Analysis of Mortality of Critically Ill Patients With COVID-19
Condition: COVID-19; Critical Illness; Effectiveness; Outcome, Fatal
MeSH terms: COVID-19; Critical Illness
Study type: Observational [Patient Registry]

Summary: 
      The recent pandemic of the COVID-19 disease has caused a national health emergency due to its
      severity and the clinical and social consequences of the disease. Crude mortality in Spain is
      9.2%. However, the causes of death of critically ill patients with COVID-19 are unknown. To
      date, no treatment has been shown to be effective for the 2019-SARS-CoV-2 infection is
      recommended. Supportive care and isolation are recommended for infected individuals.
      Currently, observational studies on critically ill patients with COVID-19 have small samples.
      The objective is to evaluate the incidence of mortality and morbidity in COVID-19 disease in
      this group of critically ill patients, as well as the risk factors associated with mortality
      and the effectiveness of the treatments used compassionately.
    

Detailed description: 
      Introduction The World Health Organization (WHO) has recently declared SARS-CoV-2 (COVID-19)
      disease as an international alarm public health emergency. This ongoing pandemic of COVID-19
      disease is devastating, despite widespread implementation of control measures, which is
      creating a challenge for national healthcare. Since the beginning of the epidemic until the
      date of this project, more than 800,000 cases have been detected in the world, of which
      almost 214,000 have been detected in Spain.

      The results of the recent analysis of clinical characteristics in a selected cohort of 1,099
      COVID-19 patients throughout China have shown that up to 15% (173 / 1,099) developed severe
      disease according to the American Thoracic clinical criteria for severe community pneumonia.
      Society, and of these seriously ill patients, 20.6% presented as admission to Intensive Care
      Units (ICU) (33/173, 19%), or the use of mechanical ventilation, both invasive and
      non-invasive. invasive (81/173, 46%) or death (14/173, 8%).

      In a retrospective study that included 52 critically ill patients with COVID-19 admitted to
      the Intensive Care Unit (ICU) from the Wuhan Jin Yin-tan Hospital (Wuhan, China), a 28-day
      mortality rate of 61% was found, although the causes of death of the patients included were
      not reported.

      Nowaday, the crude mortality in Europe is 5.4% of reported cases, although it is important to
      be noted that this calculation is subject to multiple notification biases and due to the
      different diagnostic test policies in the countries, and probable differences in healthcare
      and demographic models between countries. Similarly, in Spain, mortality with 213,024 cases
      notified to the National Surveillance Network is 10.4%. Using modeling, a mortality has been
      estimated among hospitalized cases that could reach 14% (95% confidence interval [CI] 3.9%
      -32%). However, the mortality and causes of death of critically ill patients with COVID-19 in
      Spain are still unknown.

      To date, no specific antiviral treatment that has been shown to be effective for the
      2019-SARS-CoV-2 infection is recommended. Symptomatic and supportive care, along with
      respiratory and contact isolation, are recommended for infected individuals.

      Selective digestive decontamination (SDD) is a prophylactic treatment for critically ill
      patients, mainly requiring invasive mechanical ventilation, based on an oropharyngeal paste
      and an enteral suspension containing antimicrobials (usually tobramycin, colistin, and an
      antifungal) and an intravenous antibiotic (usually a cephalosporin. second generation),
      administered during the first 4 days of ICU treatment. The goal of SDD is to prevent or
      eradicate, if present, the abnormal, oropharyngeal and intestinal transport of potentially
      pathogenic microorganisms, such as aerobic gram-negative bacilli (AGNB),
      methicillin-sensitive Staphylococcus aureus, in patients at risk of nosocomial infections. In
      critically ill patients, it has been demonstrated with a high level of evidence, that SDD
      prevents serious infections and reduces mortality. In an observational study in two hospitals
      in China, 51% of the patients developed a hospital-acquired infection and this incidence was
      associated with an increase in mortality. Therefore, the preventive strategy of SDD could be
      postulated as an alternative to reduce mortality and the incidence of infections in
      critically ill patients with COVID-19. However, this hypothesis has not been evaluated at the
      moment.

      At the present time, observational studies focused on the clinical characteristics of
      critically ill patients with COVID-19 and the factors associated with their mortality have
      small sample sizes, making knowledge of the epidemiology of critically ill patients clearly
      insufficient. And what is more relevant, this scenario of lack of knowledge, when
      extrapolated to the situation of the current outbreak in Spain, places us in the need to
      describe the epidemiological manifestations of the COVI-19 in Spain in order to handle with
      safety and efficiency the challenge of the control and treatment of the outbreak in Spain of
      the COVID-19.

      Specifically, the study will focus on critically ill patients with COVID-19 for two reasons:

      They represent the cohort of patients with the highest use of material and professional
      resources in the health system.

