Rationale

Many patients with coronavirus disease (COVID–19) need hospital admission for oxygen supplementation. A substantial number of patients need intensive care unit (ICU) admission for escalation of care. ICU doctors and nurses are struggling to provide the best care for patients with COVID–19. Practice of adjunctive and supportive treatments remains uncertain.

Objective

To determine and compare practice of adjunctive and supportive treatments for COVID–19 in the Netherlands, and to determine their independent associations with outcome.

Hypotheses

Practice of adjunctive and supportive treatments for COVID–19 varies substantially. Adjunctive and supportive treatments have an independent association with outcome in ICU patients with COVID–19.

Study design

National, multicenter, retrospective observational study.

Study population

Intensive care unit (ICU) patients with COVID–19.

Methods

In this study we will collect data on diverse treatments during the first 28 days in ICU, including (a) the types of oxygen support and awake prone positioning; (b) the types of ventilatory support, (c) rescue therapies for refractory hypoxemia during invasive ventilation (prone positioning, ventilator adjustments, continuous muscle paralysis, and extracorporeal membrane oxygenation); (d) adjunctive treatments, including thromboprophylaxis and anticoagulation, antiviral and immunomodulating therapies, and (e) experimental supportive treatments. Outcomes include duration of each adjunctive treatment, duration of ventilation, incidence of tracheostomy, duration of stay in ICU and mortality until day 90.

Study endpoints

A combination of adjunctive treatments, including types of oxygen support, ventilatory support and rescue therapies for refractory hypoxemia during invasive ventilation (primary), other adjunctive and supportive treatments, tracheostomy rate; duration of ventilation and ventilator–free days and alive at day 28 (VFD–28), duration of ICU and hospital stay, and ICU, hospital and 90–day mortality.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness

Retrospective collection of data regarding adjunctive treatments, and clinical endpoints is without risk for ICU patients.

Coronavirus disease 2019

Patients with coronavirus disease 2019 (COVID–19) are frequently hospitalized and a substantial number of them end up in an intensive care unit (ICU) for acceleration of care [1]. The Netherlands is currently facing a new surge of COVID–19 patients.

Oxygen support

Many patients with COVID–19 develop hypoxemia. Hypoxemia may respond well to standard oxygen support, like oxygen supplementation through interfaces like a nasal prong or cannula, or non–rebreather or Venturi masks––this type of support is usually provided in a normal ward. Patients with severe COVID–19 may develop ‘refractory’ hypoxemia, for which more intense oxygen support is needed, like oxygen supplementation with continuous positive airway pressure (CPAP) or via high–flow nasal oxygen (HFNO)–– this type of support usually mandates admission to an ICU.

Rescue therapies for refractory hypoxemia

If oxygenation does not improve with so–called ‘awake proning’, non–invasive ventilation and eventually invasive ventilation can be initiated. Even with invasive ventilation hypoxemia may persist [2-5]. Rescue therapies for persistent hypoxemia may include prone positioning, higher airway pressures or inverse ratio ventilation, at times in combination with continuous or intermitted muscle paralysis could be given. In certain cases, extracorporeal membrane oxygenation may even be necessary.

Adjunctive treatments

Adjunctive treatments in patients with COVID–19 can include intensified thromboprophylaxis, and in cases of suspected or proven deep venous thrombosis or pulmonary embolism, full anticoagulation. Also, various antiviral or antibacterial, and immunomodulating strategies can be used [6].

Experimental supportive care

Experimental supportive care may consist of various types of minerals or vitamins, and other pharmacological interventions [6-9].

Need for an observational study

Care for patients with COVID–19 varies widely between countries and regions, and probably also within the Netherlands. It is very well possible that variance in care are amplified by a lack of consensus on the best care for COVID–19. They all could affect outcome, though. Therefore, it is important to determine and compare practices of oxygen support, rescue therapies for refractory hypoxemia, adjunctive treatments and experimental supportive care for COVID–19, and to determine their independent associations with outcome. This study may form an important step in creating a guideline for standard care in patients with COVID–19.

Objectives

Primary objective: To determine and compare practice of oxygen support, rescue therapies for refractory hypoxemia, adjunctive treatments and experimental supportive care in patients with coronavirus disease 2019 (COVID–19) admitted to intensive care units (ICUs) in the Netherlands.

Secondary objective: To determine the independent association of practice of oxygen support, rescue therapies for refractory hypoxemia, adjunctive treatments and experimental supportive care with outcome in patients with COVID–19.

Hypothesis

Primary hypothesis: Practice of oxygen support, rescue therapies for refractory hypoxemia, adjunctive treatments and experimental supportive care for COVID–19 varies between ICUs.

Secondary hypothesis: Practice of oxygen support, rescue therapies for refractory hypoxemia, adjunctive treatments and experimental supportive care affect outcome in patients with COVID–19.

Multicenter, national, retrospective, observational study in patients with coronavirus disease 2019 (COVID–19) admitted to participating intensive care units (ICUs) in the Netherlands.

