Effect of immediate initiation of invasive ventilation on mortality in acute hypoxemic respiratory failure: a target trial emulation.

PURPOSE: Invasive ventilation is a fundamental treatment in intensive care but its precise timing is difficult to determine. This study aims at assessing the effect of initiating invasive ventilation versus waiting, in patients with hypoxemic respiratory failure without immediate reason for intubation on one-year mortality. METHODS: Emulation of a target trial to estimate the benefit of immediately initiating invasive ventilation in hypoxemic respiratory failure, versus waiting, among patients within the first 48-h of hypoxemia. The eligible population included non-intubated patients with SpO2/FiO2 ≤ 200 and SpO2 ≤ 97%. The target trial was emulated using a single-center database (MIMIC-IV) which contains granular information about clinical status. The hourly probability to receive mechanical ventilation was continuously estimated. The hazard ratios for the primary outcome, one-year mortality, and the secondary outcome, 30-day mortality, were estimated using weighted Cox models with stabilized inverse probability weights used to adjust for measured confounding. RESULTS: 2996 Patients fulfilled the inclusion criteria of whom 792 were intubated within 48 h. Among the non-invasive support devices, the use of oxygen through facemask was the most common (75%). Compared to patients with the same probability of intubation but who were not intubated, intubation decreased the hazard of dying for the first year after ICU admission HR 0.81 (95% CI 0.68-0.96, p = 0.018). Intubation was associated with a 30-day mortality HR of 0.80 (95% CI 0.64-0.99, p = 0.046). CONCLUSION: The initiation of mechanical ventilation in patients with acute hypoxemic respiratory failure reduced the hazard of dying in this emulation of a target trial.

Accounting for Competing Events When Evaluating Long-Term Outcomes in Survivors of Critical Illness.

The clinical trajectory of survivors of critical illness after hospital discharge can be complex and highly unpredictable. Assessing long-term outcomes after critical illness can be challenging because of possible competing events, such as all-cause death during follow-up (which precludes the occurrence of an event of particular interest). In this perspective, we explore challenges and methodological implications of competing events during the assessment of long-term outcomes in survivors of critical illness. In the absence of competing events, researchers evaluating long-term outcomes commonly use the Kaplan-Meier method and the Cox proportional hazards model to analyze time-to-event (survival) data. However, traditional analytical and modeling techniques can yield biased estimates in the presence of competing events. We present different estimands of interest and the use of different analytical approaches, including changes to the outcome of interest, Fine and Gray regression models, cause-specific Cox proportional hazards models, and generalized methods (such as inverse probability weighting). Finally, we provide code and a simulated dataset to exemplify the application of the different analytical strategies in addition to overall reporting recommendations.

The association between nutritional risk index and ICU outcomes across hematologic malignancy patients with acute respiratory failure.

Patients with hematological malignancies (HM) are at risk of acute respiratory failure (ARF). Malnutrition, a common association with HM, has the potential to influence ICU outcomes. Geriatric nutritional risk index (G-NRI) is a score derived from albumin and weight, which reflects risk of protein-energy malnutrition. We evaluated the association between G-NRI at ICU admission and ICU mortality in HM patients with ARF. We conducted a single center retrospective study of ventilated HM patients between 2014 and 2018. We calculated G-NRI for all patients using their ICU admission albumin and weight. Our primary outcome was ICU mortality. Secondary outcomes included duration of mechanical ventilation and ICU length of stay. Two hundred eighty patients were admitted to the ICU requiring ventilation. Median age was 62 years (IQR 51-68), 42% (n = 118) were females, and median SOFA score was 11 (IQR 9-14). The most common type of HM was acute leukemia (54%) and 40% underwent hematopoietic cell transplant. Median G-NRI was 87 (IQR 79-99). ICU mortality was 51% (n = 143) with a median duration of ventilation of 4 days (IQR 2-7). Mortality across those at severe malnutrition (NRI < 83.5) was 59% (65/111) compared to 46% (76/164) across those with moderate-no risk (p = 0.047). On multivariable analysis, severe NRI (OR 2.34, 95% CI 1.04-5.27, p = 0.04) was significantly associated with ICU mortality. In this single center, exploratory study, severe G-NRI was prognostic of ICU mortality in HM patients admitted with respiratory failure.

Oxygenation thresholds for invasive ventilation in hypoxemic respiratory failure: a target trial emulation in two cohorts.