      Given the current moment of pandemic and healthcare challenge, it is therefore pertinent to
      conduct an epidemiological surveillance of COVID-19 disease to reliably define the incidence
      of mortality and morbidity in this group of patients, as well as the risk factors for
      infection by SARS-CoV-2 associated with mortality.

      Objective The main objective is to evaluate the mortality of critically ill patients with
      COVID-19 admitted to the ICU, as well as to analyze the factors associated with mortality.

      The secondary objectives:

      To analyze the epidemiological characteristics of critically ill patients with confirmed
      COVID-19 in Spain.

      To describe the usual clinical practice in the ICU of critically ill adult patients with
      COVID-19, to identify risk patterns and possible effectiveness or adverse effects of the
      treatments received.

      To compare the mortality of critically ill patients with COVID-19 treated with SDD compared
      with those who do not received SDD.

      To describe the cause of death of critically ill patients with COVID-19 received invasive
      mechanical ventilation.

      Method Design: An observational, prospective and multicenter study will be carry out,
      envolving of 12 ICUs in Madrid (University Hospital of Getafe, as coordinating center;
      University Hospital Puerta de Hierro, University Hospital del Henares of Coslada, University
      Hospital of Torrejón, Hospital Universitario Ramón y Cajal, Hospital Infanta Cristina,
      Hospital del Tajo, Hospital Quirón Madrid Sanchinarro, Hospital Universitario Severo Ochoa,
      Hospital Universitario Gregorio Marañón, Hospital Universitario de Móstoles, Hospital
      Universitario La Princesa, Hospital Universitario La Paz, Hospital Universitario Doce de
      Octubre, and Hospital Santa Creu i Sant Pau in Barcelona). Inclusion criteria: patients over
      18 years of age who are admitted to the ICU with the confirmed diagnosis of COVID-19.

      Recruitment period: The study will start once the study has been approved by the Ethics and
      Research Committee of the Hospital Universitario de Getafe with an expected date of April
      2020, with an estimated duration of 3 months.

      Case definition: Any critically ill patients with a positive respiratory tract sample result
      (tracheal aspirate or nasopharyngeal exudate) using the PCR technique for the SARS-CoV-2
      virus and requiring admission to the ICU at trial will be considered a confirmed case of
      COVID-19 of the physician in charge of the patient.

      Data collection: Demographic variables: age, sex, reason for admission to the ICU.

      Comorbidities: severity at ICU admission (SAPSIII); Daily SOFA until day 7, diabetes
      mellitus, high blood pressure, chronic obstructive pulmonary disease, other chronic lung
      diseases (interstitial lung disease), chronic kidney failure, previous liver disease
      (cirrhosis), immunosuppression, previous heart disease (ischemic, valvular), chronic
      arrhythmias (atrial fibrillation); previous cerebrovascular disease (ischemic or
      hemorrhagic).

      Noninvasive respiratory support prior to ICU admission: non-invasive ventilation, or high
      flow therapy with nasal cannula, and duration of non-invasive respiratory support.

      Invasive respiratory support parameters during the first 7 days: tidal volume, level of
      positive end-expiratory pressure, plateau pressure, inspiratory fraction of oxygen.
      Biochemistry values and arterial blood gases, blood count and coagulation parameters on
      admission to the ICU during the first 7 days from ICU admission. Pharmacological therapies
      received for COVID-19 disease during the ICU stay: azitromycin, corticosteroids,
      hydroxychloroquine, antiretrovirals (lopinavir/ritonavir), tocilizumab, oseltamivir,
      darunabir, remdesivir, baricitinib.

      Bacterial / fungal infections acquired in the ICU (pneumonia, bacteriemia): isolated
      microorganisms in diagnostic samples, isolated microorganisms in surveillance samples
      (oropharynx and rectum if surveillance samples are available); antibiotic treatment.

      Ventilatory management: prone positioning, administration of inhaled nitric oxide,
      performance of tracheostomy, date of tracheotomy, modality of tracheotomy (surgical,
      percutaneous).

      Classification of predefined causes of death:

      Refractory hypoxemia (peripheral oxygen saturation measured by pulse oximetry less than 80%,
      or PaO2 <60 mmHg of arterial blood sample) despite maximum ventilatory support (FiO2 100%,
      PEEP level> 5 cm H2O) with maintenance MAP> 60 mmHg in the 3 hours prior to exitus lethalis.

      Refractory shock (mean arterial pressure less than 60 mmHg despite vasoactive support with
      norepinephrine at> 2 mcg / kg / min and / or dobutamine at> 20 microgr / kg / min, and serum
      lactate level> 2 mmol / L in the 3 hours prior to exitus lethalis), associated or not with
      organ failure, but with peripheral oxygen saturation measured by pulse oximetry greater than
      90%, with no evidence of documented infection in the previous 48 hours.

