The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome.

BACKGROUND: Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis. METHODS: Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared. RESULTS: At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7-22] vs. 4 (0-15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1ß, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-ß), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation. CONCLUSION: We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.

Effect of an ICU Diary on Posttraumatic Stress Disorder Symptoms Among Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Keeping a diary for patients while they are in the intensive care unit (ICU) might reduce their posttraumatic stress disorder (PTSD) symptoms. Objectives: To assess the effect of an ICU diary on the psychological consequences of an ICU hospitalization. Design, Setting, and Participants: Assessor-blinded, multicenter, randomized clinical trial in 35 French ICUs from October 2015 to January 2017, with follow-up until July 2017. Among 2631 approached patients, 709 adult patients (with 1 family member each) who received mechanical ventilation within 48 hours after ICU admission for at least 2 days were eligible, 657 were randomized, and 339 were assessed 3 months after ICU discharge. Interventions: Patients in the intervention group (n = 355) had an ICU diary filled in by clinicians and family members. Patients in the control group (n = 354) had usual ICU care without an ICU diary. Main Outcomes and Measures: The primary outcome was significant PTSD symptoms, defined as an Impact Event Scale-Revised (IES-R) score greater than 22 (range, 0-88; a higher score indicates more severe symptoms), measured in patients 3 months after ICU discharge. Secondary outcomes, also measured at 3 months and compared between groups, included significant PTSD symptoms in family members; significant anxiety and depression symptoms in patients and family members, based on a Hospital Anxiety and Depression Scale score greater than 8 for each subscale (range, 0-42; higher scores indicate more severe symptoms; minimal clinically important difference, 2.5); and patient memories of the ICU stay, reported with the ICU memory tool. Results: Among 657 patients who were randomized (median [interquartile range] age, 62 [51-70] years; 126 women [37.2%]), 339 (51.6%) completed the trial. At 3 months, significant PTSD symptoms were reported by 49 of 164 patients (29.9%) in the intervention group vs 60 of 175 (34.3%) in the control group (risk difference, -4% [95% CI, -15% to 6%]; P = .39). The median (interquartile range) IES-R score was 12 (5-25) in the intervention group vs 13 (6-27) in the control group (difference, -1.47 [95% CI, -1.93 to 4.87]; P = .38). There were no significant differences in any of the 6 prespecified comparative secondary outcomes. Conclusions and Relevance: Among patients who received mechanical ventilation in the ICU, the use of an ICU diary filled in by clinicians and family members did not significantly reduce the number of patients who reported significant PTSD symptoms at 3 months. These findings do not support the use of ICU diaries for preventing PTSD symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT02519725.

Family perceptions of clinical research and the informed consent process in the ICU.

PURPOSE: We investigated experiences of families who provide consent for research on behalf of a loved-one hospitalized in intensive care (ICU). METHODS: Multicentre, qualitative, descriptive study using semi-directive interviews in 3 ICUs. Eligible relatives were aged >18 years, and had provided informed consent for a clinical trial on behalf of a patient hospitalized in ICU. Interviews were conducted from 06/2018 to 06/2019 by a qualified sociologist, recorded and transcribed. RESULTS: Fifteen relatives were interviewed; average age 50.3 ±â€¯15 years. All emphasized their interest in clinical research, seeing it as a duty. Involving their loved-one in research allowed them to find meaning in the events. Participants underlined that trust in caregivers and communication are determinant. The strict regulation of research was perceived as a guarantee of safety. Participants felt they lacked the intellectual capacity and knowledge to question explanations. The greatest fear was not that they might incur a risk for the patient, but rather, that they might deprive the patient of a chance at a cure. CONCLUSION: Acceptance of research opportunities by relatives on behalf of decisionally-incapacitated patients is underpinned by trust in the physicians and the legislative framework. Communication and the quality of information provided by the caregivers are key.

Non-readmission decisions in the intensive care unit: A qualitative study of physicians' experience in a multicentre French study.

