
Competing interests: No competing interests
Covid-19 may have similar pathology to ARDS but this is a distinct disease and so alternative management options may exist.
There is clearly benefit in increasing alveolar paO2 by oxygen supplementation and ventilation, but if the lungs cannot deliver alveolar oxygen to the left atrium then treatment will fail.
SARS-CoV2 is known to target lung ACE2, thereby interfering with local deactivation of Angiotensin II to Angiotensin 1-7. (1). Angiotensin II acts on smooth muscle via PhosphoDiesterase 5 (PDE5) causing local vasoconstriction (2). Thus PDE5 inhibitors are credible candidate drugs to mitigate the effects of this disease. The commonly available PDE5 inhibitors, Sildanafil and Tadalafil, are out of patent and so there is no clamour from industry to trial them when in-patent agents such as Remdesivir offer investor return.
Trialists seem to hunt as a pack, seeking ever more data on similar anti-infective and anti-inflammatory agents.
Until someone, somewhere, carries out a trial of PDE5 inhibitors (and perhaps other untried but credible candidate drugs) we won’t know what their harms and benefits are in this disease. If we could reduce the incidence of respiratory failure by earlier intervention with medication that would surely be an achievement.
1. Tikellis, C.,Thomas, M.C. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease International Journal of Peptides Volume 2012, Article ID 256294, doi:10.1155/2012/256294
2. Dongsoo Kima, Toru Aizawab, Heng Weic, et al. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling J Mol Cell Cardiol. 2005 January ; 38(1): 175–184. doi:10.1016/j.yjmcc.2004.10.013
Competing interests: No competing interests
We read the article with keen interest as, despite its low 2.3% case fatality rate (1), Coronavirus Disease 2019 (COVID-19) is ravaging health systems and economies worldwide, determining an unprecedented overcharge for Intensive Care Units (ICU). (2) Between 3-10% of COVID-19 patients need hospital admission due to massive interstitial pneumonia, with the majority of them requiring prolonged mechanical ventilation. (3) An early conversion from intubation to tracheostomy is normally recommended to facilitate respiratory wean (3). In COVID-19 patients the risk of accidental decannulation during prone patient positioning and the hazard of cross-infection make an early tracheostomy unsafe. Such issues may delay patient’s extubation for up to 4 weeks. (4,5) The aim of the present communication from the Laryngotracheal Stenosis Committee of the European Laryngological Society is therefore to alert the medical community to the likely scenario of laryngo-tracheal stenosis (LTS) formation following prolonged intubation and/or tracheostomy.
Prolonged intubation exposes patients to multilevel airway injuries (between the arytenoids, at the levels of posterior commissure, the cricoid plate and trachea). (6,7) The mucosal inflammation and ischemia caused by the presence of tubes and cuffs may lead to ulceration, perichondritis, chondritis, granulomas and chondronecrosis with airway malacia, perforation and posterior glottic web. (8) The degree and depth of the laryngo-tracheal injury depends on duration of intubation, tube size, patient’s general conditions and comorbidities. (8) Even tracheostomy (percutaneous or traditional) per se, whenever performed, represents a potential damage for the airway, especially when carried on a locally inflamed situation after long-lasting intubation.
We believe that this coalescence of highly unfavorable clinical circumstances in COVID-19 patients is likely to give rise, in the near future, to an unprecedented high incidence of iatrogenic airway injuries leading to LTS formation. Of importance is trying to avoid as much as possible that LTS be misdiagnosed as asthma or lower airway diseases, thus retarding initiation of the most adequate diagnostic and therapeutic processes, or even increasing the risk of complications due to an undiagnosed airway obstruction.
Failure of extubation and prolonged weaning are important clinical scenarios in COVID-19 patients managed in ICU, since an evolving stenosis with various degrees of mucosal edema, ulcerations, fibrin, and florid granulation tissue might be the cause. (9) A close cooperation between otolaryngologists, intensive care physicians, and interventional pulmonologists is of paramount importance in managing the recently extubated patient with new-onset symptoms, since minimally-invasive approaches can often bridge the gap between emergency readmission of a recently extubated patient and recognition with definitive treatment of an evolving LTS.
Following patient discharge, new or worsening exertional dyspnea in the post-intubation COVID-19 patient should raise the possibility of LTS as the cause of these symptoms especially if associated with dry cough, wheeze, hoarseness, or swallowing problems. (10) Post-COVID-19 screening and rehabilitation should ideally be performed in multidisciplinary settings with otolaryngologists evaluating airway, voice and swallowing functions. If healthcare setup precludes a primary joint clinic, airway stenosis should be sought using a flow-volume loop or, at the very least, using the Expiratory Disproportion Index (FEV1/PEFR) as part of routine spirometry. (11) Patients with suspected LTS should be dynamically evaluated with transnasal videolaryngotracheoscopy in order to assess the dynamic functions together with degree of LTS, its nature (florid or already mature scar), airway sites involved, and length. Additional evaluation of the dynamic functions at the tracheostomy site and distal airway might necessitate flexible bronchoscopy.
