Discussion
The present multicentric study describes 1260 critically ill patients with COVID-19-associated acute respiratory failure consecutively admitted to 24 Italian ICUs during the first pandemic wave. This study specifically analyzes the trends of clinical, ventilatory and laboratory parameters throughout the entire ICU stay and their relationship with outcome. The daily values of 15 parameters associated with acute organ dysfunction (lung, liver, kidney), acid–base derangement, coagulation impairment, or systemic inflammation were associated with higher patient survival. Ten of these parameters showed different slopes between survivors and non-survivors, and the associations with the patient outcome of such slopes were stronger than the daily value of the same parameters. This finding supports the common clinical knowledge that the time course of relevant variables is more relevant than the single daily value.
The majority of the patients included in the study were elderly men with hypertension; four out of five received mechanical ventilation, about half were treated with rescue strategies for refractory hypoxemia, primary prone position, and 98% received inotropic or vasoactive drugs at least once during ICU stay.
The overall ICU mortality rate was 34%, but increased to 38% if considering only the patients undergoing mechanical ventilation at ICU admission. These findings are consistent with similar European multicenter studies [
5,
15‐
20].
In the present study, the factors showing independent association with worse ICU outcome were older age, acid–base derangement (low pH and high lactate), and SOFA at ICU admission and diabetes.
We developed a polynomial maximum likelihood multilevel regression model and a joint model to compute the association between ICU outcome and the daily value and trends of main clinical parameters. Joint modeling has the advantage over simpler methods to take into account differential missing data of the longitudinal parameter in surviving vs. dead patients (differential dropout bias). Few authors showed, in critically ill patients, that changes in clinical parameters throughout the first few days of ICU stay are different between survivors and non-survivors [
21‐
24]. However, differently from a joint model, these studies generally do not take into account the within-patient repeated measurement. Moreover, we included time backward from ICU discharge to clearly show the parameter trends over the last part of the ICU stay.
Furthermore, none of the previously cited studies compared trends to single daily values, to the best of our knowledge.
We detected a strong association between mortality and acute kidney and respiratory impairment and activation of systemic inflammation. The effect size of creatinine slope on mortality was almost twice that of daily value. Similarly, the association between the slope of systemic inflammation parameters (i.e., ferritin and C-reactive protein) and mortality were also stronger than the daily value. The association of neutrophil–lymphocyte ratio daily value with survival was instead higher than the trend. The slopes of both compliance of the respiratory system and PaO2/FiO2 are associated more strongly with mortality than the daily values, although a possible effect of therapeutic interventions should be taken into account (e.g., neuromuscular blockade and prone positioning).
Even more impressive is the role of driving pressure trend as a predictor of mortality. Multiple studies identified the driving pressure as one of the strongest predictive variables of mortality, but none of them showed the superiority of the driving pressure trend compared with the single value. In the present study, the driving pressure slope had an effect almost four times stronger than the single daily value.
We observed an early multiorgan impairment due to the COVID-19 disease already at ICU admission, which subsequently worsened during the ICU stay, mainly in non-survivors. Particularly, most of the parameters, but inflammatory markers, were already different between survivors and non-survivors at ICU admission. Such differences increase throughout the ICU stay, since the parameter time courses show different, or even opposite, slopes. Therefore, the daily analysis of parameter trends, especially the most divergent, could assist the clinician in daily patient management.
Indeed, previous studies reported early differences in the temporal changes of laboratory parameters between survivors and non-survivors [
8,
10] among hospitalized not-critically-ill patients with COVID-19.
Therefore, we can speculate that early and timely detection, possibly before ICU admission, of the more susceptible patients could limit organ injury and anticipate, if possible, optimization of the treatments.
Our study has several limitations. First, this is a retrospective–prospective study performed in 24 Italian hospitals in 12 different regions during the first wave of the COVID-19 pandemic. We cannot exclude high heterogeneity among viral load, admission policies and care management, also related to differences in the characteristics, and strain on the healthcare systems and in the socioeconomic patient’s status [
25]. Second, only ICUs interested in this research project joined the study, promoting a possible selection bias. Third, many patients were treated, during the hospital stay, with several investigational drugs (hydroxychloroquine, antivirals, steroids, tocilizumab, and others) whose effect, in a study of this nature, is difficult to evaluate without running into interpretative errors such as survivor bias. Fourth, the daily collected data represent the last available data and not the average or the worst value of the previous 24 h.