Population (base)

Patients with severe coronavirus disease 2019 (COVID–19) admitted to intensive care units (ICUs) in the Netherlands between September 2020 and January 2021 (i.e. during the second surge of COVID–19 patients). This study will not be restricted to ‘physical’ ICUs, as patients may also receive accelerated care from intensivists at other locations within a hospital during the pandemic.

Inclusion criteria

· COVID–19, confirmed with PCR; and

· Admission to one of the participating ICUs, or an emergency location that serves as an ICU during the pandemic.

Exclusion criteria

· Age < 18 years

Sample size calculation

No formal sample size calculation is needed. We expect to capture at least 1000 patients but will continue collecting data of new patients for at least 3 months.

Study parameters/endpoints

Main study parameters

· Types of oxygen support (including oxygen supplementation via nasal prong or nasal canula, non–rebreather or Venturi masks, continuous positive airway pressure (CPAP), high–flow nasal oxygen (HFNO), non–invasive ventilation (NIV) and invasive ventilation);

· Practice of awake proning;

· Characteristics of invasive ventilation;

· Rescue therapies for refractory hypoxemia (including prone positioning, higher positive–end expiratory pressure (PEEP) or inverse ratio ventilation (IRV), continuous or intermitted muscle paralysis, and extracorporeal membrane oxygenation (ECMO);

· Practice of thromboprophylaxis.

· Practice of stress ulcer prophylaxis.

· Practice of sedatives.

· Practice of muscle paralysis.

· Practice of full anticoagulation in patients with suspected or confirmed deep venous thrombosis (DVT) or pulmonary embolism (PE);

· Practice of antiviral and antimicrobial treatments (including, but not restricted to remdesivir, lopinavir–ritonavir, baloxavir marboxil, barunavir–cobicistat, favipiravir, sofosbuvir–daclatasvir, triazavirin, umifenovir and azithromycin);

· Practice of immunomodulating treatments (including, but not restricted to corticosteroids, chloroquine or hydroxychloroquine, interferon, aprepitant, colchicine, immunoglobulin, ivermectin, ruxolitinib, telmisartan, tocilizumab and convalescence plasma);

· Practice of aerosolized medication (including, but not restricted to salbutamol, ipratropium and acetylcysteine) and

· Practice of experimental supportive care (including, but not restricted to minerals or vitamins, and other pharmacologic agents, like zinc, N–acetylcysteine, and vitamins).

Other study parameters

· Duration of ventilation in survivors;

· Number of ventilator–free days and alive at day 28 (VFD–28);

· Incidence of tracheostomy;

· Proven DVT or PE;

· Incidence of gastrointestinal bleeding;

· Daily cumulative fluid balances and cumulative urine production;

· Development of acute kidney injury (AKI) and use of renal replacement therapy (RRT);

· Duration of ICU and hospital stay; and

· ICU, hospital and 90–day mortality.

Randomization, blinding and treatment allocation

Not applicable.

Study procedures

Patients are identified by the attending clinicians. Data will be collected by local investigators, or will be visited by researchers from the Amsterdam University Medical Centers, location ‘AMC’ to collect these data.

Data collection – Demographic data

· Age (age categories);

· Gender (male or female);

· Height (cm);

· Weight (kg);

· Comorbidities (categories);

· Home medication (categories);

· Disease severity scores (simplified acute physiology score (SAPS) II or Acute Physiology and Chronic Health (APACHE II) score II or IV;

· Date of start of complaints;

· Date of start of hospital admission;

· Type of oxygen support before ICU admission (nasal prong or canula, non–rebreather or Venturi mask, CPAP, HFNO or NIV);

· Date of ICU admission;

· Date and time of intubation (if applicable);

· Duration of admission in previous hospital (days); and

· Duration of invasive ventilation in previous hospital (if intubated elsewhere, days).

Data collection – Adjunctive treatments

Daily for the duration of admission at the ICU with a maximum of 28 days;

· Oxygen interfaces used (nasal prong or nasal canula, non–rebreather or Venturi mask, CPAP, HFNO, NIV and invasive ventilation);

· Awake proning (i.e., prone position in non–intubated patients) (yes/no), and if yes: duration (hours per day); and number of sessions per day;

· Prone position during invasive ventilation (yes/no), and if yes: duration (hours/day); and number of sessions per day

· Practice of sedatives (continuous or intermitted);

· Practice of muscle paralysis (continuous or intermitted);

· Practice of extracorporeal membrane oxygenation (ECMO) (yes/no); and if yes: venous–venous or venous–arterial;

· Practice of thromboprophylaxis (yes/no) and if yes: agent; and dose;

· Practice of full anticoagulation in patients with suspected or proven DVT or PE (yes/no), and if yes, indication; agent; and

· dose;

· Practice of antiviral treatments (yes/no), and if yes: agent, and dose;

· Practice of immunomodulating treatments (yes/no), and if yes: agent, and dose;

· Practice of proton pump inhibitors (PPI)(yes/no), and if yes: agent, and dose;

· Daily cumulative fluid balances (ml); and urine output (ml); and

· Experimental supportive treatments: minerals or vitamins (yes/no) and if yes: agent, and dose.