Suspension laryngoscopy under general anesthesia should be performed whenever the former examinations failed to provide the overall amount of detailed information needed. CT scan of the larynx and trachea can be complementary in evaluating the length of stenosis in case of complete airway obstruction and gives a deeper insight of a potentially altered framework due to deformity, fracture or collapse. (9)
Once diagnosed, management of the LTS should follow established principles of restoring and maintaining an airway that is capable of meeting the ventilatory demands of the patient whilst minimizing collateral injury to voice and swallowing mechanism. (11,12) All efforts should be spent to identify and treat LTS at the subacute fibro-inflammatory stage to reduce the need for major procedures.
We believe that a large surge in the incidence of post-intubation LTS in the post-COVID-19 patient population will occur. As such, a high index of suspicion should be maintained among all medical professionals, encouraging them to actively consider LTS in the differential diagnosis of every post-COVID-19 dyspnea. We furthermore suggest that identified cases should be referred to dedicated centers with expertise in the field of airway surgery and be treated by clinicians who are specifically trained in performing the full spectrum of minimally-invasive and open reconstructive approaches in order to achieve the best outcomes for a group of patients who are likely to present with complex airway pathology.
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4. Sommer DD, Engels PT, Weitzel EK, Khalili S, Corsten M, Tewfik MA, et al. Recommendations from the CSO-HNS taskforce on performance of tracheotomy during the COVID-19 pandemic. J Otolaryngol Head Neck Surg. 2020 Apr;49(1):23.
5. Cook TM, El-Boghdadly K, McGuire B, McNarry AF, Patel A, Higgs A. Consensus guidelines for managing the airway in patients with COVID-19. Anaesthesia. 2020;1–15.
6. Seegobin RD, Van Hasselt GL. Endotracheal cuff pressure and tracheal mucosal blood flow: endoscopic study of effects of four large volume cuffs. Br Med J. 1984;288(6422):965–8.
7. Sengupta P, Sessler DI, Maglinger P, Wells S, Vogt A, Durrani J, et al. Endotracheal tube cuff pressure in three hospitals, and the volume required to produce an appropriate cuff pressure. BMC Anesthesiol. 2004;4:4–9.
8. Mehel DM, Özdemir D, Çelebi M, Aydemir S, Akgül G, Özgür A. Classification of laryngeal injury in patients with prolonged intubation and to determine the factors that cause the injury. Am J Otolaryngol - Head Neck Med Surg [Internet]. 2020;(January):102432. Available from: https://doi.org/10.1016/j.amjoto.2020.102432
9. Monnier P, Dikkers FG, Eckel H, Sittel C, Piazza C, Campos G, et al. Preoperative assessment and classification of benign laryngotracheal stenosis: a consensus paper of the European Laryngological Society. Eur Arch Oto-Rhino-Laryngology. 2015;272(10):2885–96.
10. Fiz I, Monnier P, Koelmel JC, Di Dio D, Fiz F, Missale F, et al. Multicentric study applying the european laryngological society classification of benign laryngotracheal stenosis in adults treated by tracheal or cricotracheal resection and anastomosis. Laryngoscope. 2019;1–6.
11. Kocdor P, Siegel ER, Suen JY, Richter G, Tulunay-Ugur OE. Comorbidities and factors associated with endoscopic surgical outcomes in adult laryngotracheal stenosis. Eur Arch Otorhinolaryngol. 2016 Feb;273(2):419–24.
12. Gouveris H, Karaiskaki N, Koutsimpelas D, Chongolwatana C, Mann W. Treatment for adult idiopathic and Wegener-associated subglottic stenosis. Eur Arch Otorhinolaryngol. 2013 Mar;270(3):989–93.
Competing interests: No competing interests
We read the article with keen interest as the management and underlying etiopathogenesis of COVID-19 related ARDS is of utmost importance to clinicians in this era of an evolving pandemic.
We hereby intend to draw your attention to the pivotal role of radiological imaging including but not limited to non-contrast CT Chest using spiral scanner with volume reconstructions that can better evaluate the progressing stages of ARDS related complications. 
There are consensus guidelines published by the Radiology Society of North America (RSNA) [2,3] validated by the Society of Thoracic Radiology and the American College of Radiology (ACR) that substantially classify the CT appearance of COVID-19. The typical imaging features seen on CT chest are bilateral, peripheral subpleural ground glass opacities with or without consolidation with evolving crazy paving pattern or atoll sign, progressively developing into organizing pneumonia pattern leading to visual scoring (0 to 5) which very well correlates with worsening ARDS symptoms. 
Moreover, apart from the early detection of pulmonary involvement in asymptomatic cases due to its high sensitivity (>97%),  and its implication in follow-up of ARDS, high resolution CT imaging can rule out superadded bacterial infections which may lead to serious outcomes on background COVID-19 related ARDS. 
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3. Simpson S, Kay FU, Abbara S, Bhalla S, Chung JH, Chung M, et al. Radiological Society of North America Expert Consensus Statement on Reporting Chest CT Findings Related to COVID-19. Endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA. Radiology: Cardiothoracic Imaging 2020. 2:2. https://doi.org/10.1148/ryct.2020200152
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Nothing to declare.
Competing interests: No competing interests