Fifth, although we have established a sound data collection and quality control (see ESM) and maximal efforts have been employed to minimize the amount of missing data and promote data quality, being a retrospective, real-data study, no tests were made specifically for the study purposes only; thus, some parameters show some missing data. Finally, joint modeling requires several assumptions, many of which are untestable, as to the best association structure, the best covariable selection, the fit of the model, and other. Therefore, the choice of the model parameters might be considered somewhat arbitrary. Besides, model fitting is computationally complex, and not all models could mathematically converge. Finally, the interpretation of the coefficient is not immediately evident and is difficult to convey, given the complex shape of the relationship with time involving polynomials. However, we devised our analysis strategy before fitting any models, and we caution against an overconfident interpretation of results.
Acknowledgements
We thank Marina Leonardelli (Ospedale Maggiore Policlinico) and Patrizia Minunno (Ospedale Maggiore Policlinico) for administrative support. We thank: Aiello Clara, MD (Università degli Studi of Milan), Altomare Alessio, MD (Università degli Studi of Milan), Baratozzi Valentina, MD (Università degli Studi of Milan), Beltrama Virginia, MD (Università degli Studi of Milan), Benenti Claudia, MD (Università degli Studi of Milan), Brusatori Serena, MD (Università degli Studi of Milan), Caccioppola Alessio, MD (Università degli Studi of Milan), Cadone Ughi Elena, MD (Università degli Studi of Milan), Calabretta Davide, MD (Università degli Studi of Milan), De Giorgis Valentina, MD (Università degli Studi of Milan), De Razza Soraya, MD (Università degli Studi of Milan), Del Santo Gaia, MD (Università degli Studi of Milan), Di Feliciantonio Marianna, MD (Università degli Studi of Milan), Figgiaconi Virginia, MD (Università degli Studi of Milan), Filardo Clelia, MD (Università degli Studi of Milan), Garbelli Erica, MD (Università degli Studi of Milan), Giudici Giorgio, MD (Università degli Studi of Milan), Gregori Beatrice, MD (Università degli Studi of Milan), Lancioni Armando, MD (Università degli Studi of Milan), Magri Chiara, MD (Università degli Studi of Milan), Marasco Davide, MD (Università degli Studi of Milan), Marongiu Ines, MD (Università degli Studi of Milan), Mirandola Michela, MD (Università degli Studi of Milan), Montana Vincenzo, MD (Università degli Studi of Milan), Negro Carolina, MD (Università degli Studi of Milan), Pagano Martina, MD (Università degli Studi of Milan), Paladini Stefania, MD (Università degli Studi of Milan), Papaleo Anna, MD (Università degli Studi of Milan), Pelliccia Maria Rosa, MD (Università degli Studi of Milan), Penna Alessio, MD (Università degli Studi of Milan), Poggio Stefano, MD (Università degli Studi of Milan), Protti Ilaria, MD (Università degli Studi of Milan), Raimondo Matilde, MD (Università degli Studi of Milan), Roveri Giulia, MD (Università degli Studi of Milan), Russo Filippo Maria, MD (Università degli Studi of Milan), Sepulcri Ilaria, MD (Università degli Studi of Milan), and Turconi Gloria, MS (Università degli Studi of Milan). We thank all the healthcare staff of the participating ICUs. These individuals were not compensated for their role in the study.
Collaborators of the COVID-19 Italian ICU Network: Massimo Antonelli: Department of Anesthesiology, Intensive Care and Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Sacred Heart Catholic University, Rome, Italy; Michele Aspesi: Università degli Studi dell'Insubria, Ospedale di Circolo e Fondazione Macchi, Varese; Federica Baccanelli: Department of Anaesthesia and Intensive Care, Humanitas Clinical and Research Center-IRCCS, Rozzano, MI, Italy; Flavio Bassi: Department of Anesthesia and Intensive Care Medicine, ASUFC University-Hospital of Central Friuli, Udine, Italy; Giacomo Bellani: Department of Anesthesia and Intensive Care Medicine, San Gerardo Hospital ASST Monza, Monza, Italy; Angela Berselli: Department of Anesthesiology and Intensive Care, ASST Mantova–Ospedale Carlo Poma, Mantova, Italy; Andrzej Bet: Department of Anesthesia and Intensive Care, A. Manzoni Hospital, ASST Lecco, Lecco, Italy; Emanuela Biagioni: Department of Anesthesia and Intensive Care, University Hospital of Modena, Modena, Italy; Alberto Biondo: Department of Anesthesiology and Intensive Care, ASST Mantova–Ospedale Carlo Poma, Mantova, Italy; Chiara Bonenti: Department of Anesthesia and Intensive Care Medicine, Niguarda