Azoulay et al. Critical Care (2020) 24:486 https://doi.org/10.1186/s13054-020-03194-w RESEARCH Open Access International variation in the management of severe COVID-19 patients Elie Azoulay1* , Jan de Waele2, Ricard Ferrer3,4, Thomas Staudinger5, Marta Borkowska2, Pedro Povoa6, Katerina Iliopoulou7, Antonio Artigas8, Stefan J. Schaller9, Manu Shankar-Hari10, Mariangela Pellegrini11,12,13, Michael Darmon1, Jozef Kesecioglu14 and Maurizio Cecconi15 Abstract Background: There is little evidence to support the management of severe COVID-19 patients. Methods: To document this variation in practices, we performed an online survey (April 30–May 25, 2020) on behalf of the European Society of Intensive Care Medicine (ESICM). A case vignette was sent to ESICM members. Questions investigated practices for a previously healthy 39-year-old patient presenting with severe hypoxemia from COVID-19 infection. Results: A total of 1132 ICU specialists (response rate 20%) from 85 countries (12 regions) responded to the survey. The survey provides information on the heterogeneity in patient’s management, more particularly regarding the timing of ICU admission, the first line oxygenation strategy, optimization of management, and ventilatory settings in case of refractory hypoxemia. Practices related to antibacterial, antiviral, and anti-inflammatory therapies are also investigated. Conclusions: There are important practice variations in the management of severe COVID-19 patients, including differences at regional and individual levels. Large outcome studies based on multinational registries are warranted. Keywords: Coronavirus, Acute respiratory distress syndrome, Viral infection, Remdesivir Background practices for a previously healthy 39-year-old patient There is little evidence to support the optimal manage- presenting with severe hypoxemia from COVID-19 ment of severe COVID-19 patients [1, 2]. To document infection (Table 1). The 85 participating countries were whether there is a variation in practices, we performed grouped into 12 different regions [3]: continuous an online survey (April 30–May 25, 2020) on behalf of variables are described as median (interquartile range ESICM. [IQR]) and are compared between groups using the non-parametric Wilcoxon rank-sum test. Categorical variables are described as frequency (percentages) and Methods are compared between groups using Fisher’s exact test. In this online survey, a case vignette (https://www.sur- Statistical analyses were performed with R statistical veymonkey.com/r/F2FFC6S) was sent to ICU specialists software, version 3.4.3 (available online at http://www.r- who are members of ESICM. Questions investigated project.org/). A p value < 0.05 was considered significant. * Correspondence: elie.azoulay@aphp.fr 1 Médecine Intensive et Réanimation, Department of the St-Louis Hospital, APHP, Hôpital Saint-Louis, Paris University, 1 avenue Claude Vellefaux, 75010 Paris, France Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Azoulay et al. Critical Care (2020) 24:486 Page 2 of 7 Results South America (9%), North Europe (8.1%), Eastern Response rate was 20% (N = 1132 intensive care (ICU) Europe (5.3%), Middle-East (5%), North America specialists from 85 countries, including 1001 complete (4.7%), Asia (3.3%), India (2.7%), Australia-New answers). Respondents (median 45 years [IQR, 39– Zealand (1.3%), or Africa (0.6%); 54% were living in a 53], 34% women) were from Middle Europe (25%), large city (> 1 million inhabitants), and 55% were South Europe (23%), the United Kingdom (UK) (12%), working in university-affiliated hospitals. The median Table 1 Distribution of the responses to the case vignette Numbers (%) or median (interquartile ranges) Total, 1001 respondents 1. Admission to the ICU of a previously healthy 39-year-old man with severe COVID-19 Direct admission to the ICU 55% Admission in an intermediate care unit 34.2% Delayed admission to the ICU because of lack of bed 1.3% Patient stays in the emergency department 0.8% Patient admitted in the wards 8.8% 2. Initial oxygenation strategy I increase the oxygen flow to 15 l/min keeping the face mask 24.2% I change the mask for a Venturi mask 17.5% I start CPAP or noninvasive ventilation 25.5% I start high flow nasal oxygen 47.1% I intubate the patient right away 7.4% I add prone positioning on spontaneous breathing 37.9% 3. Optimizing oxygenation in a patient with a PF ratio of 84 4 h after intubation I will give neuromuscular blockade for 24–48 h 50.9% I increase and titrate PEEP to optimize recruitment 61.4% I prone the patient immediately 73.2% I am considering ECMO immediately 4.7% Let us wait a little bit 9.9% 4. Regarding the initial antibiotics All my patients receive a broad anti-bacterial agent 45.3% I only give broad anti-bacterial agent to febrile patients 11% I only give broad anti-bacterial agent if CRP or PCT are high 4.2% I only give broad anti-bacterials to patients with structural lung diseases 35.8% I never give broad anti-bacterial agent in