      Septic shock. A refractory shock which fulfill previous criteria plus the presence of a
      documented infection in the 48 hours prior to exitus lethalis.

      Others: Pulmonary thromboembolism (defined based on clinical suspicion, associated with any
      of the classifications [Wells or Geneva] according to the low, intermediate or high
      probability and the determination of the high D-dimer (> 500 μg/L) in the 24 hours prior to
      exitus lethalis; Incohercible bleeding; Yatrogenic respiratory complications (accidental exit
      of the orotracheal tube with impossibility of obtaining an artificial airway, fatal
      obstruction of the orotracheal tube); Arrhythmias: sudden unanticipated onset of malignant
      arrhythmias (irreversible ventricular fibrillation), or asystole. Arrhythmias appearing
      during the last minutes before exitus lethalis will be excluded.

      Main outcomes. ICU mortality, 28-day mortality, and hospital mortality. Secondary outcomes:
      appearance of nosocomial infections during ICU admission (ventilator-associated pneumonia ,
      nosocomial pneumonia, catheter-related bacteremia, bacteraemia); development of complications
      during ICU admission (development of acute respiratory distress, barotrauma, development of
      organ failure [cardiovascular, renal, hepatic, hematological]), duration of mechanical
      ventilation, length of ICU stay, length of hospital stay, withdrawald of life support, and
      cause of mortality.

      Statistic analysis. Given the estimated mortality of 40% of the cases hospitalized in the
      ICU, a convenience sample size of 600 participants will be estimated. Considering a loss of
      15% for the outcomes, 750 subjects will finally be included.

      To evaluate the risk factors associated with the mortality of critically ill patients with
      COVID-19, a logistic model adjusted for baseline variables (age, severity at ICU admission),
      empirical treatment received, failure of non-invasive respiratory support will be performed.

      The effectiveness of empirical treatments for COVID-19 will be performed through logistic
      analysis adjusted for age, severity at admission and complications during ICU admission.

      In addition, a stratified cluster analysis will be proposed for ICUs that apply the SDD
      strategy and units that do not routinely use SDD.

      Data quality. The data will be reviewed and approved by the Steering Committee of the study
      and validated by the collaborating researcher responsible for each center. All data will be
      centrally reviewed. Alerts will be sent for lost data, aberrant data or discrepancies
      thereof.

      At each center, local study investigators will review data from 5% of randomly selected
      participants, and all participants about whom evaluators may have questions about
      inconsistent data.

      The data collection of all included cases will be verified by an independent research
      coordinator hired through an external CRO and who will evaluate the quality of data
      collection independently of the main researcher. Data collection will be re-evaluated until
      the forms and all results are completed.

      Full data will be required to include subjects in the final analysis, and only subjects
      without missing data will be accepted for the primary variables or patients with missing data
      less than 10% for the secondary variables, if these cannot be retrieved by the investigators.
      All bizarre data will be sent to the reference centers for verification. The presence of
      missing data in the main variables will be reason for the exclusion of the participant in the
      analysis.

      Ethical-legal aspects. The study will be carried out in accordance with the updated Helsinki
      declaration in its latest version. The study protocol, together with the data collection
      sheets and Annexes will be sent for approval to the Ethics and Research Committee of the
      University Hospital of Getafe, and will ask them for a waiver consent due to the
      characteristics of the study design (non-intervention study for statistical purposes, action
      plan to improve the quality of care, in a health emergency situation), as provided in the
      spanish laws.

      This study does not include any control group. Participation in this study does not imply any
      risk for the included patients since it is based on the usual clinical practice in common use
      in all hospitals, which are already applied at the Getafe University Hospital.

      The study will be based on the Spanish legislation for biomedical research, and in accordance
      with national laws of Protection of Personal Data and guarantee of them that the identity of
      the subject will be kept confidential and anonymous throughout the study, in such a way that
      no personal data will be collected that allows the identification of the subjects included
      and only the data necessary to achieve the study objectives will be collected.

      Confidentiality The use, disclosure, publication or dissemination of the document is not
      authorized in any way without the written consent of the Steering Committee. Given that the
      study proposes the analysis of the usual clinical practice, it is considered not pertinent to
      contract a civil liability insurance, since it is a low-intensity clinical study.

      During the period of inclusion of the participants, the database to which only the study
      coordinating team (principal investigator and co-investigators) will have access will be
      generated anonymously, with irreversible dissociation of personal data.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Case definition : Any critically ill patients with a positive respiratory tract sample
        result (tracheal aspirate or nasopharyngeal exudate) using the PCR9 technique for the
        SARS-CoV-2 virus and requiring admission to the ICU at trial will be considered a confirmed
        case of COVID-19 disease of the doctor responsible for the sick.