Ca’ Granda, Milan, Italy; Nicola Bottino: Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Tiziana Bove: Department of Medicine, University of Udine, Udine, Italy; Luca Brazzi: Dipartimento di Anestesia, Terapia Intensiva, e Emergenza, Città della Salute e della Scienza Hospital, Turin, Italy; Ilaria Buquicchio: UOC Anestesia e Rianimazione, ASST Nord Milano Ospedale Edoardo Bassini Cinisello Balsamo; Stefano Busani: Department of Anesthesia and Intensive Care, University Hospital of Modena, Modena, Italy; Luca Cabrini: Università degli Studi dell'Insubria, Ospedale di Circolo e Fondazione Macchi, Varese; Angelo Calini: Department of Anesthesia and Intensive Care Medicine, Niguarda Ca' Granda, Milan, Italy; Plinio Calligaro: UOC Anestesia e Rianimazione, AULSS 9 Scaligera Ospedale Magalini di Villafranca; Leonarda Pia Cantatore: Department of medical and surgical sciences, Intensive care unit, University of Foggia, Italy; Simone Carelli: Department of Anesthesiology, Intensive Care and Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Eleonora Carlesso: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Andrea Carsetti: Anesthesia and Intensive Care Unit, Azienda Ospedaliero Universitaria Ospedali Riuniti, Ancona, Italy; Gian Paolo Castelli: Department of Anesthesiology and Intensive Care, ASST Mantova–Ospedale Carlo Poma, Mantova, Italy; Sara Cavallini: Division of Anaesthesia, Analgesia, and Intensive Care - Department of Medicine and Surgery - University of Perugia, Italy; Maurizio Cecconi: Department of Anaesthesia and Intensive Care, Humanitas Clinical and Research Center-IRCCS, Rozzano, MI, Italy; Giacomo Cimicchi: UOC Anestesia e Rianimazione Desio, ASST- Monza, Monza, Italy; Giuseppe Citerio: Department of Anesthesia and Intensive Care Medicine, San Gerardo Hospital ASST Monza, Monza, Italy; Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy; Irene Coloretti: Department of Anesthesia and Intensive Care, University Hospital of Modena, Modena, Italy; Andrea Coppadoro: Department of Anesthesia and Intensive Care Medicine, San Gerardo Hospital ASST Monza, Monza, Italy; Daniele Corti: U.O.C. Anestesia e Rianimazione, Ospedale L. Mandic Merate, ASST Lecco; Lorenzo Dall’Ara: Department of Anesthesia and Intensive Care, University Hospital of Modena, Modena, Italy; Francesca Dalla Corte: Department of Anaesthesia and Intensive Care, Humanitas Clinical and Research Center-IRCCS, Rozzano, MI, Italy; Edoardo De Robertis: Division of Anaesthesia, Analgesia, and Intensive Care - Department of Medicine and Surgery - University of Perugia, Italy; Valentina Di Gravio: Department of Anesthesiology, Intensive Care and Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Mattia Erba: Department of Anesthesia and Intensive Care, A. Manzoni Hospital, ASST Lecco, Lecco, Italy; Giulia Evasi: Department of Anesthesia and Intensive Care, A. Manzoni Hospital, ASST Lecco, Lecco, Italy; Alberto Facchini: UOC Anestesia e Rianimazione Desio, ASST- Monza, Monza, Italy; Vito Fanelli: Dipartimento di Anestesia, Terapia Intensiva, ed Emergenza, Città della Salute e della Scienza Hospital, Turin, Italy; Giancarlo Feliciotti: Università degli Studi dell'Insubria, Ospedale di Circolo e Fondazione Macchi, Varese; Chiara Ferraris Fusarini: UOC Laboratorio Analisi, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; Gioconda Ferraro: UOC Anestesia e Rianimazione, AULSS 5 Polesana Ospedale di Rovigo e di Trecenta; Gaetano Florio: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Giuseppe Foti: Department of Anesthesia and Intensive Care Medicine, San Gerardo Hospital ASST Monza, Monza, Italy; Roberto Fumagalli: Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy; Department of Anesthesia and Intensive Care Medicine, Niguarda Ca' Granda, Milan, Italy; Giuseppe Gagliardi: UOC Anestesia e Rianimazione, AULSS 5 Polesana Ospedale di Rovigo e di Trecenta; Roberta Garberi: Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy; Hedwige Gay: Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy; Laura Giacchè: Division of Anaesthesia, Analgesia, and Intensive Care - Department of Medicine and Surgery - University of Perugia, Italy; Massimo Girardis: Department of Anesthesia and Intensive Care, University Hospital of Modena, Modena, Italy; Riccardo Giudici: Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy; Department of Anesthesia and Intensive Care Medicine, Niguarda Ca’ Granda, Milan, Italy; Giacomo Grasselli: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Domenico Grieco: Department of Anesthesiology, Intensive Care and Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Lorenzo Guiotto: Department of Anesthesia and Intensive Care, A. Manzoni Hospital, ASST Lecco, Lecco, Italy; Amedeo Guzzardella: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Thomas Langer: Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy; Department of Anesthesia and Intensive Care Medicine, Niguarda Ca' Granda, Milan, Italy; Federico Longhini: Department of Medical and Surgical Sciences, University Magna Grecia of Catanzaro, Catanzaro, Italy; Andrea Manzan: Anesthesia and Intensive Care Unit, AOU Sassari, Italy; Davide Maraggia: Università degli Studi dell'Insubria, Ospedale di Circolo e Fondazione Macchi, Varese; Angelo Milani: Department of Anaesthesia and Intensive Care, Humanitas Clinical and Research Center-IRCCS, Rozzano, MI, Italy; Lucia Mirabella: Department of medical and surgical sciences, Intensive care unit, University of Foggia, Italy; Anna Mischi: Department of Anesthesiology and Intensive Care, ASST Mantova–Ospedale Carlo Poma, Mantova, Italy; Carlo Montalto: Department of Anesthesiology and Intensive Care, ASST Mantova–Ospedale Carlo Poma, Mantova, Italy; Sara Mormina: U.O.C. Anestesia e Rianimazione, Ospedale L. Mandic Merate, ASST Lecco; Valentina Noseda: UOC Anestesia e Rianimazione Desio, ASST- Monza, Monza, Italy; Chiara Paleari:
Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Daniela Pasero: Anesthesia and Intensive Care Unit, AOU Sassari, Italy; Matteo Pedeferri: U.O.C. Anestesia e Rianimazione, Ospedale L. Mandic Merate, ASST Lecco; Antonio Pesenti: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Angelo Pezzi: UOC Anestesia e Rianimazione, ASST Nord Milano Ospedale Edoardo Bassini Cinisello Balsamo; Giacinto Pizzilli: Anesthesia and Intensive Care Medicine, Policlinico di Sant’Orsola, Alma Mater Studiorum University of Bologna, Bologna, Italy; Matteo Pozzi: Department of Anesthesia and Intensive Care Medicine, San Gerardo Hospital ASST Monza, Monza, Italy; Paolo Properzi: Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Alessandro Protti: Department of Anaesthesia and Intensive Care, Humanitas Clinical and Research Center-IRCCS, Rozzano, MI, Italy; Marco V. Ranieri: Anesthesia and Intensive Care Medicine, Policlinico di Sant’Orsola, Alma Mater Studiorum University of Bologna, Bologna, Italy; Michela Rauseo: Department of medical and surgical sciences, Intensive care unit, University of Foggia, Italy; Roberto Rona: Department of Anesthesia and Intensive Care Medicine, San Gerardo Hospital ASST Monza, Monza, Italy; Vincenzo Russotto: Department of Anesthesia and Intensive Care Medicine, San Gerardo Hospital ASST Monza, Monza, Italy; Luca Saccarelli: Division of Anaesthesia, Analgesia, and Intensive Care - Department of Medicine and Surgery - University of Perugia, Italy; Luigia Scudeller: Clinical Trials Team, Scientific Direction, IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Italy; Giuseppe Servillo: Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples “Federico II”, Naples, Italy; Paolo Severgnini: Università degli Studi dell'Insubria, Ospedale di Circolo e Fondazione Macchi, Varese; Savino Spadaro: Department morphology, surgery and experimental medicine. Section of intensive care. University of Ferrara; Sofia Spano: Department of Anaesthesia and Intensive Care, Humanitas Clinical and Research Center-IRCCS, Rozzano, MI, Italy; Nino Stocchetti: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Paola Tagliabue: Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Tommaso Tonetti: Anesthesia and Intensive Care Medicine, Policlinico di Sant’Orsola, Alma Mater Studiorum University of Bologna, Bologna, Italy; Livio Tullo: Department of medical and surgical sciences, Intensive care unit, University of Foggia, Italy; Luigi Vetrugno: Department of Medicine, University of Udine, Udine, Italy; Department of Anesthesia and Intensive Care Medicine, ASUFC University-Hospital of Central Friuli, Udine, Italy; Martina Viganò: Department of Anesthesia and Intensive Care, A. Manzoni Hospital, ASST Lecco, Lecco, Italy; Luigi Vivona: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Carlo Alberto Volta: Department of morphology, surgery and experimental medicine. Section of intensive care. University of Ferrara; Vanessa Zambelli: Department of Anesthesia and Intensive Care Medicine, San Gerardo Hospital ASST Monza, Monza, Italy; Alberto Zanella: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Andrea Zanoni: Anesthesia and Intensive Care Medicine, Policlinico di Sant’Orsola, Alma Mater Studiorum University of Bologna, Bologna, Italy.