severe viral infections 3.7% 5. Regarding initial anti-viral therapy, several options are possible The level of evidence is so low that there is nothing I can give 48.9% I prescribe (hydroxy)chloroquine 42.7% I prescribe lopinavir/ritonavir 17.0% I prescribe remdesivir 15% I prescribe another anti-viral drug 4.6% 6. Are you starting an anti-inflammatory therapy? No 52.4% Yes IL-1 or IL-6 blockade 24.8% Yes, complement blockade 1.4% Yes, steroids 31.5% Yes, another anti-inflammatory drug 2.4% Azoulay et al. Critical Care (2020) 24:486 Page 3 of 7 (IQR) number of ICU beds was increased from 20 Respondents were then asked about the first-line (11–36) to 35 (20–60) during the pandemic surge. oxygenation strategy, which varied significantly across As the patient had 88 (peripheral oxygen saturation) regions (Fig. 2, P < 0.0001). First-line high flow nasal SpO2 on 9 l/min of oxygen, direct ICU admission was cannula (HFNC) was used by 22.9% of the respon- reported in 56% (30–90%) of the respondents, with dents (0% in Australia-New Zealand, 38% in Eastern significant variation across regions (Fig. 1, P < 0.0001). Europe). Noninvasive ventilation was used by 25.5% Most intensivists not directly admitting patients to of the respondents (5.4% in North America, 43.6% in the ICU would admit them to an intermediate care the UK). Interestingly, 8% of the respondents were unit managed by intensivists. However, the issue of using first-line intubation (0% in Australia-New Zea- bed availability was reported in South Europe (4.5%), land, 23% in Asia). Women less frequently initiated South America (2.9%), Scandinavia (1.6%), Middle HFNC (32% vs. 42%, P = 0.02). The availability of an Europe (1.6%), and the UK (1.1%). Should the patient intermediate care unit influenced the use of HFNC or be not admitted to the ICU, a rapid response team non-invasive ventilation (NIV) (32.8% vs. 21.7%, P = would be involved in 29% of the cases, the ICU spe- 0.03). Along this line, a higher number of ICU beds cialist would make the outreach her/himself in 24% of (24 (12–40) vs. 18 (10–30) beds, P = 0.0009) was asso- the cases, or an ICU nurse would be involved in 7% ciated with the use of HFNC and NIV. Interestingly, of the cases. In all other cases, ward or ED physicians 37.5% were using prone positioning in awake non- would manage the patients. Direct ICU admission was ventilated patients. To assess whether HFNC or NIV significantly associated with baseline number of ICU should be continued, ICU specialists relied on SpO2 beds (22 [12–40] vs. 18 [10–30] beds, P < 0.0001) and (85.7%), respiratory rate (71.4%), followed by dyspnea with the number of COVID-19 patients managed (30 (47.1%), and comfort (45.4%). Criteria for intubation [11–52] vs. 38 [20–70] patients, P = 0.001), as well as included clinical signs of respiratory distress (94%), with management of patients in large cities (56.9% vs. high oxygen flow to maintain a SpO2 of 95% (33.5%), 49.6%, P = 0.04). or low SpO2 only (25.6%). Fig. 1 World map displaying practice variations across regions regarding direct admission to the ICU or the intermediate care unit Azoulay et al. Critical Care (2020) 24:486 Page 4 of 7 Following intubation, the patient had a partial Antibiotic prescribing was routine for all patients pressure of oxygen/fraction of inspired oxygen (P/F) in 44.2% of the respondents and biomarker-guided in ratio of 84 mmHg. Although prone positioning 36.5%, without significant variation across regions. (71.2%) and neuromuscular blockade (59.7%) were Routine antibiotics were more frequently used by often used to optimize oxygenation, the practice respondents working in university-affiliated hospitals varied significantly across countries. For instance, (48.3% vs. 40.9%, P = 0.03) and those living in large prone positioning was performed in 70–85% of the cities (49.3% vs. 40.2%, P = 0.01). Biomarker-guided cases in Asia, India, Eastern Europe, Middle Europe, antibiotic therapy was less frequent in large cities South America, South Europe, and the UK, whereas (47.3% vs. 57.4%, P = 0.007). Regarding antiviral Africa, Australia-New Zealand, Middle East, North therapy, 48.9% reported not prescribing antivirals, America, and Scandinavia were in the 50–70% range 42.6% were giving hydroxychloroquine, 17% (Fig. 3, P < 0.0001). Respondent’s age was associated lopinavir-ritonavir, and 15% remdesivir. Figure 4 dis- with the use of prone positioning (46 [39–54] vs. 44 plays significant variation in antiviral prescriptions [37–51] years, P = 0.007). Older respondent’s age (45 across regions (P < 0.0001). Physicians not prescrib- [37–52] vs. 47 [40–55] years, P = 0.0001), living in a ing antivirals were older (47 [40–54] vs. 44 [37–51] large city (54.2% vs. 46.8%, P = 0.03), and a higher years, P < 0.0001), and more frequently men (55.4% number of COVID-19 patients managed (35 [15–65] vs. 39.9%, P < 0.0001). Conversely, those prescribing vs. 30 [12–55] patients, P = 0.02) were associated hydroxychloroquine were younger (43 [37–50] vs. 47 with the use of neuromuscular blockade. [40–54] years, P < 0.0001), and more frequently Fig. 2 World map displaying practice variations across regions regarding the use of noninvasive oxygenation strategies Azoulay et al. Critical Care (2020) 24:486 Page 5 of 7 Fig. 3 World map displaying practice variations across regions regarding the use of neuromuscular blockades and prone positioning women (41.7% vs. 28.2%, P < 0.0001). There was care. Learning from this heterogeneity will not only significant variation in the use of interleukin-6 (IL- raise hypothesis on optimal patient’s management, 6)/IL-1 blockade or of corticosteroids across but also serves as a tool to suggest personalized countries (P < 0.0001 for both tests). Other collected management for each clinical phenotype [6, 7]. variables were not associated with the use of anti- This study has several limitations. First, the study inflammatory drugs. suffers from a nonresponse bias of 80%. Second, even though only physicians have responded, we Discussion cannot ascertain that all of them had the clinical ex- This survey highlights important practice variations pertise and the experience of managing COVID-19 in the management of severe COVID-19 patients, patients. Last, questions about specific treatments including differences at regional and individual did not take into account the fact that the level of levels. This illustrates that neither IDSA nor Surviv- evidence has changed over time. ing Sepsis Guidelines did recommend any of these treatments, but instead encouraged inclusion of pa- tients into trials [1, 4, 5]. Since the publication of Conclusion these guidelines, no more evidence has been made As no management guidelines have allowed to available to ascertain that these specific COVID-19 guide practices for the COVID-19 pandemic, therapies should be included in the standard of heterogeneous behaviors are reported. Large Azoulay et al. Critical Care (2020) 24:486 Page 6 of 7 Fig. 4 World map displaying practice variations across regions regarding the use of antiviral agents outcome studies based on multinational registries Consent for publication are warranted. All participants consented. Acknowledgements Competing interests We are indebted to Dominique de Boom, Nicolas Vander Elst, and Guy The authors declare no conflict of interest in relation to this survey. Francois from the ESICM office for their fast and high-quality support to pre- pare this survey and its diffusion. Author details 1 Médecine Intensive et Réanimation, Department of the St-Louis Hospital, Authors’ contributions APHP, Hôpital Saint-Louis, Paris University, 1 avenue Claude Vellefaux, 75010 All authors contributed to the design, the development of the instrument, Paris, France. 2Department of Critical Care Medicine, Ghent University and interpretation of data. All authors have approved the submitted Hospital, 9000 Gent, Netherlands. 3Shock, Organ Dysfunction, and manuscript. Resuscitation Research Group (SODIR), Instituto de Investigación de Vall d’Hebron, Barcelona, Spain. 4Departmento de Medicina Intensiva, Hospital Universitario de Vall d́ Hebron, Centro de Investigación Biomédica en Red Funding (CIBER) de Enfermedades Respiratorias, Barcelona, Spain. 5Department of None Medicine I, Intensive Care Unit, Medical University of Vienna, Vienna General Hospital, Vienna, Austria. 6NOVA Medical School, CHRC, New University of Availability of data and materials Lisbon, Unidade de Cuidados Intensivos Polivalente, Hospital de São Fully available upon request. Francisco Xavier, CHLO, Estrada Do Forte Do Alto Do Duque, 1449-005 Lisbon, Portugal. 7Hellenic Army, ICU Nurse Manager General Military Ethics approval and consent to participate Hospital, Athens, Greece. 8Critical Care Center, Sabadell Hospital, University All participants agreed online to complete the survey. Institute Parc Taulí, Autonomous University of Barcelona, Ciberes, Barcelona, Azoulay et al. Critical Care (2020) 24:486 Page 7 of 7 Spain. 9Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Anesthesiology and Surgical Intensive Care, Berlin, Germany. 10School of Immunology and Microbial Science, Kings College London. Guy’s and St Thomas’ NHS Foundation Trust, ICU Support Offices, St Thomas’ Hospital, London, UK. 11Department of Surgical Sciences and Central Intensive Care Unit, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 12Department of Anesthesia, Operation, and Intensive Care; Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 13 Department of Anesthesiology and Intensive Care Medicine, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 14Department of Intensive Care Medicine, Division of Anesthesiology, Intensive Care and Emergency Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 15Humanitas Clinical and Research Center, Humanitas University, Milan, Italy. Received: 17 June 2020 Accepted: 20 July 2020 References 1. Alhazzani W, Møller MH, Arabi YM, et al. 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