Data collection – Ventilator settings and parameters (once per day, at 12:00)

· ventilation mode;

· positive end–expiratory pressure (PEEP) (cm H₂O);

· plateau pressure (cm H₂O);

· respiratory rate (/min);

· inspired fraction of oxygen (FiO₂) (%);

· saturation of peripheral oxygen (SpO₂) (%); and

· PaO2 (kPa).

Data collection – Follow–up

· date of successful extubation (date);

· oxygen support after extubation (categories, including nasal prong or canula, non–rebreather or Venturi mask, CPAP, HFNO, and NIV);

· date of tracheostomy; and if yes, where performed (ICU; or operating room), and date of decannulation (date);

· ICU discharge (date);

· readmission (if applicable) and if yes: readmission date;

· development of deep venous thrombosis (yes/no);

· development of pulmonary embolism (yes/no);

· development of acute kidney injury (AKI) (yes/no);

· development of gastrointestinal bleeding (yes/no);

· use of renal replacement therapy (RRT) (yes/no);

· life status at day 7, day 28 and day 90;

· date of hospital discharge (date);

· ICU, hospital and 90–day mortality; and

· date of passing (date).

Data collection – Other

On ICU level, data on standard ventilator care including, but not restricted to active or passive humidification, tracheal suctioning procedures and manual hyperinflation will be collected.

Withdrawal of individual subjects

Not applicable.

Replacement of individual subjects after withdrawal

Not applicable.

Follow–up of subjects withdrawn from treatment

Not applicable.

Premature termination of the study

Not applicable.

Descriptive statistics will be reported as number and relative proportions for categorical variables and median (quartile 25% – quartile 75%) for continuous variables. For baseline characteristics, the groups will be compared using Fisher exact tests for categorical variables and Wilcoxon rank–sum test for continuous variables. The impact of adjunctive therapies on outcomes will be assessed through regression modelling according to the distribution of each outcome. Time-to-event outcomes will be reported in Kaplan-Meier curves and compared with Cox proportional hazard models. For each analysis proposed, a complete statistical analysis plan will be prepared, finalized and made available before starting the analyses.

All analyses were will be conducted in R v.4.0.2 and a p value < 0.05 was will be considered statistically significant.

Regulation statement

This study will be conducted according to the principles of the Declaration of Helsinki (revision Fortaleza, Brazil, October 2013).

Recruitment and consent

Since the proposed study concerns a service review, no research related interventions will take place. Therefore, no ethical concerns exist. As pseudo anonymous data, which can no longer be attributed to a specific data subject will be used, there is no concern for informed consent.

Benefits and risks assessment, group relatedness

This study does not result in any risk or burdens to patients.

Compensation for injury

Not applicable.

Handling and storage of data and documents

Subject data will be stored a pseudonymized, which means that relating the individual data to identifiable patients would require disproportional effort. Used data as written in the case report form will not contain any identifiable or relatable data. All handling of personal data will comply with the General Data Protection Regulation and the ‘Reuse of care data for the purpose of research’ standard of the AMC.

Monitoring and Quality Assurance

Not applicable.

Amendments

Not applicable.

Annual progress report

Not applicable.

Temporary halt and (prematurely) end of study report

Not applicable.

Public disclosure and publication policy

Not applicable.

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2. Matthay, M.A., J.M. Aldrich, and J.E. Gotts, Treatment for severe acute respiratory distress syndrome from COVID-19. Lancet Respir Med, 2020. 8(5): p. 433-434.

3. Mittermaier, M., et al., Evaluation of PEEP and prone positioning in early COVID-19 ARDS.EClinicalMedicine, 2020: p. 100579.

4. Tu, G.W., et al., Prone positioning in high-flow nasal cannula for COVID-19 patients with severe hypoxemia: a pilot study. Ann Transl Med, 2020. 8(9): p. 598.

5. Zeng, Y., et al., Prognosis when using extracorporeal membrane oxygenation (ECMO) for critically ill COVID-19 patients in China: a retrospective case series. Crit Care, 2020. 24(1): p. 148.

6. COVID 19 clinical evidence taskforce; Available from: https://covid19evidence.net.au/.

7. Entrenas Castillo, M., et al., "Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study". J Steroid Biochem Mol Biol, 2020. 203: p. 105751.

8. Wessels, I., B. Rolles, and L. Rink, The Potential Impact of Zinc Supplementation on COVID-19 Pathogenesis. Front Immunol, 2020. 11: p. 1712.

9. Bauer, S.R., et al., What is the role of supplementation with ascorbic acid, zinc, vitamin D, or N-acetylcysteine for prevention or treatment of COVID-19? Cleve Clin J Med, 2020.