PURPOSE: Deciding not to re-admit a patient to the intensive care unit (ICU) poses an ethical dilemma for ICU physicians. We aimed to describe and understand the attitudes and perceptions of ICU physicians regarding non-readmission of patients to the ICU. MATERIALS AND METHODS: Multicenter, qualitative study using semi-directed interviews between January and May 2019. All medical staff working full-time in the ICU of five participating centres (two academic and three general, non-academic hospitals) were invited to participate. Participants were asked to describe how they experienced non-readmission decisions in the ICU, and to expand on the manner in which the decision was made, but also on the traceability and timing of the decision. Interviews were recorded, transcribed and analyzed using textual content analysis. RESULTS: In total, 22 physicians participated. Interviews lasted on average 26±7 minutes. There were 14 men and 8 women, average age was 35±9 years, and average length of ICU experience was 7±5 years. The majority of respondents said that they regretted that the question of non-readmission was not addressed before the initial ICU admission. They acknowledged that the ICU stay did lead to more thorough contemplation of the overall goals of care. Multidisciplinary team meetings could help to anticipate the question of readmission within the patient's care pathway. Participants reported that there is a culture of collegial decision-making in the ICU, although the involvement of patients, families and other healthcare professionals in this process is not systematic. The timing and traceability of non-readmission decisions are heterogeneous. CONCLUSIONS: Non-readmission decisions are a major issue that raises ethical questions surrounding the fact that there is no discussion of the patient's goals of care in advance. Better anticipation, and better communication with the patients, families and other healthcare providers are suggested as areas that could be targeted for improvement.

Criteria deemed important by the relatives for designating a reference person for patients hospitalized in ICU.

PURPOSE: We investigated the criteria that patients' relatives deem important for choosing, among themselves, the person best qualified to interact with the caregiving staff. METHODS: Exploratory, observational, prospective, multicentre study between 1st March and 31st October 2018 in 2 intensive care units (ICUs). A 12-item questionnaire was completed anonymously by family members of patients hospitalized in the ICU 3 and 5 days after the patient's admission. Relatives were eligible if they understood French and if no surrogate had been appointed by the patient prior to ICU admission. More than one relative per patient could participate. RESULTS: In total, 87 relatives of 73 patients completed the questionnaire, average age of relatives was 58 ± 15 years, 46% were the spouse, 30% were children/grandchildren. Items classed as being the most important attributes for a reference person were: good knowledge of the patient's wishes and values; an emotional attachment to the patient; being a family member; and having an adequate understanding of the clinical status and clinical history. CONCLUSION: This study identifies the attributes considered by relatives to be most important for designating, among themselves, a reference person for a patient hospitalized in the ICU.

Influence of deprivation on initial severity and prognosis of patients admitted to the ICU: the prospective, multicentre, observational IVOIRE cohort study.

BACKGROUND: The influence of socioeconomic status on patient outcomes is unclear. We assessed the impact of socioeconomic deprivation on severity of illness at intensive care unit (ICU) admission, and on the risk of death at 3 months after ICU admission. METHODS: The IVOIRE study was a prospective, observational, multicentre cohort study in the ICU of 8 participating hospitals in France, including patients aged ≥ 18 years admitted to the ICU and receiving at least one life support therapy for organ failure. The primary outcomes were severity at admission (assessed by SAPSII score), and mortality at 3 months. Socioeconomic data were obtained from interviews with patients or family. Deprivation was assessed using the EPICES score. RESULTS: Among 1294 patents included between 2013 and 2016, 629 (48.6%) were classed as deprived and differed significantly from non-deprived subjects in terms of sociodemographic characteristics and pre-existing conditions. The mean SAPS II score at admission was 50.1 ± 19.4 in deprived patients and 52.3 ± 17.3 in non-deprived patients, with no significant difference by multivariable analysis (ß = - 1.85 [95% CI - 3.86; + 0.16, p = 0.072]). The proportion of death was 31.1% at 3 months, without significant differences between deprived and non-deprived patients, even after adjustment for confounders. CONCLUSIONS: Deprivation is frequent in patients admitted to the ICU and is not associated with disease severity at admission, or with mortality at 3 months between deprived and non-deprived patients. Trial registration The IVOIRE cohort is registered with ClinicalTrials.gov under the identifier NCT01907581, registration date 17/7/2013.

