Rationale: Whether patients with coronavirus disease (COVID-19) may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. Objectives: To estimate the effect of ECMO on 90-day mortality versus IMV only. Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO versus no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 < 80 or PaCO2 ⩾ 60 mm Hg). We controlled for confounding using a multivariable Cox model on the basis of predefined variables. Measurements and Main Results: A total of 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability on Day 7 from the onset of eligibility criteria (87% vs. 83%; risk difference, 4%; 95% confidence interval, 0–9%), which decreased during follow-up (survival on Day 90: 63% vs. 65%; risk difference, −2%; 95% confidence interval, −10 to 5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand and when initiated within the first 4 days of IMV and in patients who are profoundly hypoxemic. Conclusions: In an emulated trial on the basis of a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and regions with ECMO capacities specifically organized to handle high demand.
Abstract Background Delaying time to prone positioning (PP) may be associated with higher mortality in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). We evaluated the use and the impact of early PP on clinical outcomes in intubated patients hospitalized in intensive care units (ICUs) for COVID-19. Methods All intubated patients with ARDS due to COVID-19 were involved in a secondary analysis from a prospective multicenter cohort study of COVID-ICU network including 149 ICUs across France, Belgium and Switzerland. Patients were followed-up until Day-90. The primary outcome was survival at Day-60. Analysis used a Cox proportional hazard model including a propensity score. Results Among 2137 intubated patients, 1504 (70.4%) were placed in PP during their ICU stay and 491 (23%) during the first 24 h following ICU admission. One hundred and eighty-one patients (36.9%) of the early PP group had a PaO 2 /FiO 2 ratio > 150 mmHg when prone positioning was initiated. Among non-early PP group patients, 1013 (47.4%) patients had finally been placed in PP within a median delay of 3 days after ICU admission. Day-60 mortality in non-early PP group was 34.2% versus 39.3% in the early PP group ( p = 0.038). Day-28 and Day-90 mortality as well as the need for adjunctive therapies was more important in patients with early PP. After propensity score adjustment, no significant difference in survival at Day-60 was found between the two study groups (HR 1.34 [0.96–1.68], p = 0.09 and HR 1.19 [0.998–1.412], p = 0.053 in complete case analysis or in multiple imputation analysis, respectively). Conclusions In a large multicentric international cohort of intubated ICU patients with ARDS due to COVID-19, PP has been used frequently as a main treatment. In this study, our data failed to show a survival benefit associated with early PP started within 24 h after ICU admission compared to PP after day-1 for all COVID-19 patients requiring invasive mechanical ventilation regardless of their severity.
To evaluate the respective impact of standard oxygen, high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) on oxygenation failure rate and mortality in COVID-19 patients admitted to intensive care units (ICUs). Multicenter, prospective cohort study (COVID-ICU) in 137 hospitals in France, Belgium, and Switzerland. Demographic, clinical, respiratory support, oxygenation failure, and survival data were collected. Oxygenation failure was defined as either intubation or death in the ICU without intubation. Variables independently associated with oxygenation failure and Day-90 mortality were assessed using multivariate logistic regression. From February 25 to May 4, 2020, 4754 patients were admitted in ICU. Of these, 1491 patients were not intubated on the day of ICU admission and received standard oxygen therapy (51%), HFNC (38%), or NIV (11%) (P < 0.001). Oxygenation failure occurred in 739 (50%) patients (678 intubation and 61 death). For standard oxygen, HFNC, and NIV, oxygenation failure rate was 49%, 48%, and 60% (P < 0.001). By multivariate analysis, HFNC (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.36-0.99, P = 0.013) but not NIV (OR 1.57, 95% CI 0.78-3.21) was associated with a reduction in oxygenation failure). Overall 90-day mortality was 21%. By multivariable analysis, HFNC was not associated with a change in mortality (OR 0.90, 95% CI 0.61-1.33), while NIV was associated with increased mortality (OR 2.75, 95% CI 1.79-4.21, P < 0.001). In patients with COVID-19, HFNC was associated with a reduction in oxygenation failure without improvement in 90-day mortality, whereas NIV was associated with a higher mortality in these patients. Randomized controlled trials are needed.