What are the characteristics that lead physicians to perceive an ICU stay as non-beneficial for the patient?

PURPOSE: We sought to describe the characteristics that lead physicians to perceive a stay in the intensive care unit (ICU) as being non-beneficial for the patient. MATERIALS AND METHODS: In the first step, we used a multidisciplinary focus group to define the characteristics that lead physicians to consider a stay in the ICU as non-beneficial for the patient. In the second step, we assessed the proportion of admissions that would be perceived by the ICU physicians as non-beneficial for the patient according to our focus group's definition, in a large population of ICU admissions in 4 French ICUs over a period of 4 months. RESULTS: Among 1075 patients admitted to participating ICUs during the study period, 155 stays were considered non-beneficial for the patient, yielding a frequency of 14.4% [95% confidence interval (CI) 8.9, 19.9]. Average age of these patients was 72 ±12.8 years. Mortality was 43.2% in-ICU [95%CI 35.4, 51.0], 55% [95%CI 47.2, 62.8] in-hospital. The criteria retained by the focus group to define a non-beneficial ICU stay were: patient refusal of ICU care (23.2% [95%CI 16.5, 29.8]), and referring physician's desire not to have the patient admitted (11.6% [95%CI 6.6, 16.6]). The characteristics that led physicians to perceive the stay as non-beneficial were: patient's age (36.8% [95%CI 29.2, 44.4]), unlikelihood of recovering autonomy (61.9% [95%CI 54.3, 69.6]), prior poor quality of life (60% [95%CI 52.3, 67.7]), terminal status of chronic disease (56.1% [95%CI 48.3, 63.9]), and all therapeutic options have been exhausted (35.5% [95%CI 27.9, 43.0]). Factors that explained admission to the ICU of patients whose stay was subsequently judged to be non-beneficial included: lack of knowledge of patient's wishes (52% [95%CI 44.1, 59.9]); decisional incapacity (sedation) (69.7% [95%CI 62.5, 76.9]); inability to contact family (34% [95%CI 26.5, 41.5]); pressure to admit (from family or other physicians) (50.3% [95%CI 42.4, 58.2]). CONCLUSIONS: Non-beneficial ICU stays are frequent. ICU admissions need to be anticipated, so that patients who would yield greater benefit from other care pathways can be correctly oriented in a timely manner.

Corporeal Compression at the Onset of Septic shock (COCOONs): a compression method to reduce fluid balance of septic shock patients.

Fluid overload in septic intensive care unit (ICU) patients is common and strongly associated with poor outcome. There is currently no treatment for capillary leak, which is mainly responsible for high positive fluid balance (FB) in sepsis. We hypothesized that increasing interstitial pressure with extensive corporeal compression would reduce FB. The objective of this study was to evaluate the feasibility, efficacy, and safety of a compression treatment during sepsis. This pilot, two-center, single-arm trial enrolled critically ill, non-surgical, septic patients receiving mechanical ventilation. The therapeutic intervention was the early application of compression bandages on more than 80% of the body surface. The primary outcome was negative net FB on day 7. The primary endpoint was reached in 29 of 45 patients (64%) with available data, for a planned objective of 26. By day 4, cumulative FB was 7280 ml [3300-9700]. SOFA- and aged-matched patients from a historical cohort had a significantly higher FB at 1, 2 and 7 days. Tolerance was good, although low-stage pressure ulcers were observed in 16 patients (26%). No effect on intra-abdominal pressure or respiratory plateau pressure was observed. In conclusion, corporeal compression demonstrated potential efficacy in limiting FB during septic shock, with acceptable feasibility and tolerance.