Abstract Background Previous retrospective research has shown that maintaining prone positioning (PP) for an average of 40 h is associated with an increase of survival rates in intubated patients with COVID-19-related acute respiratory distress syndrome (ARDS). This study aims to determine whether a cumulative PP duration of more than 32 h during the first 2 days of intensive care unit (ICU) admission is associated with increased survival compared to a cumulative PP duration of 32 h or less. Methods This study is an ancillary analysis from a previous large international observational study involving intubated patients placed in PP in the first 48 h of ICU admission in 149 ICUs across France, Belgium and Switzerland. Given that PP is recommended for a 16-h daily duration, intensive PP was defined as a cumulated duration of more than 32 h during the first 48 h, whereas standard PP was defined as a duration equal to or less than 32 h. Patients were followed-up for 90 days. The primary outcome was mortality at day 60. An Inverse Probability Censoring Weighting (IPCW) Cox model including a target emulation trial method was used to analyze the data. Results Out of 2137 intubated patients, 753 were placed in PP during the first 48 h of ICU admission. The intensive PP group ( n = 79) had a median PP duration of 36 h, while standard PP group ( n = 674) had a median of 16 h during the first 48 h. Sixty-day mortality rate in the intensive PP group was 39.2% compared to 38.7% in the standard PP group ( p = 0.93). Twenty-eight-day and 90-day mortality as well as the ventilator-free days until day 28 were similar in both groups. After IPCW, there was no significant difference in mortality at day 60 between the two-study groups (HR 0.95 [0.52–1.74], p = 0.87 and HR 1.1 [0.77–1.57], p = 0.61 in complete case analysis or in multiple imputation analysis, respectively). Conclusions This secondary analysis of a large multicenter European cohort of intubated patients with ARDS due to COVID-19 found that intensive PP during the first 48 h did not provide a survival benefit compared to standard PP.
Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) and requiring intensive care unit (ICU) have a high incidence of hospital-acquired infections; however, data regarding hospital acquired bloodstream infections (BSI) are scarce. We aimed to investigate risk factors and outcome of BSI in critically ill coronavirus infectious disease-19 (COVID-19) patients.We performed an ancillary analysis of a multicenter prospective international cohort study (COVID-ICU study) that included 4010 COVID-19 ICU patients. For the present analysis, only those with data regarding primary outcome (death within 90 days from admission) or BSI status were included. Risk factors for BSI were analyzed using Fine and Gray competing risk model. Then, for outcome comparison, 537 BSI-patients were matched with 537 controls using propensity score matching.Among 4010 included patients, 780 (19.5%) acquired a total of 1066 BSI (10.3 BSI per 1000 patients days at risk) of whom 92% were acquired in the ICU. Higher SAPS II, male gender, longer time from hospital to ICU admission and antiviral drug before admission were independently associated with an increased risk of BSI, and interestingly, this risk decreased over time. BSI was independently associated with a shorter time to death in the overall population (adjusted hazard ratio (aHR) 1.28, 95% CI 1.05-1.56) and, in the propensity score matched data set, patients with BSI had a higher mortality rate (39% vs 33% p = 0.036). BSI accounted for 3.6% of the death of the overall population.COVID-19 ICU patients have a high risk of BSI, especially early after ICU admission, risk that increases with severity but not with corticosteroids use. BSI is associated with an increased mortality rate.