Adhering to the procalcitonin algorithm allows antibiotic therapy to be shortened in patients with ventilator-associated pneumonia.

PURPOSE: Ventilator-associated pneumonia (VAP) increases exposure to antibiotics. Physicians are however reluctant to shorten treatment, arguing this could lead to failures and worse outcome. Monitoring procalcitonin (PCT) has proven effective for decreasing exposure to antibiotics in randomized controlled trials, but additional "real-life" studies are needed. MATERIALS AND METHODS: All patients with VAP in whom ABT was stopped before death or discharge were included in this 5-year prospective cohort study. Patients in whom ABT was stopped in accordance with the algorithm ("PCT-guided" group: ABT withdrawal strongly encouraged if PCT < 0.5 ng/mL or < 80% peak value) were compared to those with ABT continuation despite PCT decrease ("not PCT-guided" group). The primary endpoint was ABT duration. The secondary endpoint was unfavorable VAP outcome (i.e. death or relapse). RESULTS: We included 157 of the 316 patients with microbiologically-proven VAP. The algorithm was overruled in 81 patients (51.6%). ABT duration was significantly longer in these patients than in the PCT-guided group (9.5 vs. 8.0 days; p = .02), although baseline and VAP characteristics did not differ. The rate of unfavorable outcomes was comparable (46.9% vs. 51.3%; p = .69). CONCLUSIONS: PCT-guided ABT adherence appears safe for patients with VAP and is likely to reduce exposure to antibiotics.

Impact of a stay in the intensive care unit on the preparation of Advance Directives: Descriptive, exploratory, qualitative study.

BACKGROUND: Our objective was to assess, through a qualitative, exploratory study, the thought processes of patients regarding the formulation of advance directives (AD) after a stay in the ICU. METHODS: The study was conducted from May to July 2016 using telephone interviews performed by four senior ICU physicians. Inclusion criteria were: patients discharged from ICU to home>3 months earlier. Semi-directive interviews with patients focused on 5 main points surrounding AD. RESULTS: In total, among 159 eligible patients, data from 94 (59%) were available for analysis. Among all those interviewed, 83.5% had never heard of "advance directives". Only 2% had executed AD before ICU admission, and 7% expressed a desire to prepare AD further to their ICU stay. Among the barriers to preparation of AD, lack of information was the main reason cited for not executing AD. Patients noted the following in their AD: withdrawal of life-support in case of vegetative/minimally conscious state or when there is no longer any hope, in case of uncontrollable pain, and if impossible to wean from mechanical ventilation. CONCLUSION: The ideal time to engage patients in these discussions is most likely well before an acute health event occurs, although this warrants further investigation both before and after ICU admissions.

Intersecting vulnerabilities in professionals and patients in intensive care.

In the context of healthcare delivery, the vulnerabilities of patients in the intensive care unit (ICU) are intricately linked with those experienced on a daily basis by caregivers in the ICU in a symbiotic relation, whereby patients who are suffering can in turn engender suffering in the caregivers. In the same way, caregivers who are suffering themselves may be a source of suffering for their patients. The vulnerabilities of both patients and caregivers in the ICU are simultaneously constituted through a process that is influenced on the one hand by the healthcare objectives of the ICU, and on the other hand, by the conformity of the patients who are managed in that ICU. The specific challenges of management in high-technology units such as an ICU may have consequences on the practices and work conditions of healthcare professionals. Constructing the patient, collectively redefining the patient's identity, and ascribing the patient to a specific healthcare trajectory enables professionals to circumscribe, contain and fight against the spectrum of extreme vulnerabilities of their patients. Imposing this normative framework is the sole means of guiding these professionals through their daily practices. In spite of this, situations of suffering remain a constitutive feature of the caregiving relation in the ICU.

What are the ethical issues in relation to the role of the family in intensive care?