Limitations of life-sustaining therapies (LST) practices are frequent and vary among intensive care units (ICUs). However, scarce data were available during the COVID-19 pandemic when ICUs were under intense pressure. We aimed to investigate the prevalence, cumulative incidence, timing, modalities, and factors associated with LST decisions in critically ill COVID-19 patients. We did an ancillary analysis of the European multicentre COVID-ICU study, which collected data from 163 ICUs in France, Belgium and Switzerland. ICU load, a parameter reflecting stress on ICU capacities, was calculated at the patient level using daily ICU bed occupancy data from official country epidemiological reports. Mixed effects logistic regression was used to assess the association of variables with LST limitation decisions. Among 4671 severe COVID-19 patients admitted from February 25 to May 4, 2020, the prevalence of in-ICU LST limitations was 14.5%, with a nearly six-fold variability between centres. Overall 28-day cumulative incidence of LST limitations was 12.4%, which occurred at a median of 8 days (3-21). Median ICU load at the patient level was 126%. Age, clinical frailty scale score, and respiratory severity were associated with LST limitations, while ICU load was not. In-ICU death occurred in 74% and 95% of patients, respectively, after LST withholding and withdrawal, while median survival time was 3 days (1-11) after LST limitations. In this study, LST limitations frequently preceded death, with a major impact on time of death. In contrast to ICU load, older age, frailty, and the severity of respiratory failure during the first 24 h were the main factors associated with decisions of LST limitations.
Abstract Background Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) and requiring mechanical ventilation suffer from a high incidence of ventilator associated pneumonia (VAP), mainly related to Enterobacterales. Data regarding extended-spectrum beta-lactamase producing Enterobacterales (ESBL-E) VAP are scarce. We aimed to investigate risk factors and outcomes of ESBL-E related VAP among critically ill coronavirus infectious disease-19 (COVID-19) patients who developed Enterobacterales related VAP. Patients and methods We performed an ancillary analysis of a multicenter prospective international cohort study (COVID-ICU) that included 4929 COVID-19 critically ill patients. For the present analysis, only patients with complete data regarding resistance status of the first episode of Enterobacterales related VAP (ESBL-E and/or carbapenem-resistant Enterobacterales, CRE) and outcome were included. Results We included 591 patients with Enterobacterales related VAP. The main causative species were Enterobacter sp (n = 224) , E. coli (n = 111) and K. pneumoniae (n = 104). One hundred and fifteen patients (19%), developed a first ESBL-E related VAP, mostly related to Enterobacter sp (n = 40), K. pneumoniae (n = 36), and E. coli (n = 31). Eight patients (1%) developed CRE related VAP. In a multivariable analysis, African origin (North Africa or Sub-Saharan Africa) (OR 1.7 [1.07–2.71], p = 0.02), time between intubation and VAP (OR 1.06 [1.02–1.09], p = 0.002), PaO 2 /FiO 2 ratio on the day of VAP (OR 0.997 [0.994–0.999], p = 0.04) and trimethoprim-sulfamethoxazole exposure (OR 3.77 [1.15–12.4], p = 0.03) were associated with ESBL-E related VAP. Weaning from mechanical ventilation and mortality did not significantly differ between ESBL-E and non ESBL-E VAP. Conclusion ESBL-related VAP in COVID-19 critically-ill patients was not infrequent. Several risk factors were identified, among which some are modifiable and deserve further investigation. There was no impact of resistance of the first Enterobacterales related episode of VAP on outcome.
'The most sophisticated intensive care often becomes unnecessarily expensive terminal care where the pre-ICU system is uncoordinated or undeveloped' – Peter Safar, 1974 Critical illness refers to life-threatening conditions resulting from an acute disease, injury, adverse environmental influence, poisoning, surgery, or decompensation of a chronic disease. It is an exquisitely time-sensitive condition, and early identification, support, and treatment significantly impact outcome. Pathologies which have the potential to become life-threatening often originate before the patient presents to the hospital, which explains the prevalence of evolving or established critical illness seen in the emergency departments (EDs). The common maxim where 'prevention is better than cure' implies that the earlier the treatment the better the outcome in other words, 'the earlier the better'. It is obvious and advantageous that evidence-based critical care should not be limited to the ICU but rather initiated as early as possible and regardless of the geographical location, whether in the prehospital setting or ED. Peter Safar was the first to indicate that efforts to enhance the chances of survival and organ recovery from critical illness must not only focus on patient management in the ICU, but address the entire patient pathway from the prehospital scene, the ED to the ICU, further including the operating room and general wards [1]. He referred to critical care as the continuum of care the critically ill or injured patient requires to recover. An USA study reported that the number of ED admissions to an ICU increased by 79% between 2001 and 2009. The time that these critically ill patients spent in the ED also increased in parallel [2]. A systematic review showed that ED boarding of critically ill patients was common, and this specific aspect alone was associated with worse clinical outcomes [3,4]. Gaieski et al. observed an increased delay in critical care as ED occupancy increased, implying that ED overcrowding might affect patient outcome [5]. A 2009 study described low rates of critical care interventions in the ED as a contributing factor to poor outcome [6]. However, more recent publications demonstrate no association between ED boarding and mortality, when appropriate critical care is delivered in the ED [7,8]. Essential critical care interventions such as basic airway management in patients with compromised airways as well as chest compressions and defibrillation in cardiac arrest are known to save lives [9]. Even advanced techniques such as extracorporeal life support further improve the chances of survival in patients with refractory cardiac arrest, when introduced early after collapse or on ED arrival [9–11]. After the initial resuscitation phase, critical care must be continued without interruption to optimally stabilize vital functions, minimize organ damage, and avoid renewed deterioration. Current scientific evidence suggests that early delivery of critical care in the ED can halt and, in some patients, even reverse acute organ dysfunction [12,13], reduce the need for ICU admission, shorten ICU and hospital length of stay, and improve both short-term as well as long-term survival [12–17]. These positive effects on patient outcome further translate into increased ICU bed availability for critically ill patients originating from other hospital areas than the ED (e.g. patients after major elective surgery or those deteriorating on hospital wards). An economic analysis revealed that critical care delivery in the ED is cost-effective [18], a finding that is of particular importance in healthcare systems with payment-per-diagnosis reimbursement. Several models on how to provide critical care in the ED have been published. These critical care delivery solutions vary substantially ranging from the 'ICU without walls' model, where ICU staff goes to the ED when needed, to direct ICU or coronary angiography suite admission of selected emergency patients (e.g. those with ST-elevation myocardial infarction), ED-based early intervention teams, telemonitoring solutions, dedicated critical care resuscitation units, and ED-ICUs staffed by emergency physicians [13,14,17,19]. Although scientific data on the comparative effectiveness of the different ED critical care delivery models are lacking, it is unlikely that a single model will be suitable and effective in all settings. Given the substantial differences in ED structures, organization, staffing and processes between hospitals, regions, and countries in Europe [20], it appears that EDs must choose the most feasible and appropriate ED critical care delivery model for their setting. Regardless of the model chosen, the practicability of critical care in the ED hinges on the availability of specific prerequisites (Fig. 1).Fig. 1: Overview of prerequisites, critical care interventions, and associated effects of critical care provision in the emergency department on patient outcomes. 