A large proportion of patients admitted to the intensive care unit (ICU) are unable to express themselves, often due to acute illness, shock or trauma, and this precludes any communication and/or consent for care that might reflect their wishes and opinions. In such cases, the only solution for the ICU physician is to include the patient's family in the healthcare decisions. This can represent a significant burden on the family, on top of the psychological distress of the ICU environment and hospitalisation of their relatives, and many family members may suffer from anxiety, depression or symptoms of post-traumatic stress disorder (PTSD) during or after the hospitalisation and/or death of a loved one in the ICU. Good communication remains the cornerstone of family satisfaction in the ICU. Information imparted to the patient and/or family should cover diagnosis, prognosis and treatment. Information should be given orally, in person, using accessible language. Several other measures that can lessen the burden on the families of patients in the ICU and help to reduce anxiety and stress are also detailed in this review. Overall, family-centred care in the ICU requires a systematic communication strategy within the healthcare team, combined with an environment that is as amenable as possible to the family's presence and involvement, in order to maximize family satisfaction with ICU care, and ensure that the patient's values and preferences are respected.

What are the ethical aspects surrounding the collegial decisional process in limiting and withdrawing treatment in intensive care?

The decision to limit or withdraw life-support treatment is an integral part of the job of a physician working in the intensive care unit, and of the approach to care. However, this decision is influenced by a number of factors. It is widely accepted that a medical decision that will ultimate lead to end-of-life in the intensive care unit (ICU) must be shared between all those involved in the care process, and should give precedence to the patient's wishes (either directly expressed by the patient or in written form, such as advance directives), and taking into account the opinion of the patient's family, including the surrogate if the patient is no longer capable of expressing themselves. A number of questions still remain unanswered regarding how decisions to limit or withdraw treatment are taken in daily practice, especially when this decision can be anticipated. We discuss here the collegial procedure for decision-making, in particular in the context of recent French legislation on end-of-life issues. We describe how collegial decision-making procedures should be carried out, and what points are covered in shared discussions regarding decisions to limit or withdraw life-sustaining therapies.

What are the ethical questions raised by the integration of intensive care into advance care planning?

A major goal of intensive care units (ICUs) is to offer optimal management, but for many patients admitted to the ICU, they are unlikely to yield any lasting benefit. In this context, the ICU physician remains a key intermediary, particularly when a decision regarding possible limitation or withdrawal of life-sustaining therapy becomes necessary. The possibility of admission to the ICU, and the type of care the patient would like to receive there, should be integrated into the healthcare project in agreement with the patient, regardless of the stage of disease that the patient suffers from. These dispositions should be recorded in the patient's file, and should respect the progressive nature of both the disease itself, and the discussions necessary in such complex situations. The ICU physician can serve as a valuable consultant for the treating physician, in particular to guide patient choices when formalizing their healthcare preferences in the form of advance care planning (ACP) or advance directives (AD). Ideally, the best time to address this issue is before the patient's clinical situation deteriorates towards an acute emergency, and providing complete and transparent information to inform the patient's choices.

What are the ethical aspects surrounding intensive care unit admission in patients with cancer?

Improvements in living conditions and increasing life expectancy have combined to result in ever older patients being admitted to hospital. In parallel, the increasing incidence of cancer, along with the improved efficacy of anti-cancer therapies has led to greater needs for intensive care among cancer patients. The objectives underpinning the management of cancer patients in the intensive care unit (ICU) are to achieve a return to a clinical status that would allow the patient to be either, transferred back to the original unit, or discharged from the hospital with an acceptable quality of life, and where warranted, pursuit of cancer therapy. The relevance of ICU admission should be assessed systematically for patients with active cancer. The decision needs to be made taking into account the expected benefit for the patient, the life-support therapies that are possible with discussion about a care project, and also considering the future quality of life and the short and long-term prognosis. Anticipating the question of potential ICU admission should help protect the patient against both inappropriate refusal of intensive care, and inappropriate admission to the ICU that might only lead to unreasonable therapeutic obstinacy. The intensive care physician has a major role to play in helping the cancer patient to develop an appropriate and flexible healthcare project. Anticipating the question of ICU admission in advance, as well as a close alliance between the oncologist and the intensive care physician are the two keys to the success of a healthcare project focused on the patient.