1, including training and experience in technical and non-technical skills; 2, area where critically ill patients can be resuscitated, stabilized, and monitored until disposition to an ICU, non-ICU ward, or ED discharge; 3, equipment, drugs, and consumables needed for continuous patient monitoring (e.g. end-tidal carbon dioxide, invasive pressure measurement), rapid diagnostic work-up (e.g. point-of-care tests including blood gas analysis and viscoelastic tests, bedside point-of-care ultrasound), and critical care interventions (e.g. rapid sequence induction, noninvasive and invasive mechanical ventilation, continuous infusion of vasodilators, vasopressors or inotropic agents, extracorporeal life support). ED, emergency department.ED critical care encompasses more than resuscitation, interventions, and continuous patient monitoring. In patients too old, frail, and/or sick to benefit from ICU admissions, effective and timely diagnostics and noninvasive critical care interventions (e.g. noninvasive positive pressure ventilation) can rapidly help to clarify the underlying pathology, relieve symptoms, and may even reverse organ dysfunction. A time-limited trial of noninvasive organ support in the ED facilitates the assessment of physiological reserves contributing to the decision whether to continue with organ support or turn focus to palliative care measures [21]. Another key patient-centred aspect of providing critical care in the ED is the creation of an opportunity to discuss and document patient preferences and advanced care planning before ICU and hospital admission. As a minimum, the first-line, foundational care of critically ill patients, termed Essential Emergency and Critical Care [22], should be provided to all critically ill patients in the ED and throughout the hospital. A further advantage of the systematic delivery of critical care in the ED is the possibility to harmonize and expand critical care research to early phases of critical illness. Delayed study inclusion (e.g. only after ICU admission) may be one of the reasons why some putatively effective therapies did not translate into improved outcomes [23]. As a European group of emergency and critical care physicians, we would like to emphasize the importance and unquestionable need for timely critical care delivery in the ED. The ED treatment phase is a crucial part of the continuum of care for critically ill patients. Early evidence-based critical care interventions in the ED can effectively attenuate or even reverse organ dysfunction and possibly even improve the chances of survival. Further research will be essential to validate these findings across the various healthcare systems and geographical regions. Acknowledgements The Critical Care in Emergency Medicine Interest Group: Mo Al-Hadad, MD, Intensive Care Unit, Queen Elizabeth University Hospital, Glasgow, United Kingdom; Raed Arafat, MD, Department of Emergency Situations, Ministry of Internal Affairs, Bucharest, Romania; Tim Baker, MBChB, PhD, Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden; Martin Balik, MD, PhD, Department of Anaesthesiology and Intensive Care, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, Czechia; Wilhelm Behringer, MD, MBA, MSc, Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria; Ruth Brown, MD, Emergency Department, St. Mary's Hospital, Imperial College Healthcare, London, United Kingdom; Luca Carenzo, MD, Department of Anesthesia and Intensive Care Medicine, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Jim Connolly, MD, Accident and Emergency, Great North Trauma and Emergency Care, Newcastle-upon-Tyne, United Kingdom; Daniel Dankl, MD, Department of Anesthesiology, Perioperative and General Intensive Care, Salzburg University Hospital and Paracelsus Private Medical University, Salzburg, Austria; Christoph Dodt, MD, Department of Emergency Medicine, München Klinik, Munich, Germany; Martin W. Dünser, MD, Department of Anaesthesiology and Critical Care Medicine, Kepler University Hospital and Johannes Kepler University Linz, Linz, Austria; Aristomenis Exadaktylos, MD, Department of Emergency Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Tobias Gauss, MD, Anesthesia and Critical Care, Grenoble Alpes, University Hospital, Grenoble, France; Srdjan Gavrilovic, MD, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia and Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica, Serbia; Said Hachimi-Idrissi, MD, PhD, Department of Emergency Medicine, Ghent University Hospital, Ghent, Belgium and Faculty of Medicine and Pharmacy, Vrije Universiteit Brussels, Brussels, Belgium; Matthias Haenggi, MD, Institute of Intensive Care Medicine, University Hospital Zürich and University of Zürich, Zürich, Switzerland; Harald Herkner, MD; Michael Joannidis, MD, Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria; Abdo Khoury, MD, PhD, Department of Emergency Medicine and Critical Care, Besançon University Hospital, Besançon; Michaela Klinglmair, RN, Department of Anaesthesiology and Critical Care Medicine, Kepler University Hospital and Johannes Kepler University Linz, Linz, Austria; Robert Leach, MD, Department of Emergency Medicine, Centre Hospitalier de Wallonie Picarde, Tournai, Belgium; Marc Leone, MD, Department of Anesthesiology and Intensive Care Unit, North Hospital, Aix Marseille Université, Assistance Publique Hôpitaux Universitaires de Marseille, Marseille, France; David Lockey, MD, University of Bristol, Bristol, United Kingdom; Jens Meier, MD, Department of Anaesthesiology and Critical Care Medicine, Kepler University Hospital and Johannes Kepler University Linz, Linz, Austria; Matthias Noitz, MD, Department of Anaesthesiology and Critical Care Medicine, Kepler University Hospital and Johannes Kepler University Linz, Linz, Austria; Roberta Petrino, MD, Emergency Medicine Unit, Ospedale Regionale di Lugano, EOC, Switzerland; Sirak Petros, MD, Medical ICU, University Hospital of Leipzig, Leipzig, Germany; Patrick Plaisance, MD, PhD, Emergency Department, Hôpital Lariboisière, Paris, France; Jacobus Preller, FRCP, John Farman ICU, Cambridge University Hospital NHS Foundation Trust, Cambridge, United Kingdom; Luis Garcia-Castrillo Riesgo, MD, Emergency Department, Hospital Marqués de Valdecilla, Santander, Spain; Carl Otto Schell, MD, Centre for Clinical Research, Sörmland, Uppsala University, Uppsala, Sweden; Jana Šeblová, MD, PhD, Paediatric Emergency Department, Motol University Hospital, Prague, Czechia; Christian Sitzwohl, MD, Department of Anaesthesiology and Intensive Care Medicine, St. Josef Hospital Vienna, Vienna, Austria; Christian Baaner Skjaerbaek, MD, Emergency Department, Regionshospitalet Randers, Randers, Denmark; Markus Skrifvars, MD, PhD, Department of Emergency Care and Services, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Kjetil Sunde, MD, PhD, Department of Anesthesia and Intensive Care Medicine, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Tina Tomić Mahečić, MD, PhD, Department of Anesthesiology and Intensive Care Medicine, Clinical Hospital Centre Zagreb, Zagreb, Croatia; Helmut Trimmel, MD, Department of Anesthesiology, Emergency and Critical Care Medicine General Hospital Wiener Neustadt, Wiener Neustadt, Austria; Andreas Valentin, MD, Department of Internal Medicine, Cardiology and Intensive Care Medicine, Klinik Donaustadt, Vienna, Austria; Volker Wenzel, MD, Department of Anesthesiology, Intensive Care Medicine, Pain Therapy and Emergency Medicine, Klinikum Friedrichshafen, Friedrichshafen, Germany and Department of Anesthesiology, University of Florida, Gainesville, Florida, USA Conflicts of interest There are no conflicts of interest.
Abstract Background Predicting outcomes of critically ill intensive care unit (ICU) patients with coronavirus-19 disease (COVID-19) is a major challenge to avoid futile, and prolonged ICU stays. Methods The objective was to develop predictive survival models for patients with COVID-19 after 1-to-2 weeks in ICU. Based on the COVID–ICU cohort, which prospectively collected characteristics, management, and outcomes of critically ill patients with COVID-19. Machine learning was used to develop dynamic, clinically useful models able to predict 90-day mortality using ICU data collected on day (D) 1, D7 or D14. Results Survival of Severely Ill COVID (SOSIC)-1, SOSIC-7, and SOSIC-14 scores were constructed with 4244, 2877, and 1349 patients, respectively, randomly assigned to development or test datasets. The three models selected 15 ICU-entry variables recorded on D1, D7, or D14. Cardiovascular, renal, and pulmonary functions on prediction D7 or D14 were among the most heavily weighted inputs for both models. For the test dataset, SOSIC-7’s area under the ROC curve was slightly higher (0.80 [0.74–0.86]) than those for SOSIC-1 (0.76 [0.71–0.81]) and SOSIC-14 (0.76 [0.68–0.83]). Similarly, SOSIC-1 and SOSIC-7 had excellent calibration curves, with similar Brier scores for the three models. Conclusion The SOSIC scores showed that entering 15 to 27 baseline and dynamic clinical parameters into an automatable XGBoost algorithm can potentially accurately predict the likely 90-day mortality post-ICU admission (sosic.shinyapps.io/shiny). Although external SOSIC-score validation is still needed, it is an additional tool to strengthen decisions about life-sustaining treatments and informing family members of likely prognosis.