What are the ethical dimensions in the profession of intensive care specialist?

Two essential components of the profession of a medical doctor are the constant review of the patient's therapeutic project, and collaboration between healthcare professionals. The profession of intensive care unit (ICU) physician goes further in terms of responsibility, vis-à-vis the intensive treatments dispensed to the patients, and the physician's responsibilities towards the patient's family and the caregiving team, also bearing in mind that ICU care is costly in terms of human and financial resources. In this review, we address the profession of ICU physician from the perspective of the ethical questions that arise constantly, focusing on the timeframe of the reflection process. Firstly, admission to the ICU must be anticipated. The concept of advance care planning is a suitable tool for this, and in case of non-admission to the ICU, does not by any means constitute an abandonment of the patient, because palliative care can also be anticipated, with a view to avoiding suffering for the patient and their family. Next, during an ICU stay, while the technical aspects undoubtedly characterise the ICU best at the start of the patient's stay, the process of reflection rapidly becomes preponderant, and involves the analysis of often complex situations with a view to defining the level of therapeutic engagement and optimizing the care dispensed to the patient. Last, a further ethical issue concerns the decision to re-admit (or not) a patient to the ICU. This decision can be made, for example, in the framework of a systematic, formalised, structured, multidisciplinary meeting at the end of an ICU stay, using a similar procedure to that implemented for decisions relating to withholding or withdrawal of life-sustaining therapies. The profession of ICU physician is not simply a question of prolonging or sustaining life, but is also fraught with ethical questions about how best to employ their competences. In this regard, it is essential to foster interdisciplinary collaboration, and emphasise the need for ICU physicians to be involved in the development of therapeutic projects, particularly when the disease in question is likely to be complicated by acute situations that may require admission of the patient to the ICU.

The ICU-Diary study: prospective, multicenter comparative study of the impact of an ICU diary on the wellbeing of patients and families in French ICUs.

BACKGROUND: Post-intensive care syndrome includes the multiple consequences of an intensive care unit (ICU) stay for patients and families. It has become a new challenge for intensivists. Prevention programs have been disappointing, except for ICU diaries, which report the patient's story in the ICU. However, the effectiveness of ICU diaries for patients and families is still controversial, as the interpretation of the results of previous studies was open to criticism hampering an expanded use of the diary. The primary objective of the study is to evaluate the post-traumatic stress syndrome in patients. The secondary objectives are to evaluate the post-traumatic stress syndrome in families, anxiety and depression symptoms in patients and families, and the recollected memories of patients. Endpoints will be evaluated 3 months after ICU discharge or death. METHODS: A prospective, multicenter, randomized, assessor-blind comparative study of the effect of an ICU diary on patients and families. We will compare two groups: one group with an ICU diary written by staff and family and given to the patient at ICU discharge or to the family in case of death, and a control group without any ICU diary. Each of the 35 participating centers will include 20 patients having at least one family member who will likely visit the patient during their ICU stay. Patients must be ventilated within 48 h after ICU admission and not have any previous chronic neurologic or acute condition responsible for cognitive impairments that would hamper their participation in a phone interview. Three months after ICU discharge or death of the patient, a psychologist will contact the patient and family by phone. Post-traumatic stress syndrome will be evaluated using the Impact of Events Scale-Revised questionnaire, anxiety and depression symptoms using the Hospital Anxiety and Depression Scale questionnaire, both in patients and families, and memory recollection using the ICU Memory Tool Questionnaire in patients. The content of a randomized sample of diaries of each center will be analyzed using a grid. An interview of the patients in the intervention arm will be conducted 6 months after ICU discharge to analyze in depth how they use the diary. DISCUSSION: This study will provide new insights on the impact of ICU diaries on post-traumatic stress disorders in patients and families after an ICU stay. TRIAL REGISTRATION: ClinicalTrial.gov, ID: NCT02519725 . Registered on 13 July 2015.