BACKGROUND: The optimal thresholds for the initiation of invasive ventilation in patients with hypoxemic respiratory failure are unknown. Using the saturation-to-inspired oxygen ratio (SF), we compared lower versus higher hypoxemia severity thresholds for initiating invasive ventilation. METHODS: This target trial emulation included patients from the Medical Information Mart for Intensive Care (MIMIC-IV, 2008-2019) and the Amsterdam University Medical Centers (AmsterdamUMCdb, 2003-2016) databases admitted to intensive care and receiving inspired oxygen fraction ≥ 0.4 via non-rebreather mask, noninvasive ventilation, or high-flow nasal cannula. We compared the effect of using invasive ventilation initiation thresholds of SF < 110, < 98, and < 88 on 28-day mortality. MIMIC-IV was used for the primary analysis and AmsterdamUMCdb for the secondary analysis. We obtained posterior means and 95% credible intervals (CrI) with nonparametric Bayesian G-computation. RESULTS: We studied 3,357 patients in the primary analysis. For invasive ventilation initiation thresholds SF < 110, SF < 98, and SF < 88, the predicted 28-day probabilities of invasive ventilation were 72%, 47%, and 19%. Predicted 28-day mortality was lowest with threshold SF < 110 (22.2%, CrI 19.2 to 25.0), compared to SF < 98 (absolute risk increase 1.6%, CrI 0.6 to 2.6) or SF < 88 (absolute risk increase 3.5%, CrI 1.4 to 5.4). In the secondary analysis (1,279 patients), the predicted 28-day probability of invasive ventilation was 50% for initiation threshold SF < 110, 28% for SF < 98, and 19% for SF < 88. In contrast with the primary analysis, predicted mortality was highest with threshold SF < 110 (14.6%, CrI 7.7 to 22.3), compared to SF < 98 (absolute risk decrease 0.5%, CrI 0.0 to 0.9) or SF < 88 (absolute risk decrease 1.9%, CrI 0.9 to 2.8). CONCLUSION: Initiating invasive ventilation at lower hypoxemia severity will increase the rate of invasive ventilation, but this can either increase or decrease the expected mortality, with the direction of effect likely depending on baseline mortality risk and clinical context.

Association of Positive End-Expiratory Pressure and Lung Recruitment Selection Strategies with Mortality in Acute Respiratory Distress Syndrome: A Systematic Review and Network Meta-analysis.

Rationale: The most beneficial positive end-expiratory pressure (PEEP) selection strategy in patients with acute respiratory distress syndrome (ARDS) is unknown, and current practice is variable. Objectives: To compare the relative effects of different PEEP selection strategies on mortality in adults with moderate to severe ARDS. Methods: We conducted a network meta-analysis using a Bayesian framework. Certainty of evidence was evaluated using grading of recommendations assessment, development and evaluation methodology. Measurements and Main Results: We included 18 randomized trials (4,646 participants). Compared with a lower PEEP strategy, the posterior probability of mortality benefit from a higher PEEP without lung recruitment maneuver (LRM) strategy was 99% (risk ratio [RR], 0.77; 95% credible interval [CrI], 0.60-0.96, high certainty), the posterior probability of benefit of the esophageal pressure-guided strategy was 87% (RR, 0.77; 95% CrI, 0.48-1.22, moderate certainty), the posterior probability of benefit of a higher PEEP with brief LRM strategy was 96% (RR, 0.83; 95% CrI, 0.67-1.02, moderate certainty), and the posterior probability of increased mortality from a higher PEEP with prolonged LRM strategy was 77% (RR, 1.06; 95% CrI, 0.89-1.22, low certainty). Compared with a higher PEEP without LRM strategy, the posterior probability of increased mortality from a higher PEEP with prolonged LRM strategy was 99% (RR, 1.37; 95% CrI, 1.04-1.81, moderate certainty). Conclusions: In patients with moderate to severe ARDS, higher PEEP without LRM is associated with a lower risk of death than lower PEEP. A higher PEEP with prolonged LRM strategy is associated with increased risk of death when compared with higher PEEP without LRM.

Helmet noninvasive ventilation compared to facemask noninvasive ventilation and high-flow nasal cannula in acute respiratory failure: a systematic review and meta-analysis.

BACKGROUND: Although small randomised controlled trials (RCTs) and observational studies have examined helmet noninvasive ventilation (NIV), uncertainty remains regarding its role. We conducted a systematic review and meta-analysis to examine the effect of helmet NIV compared to facemask NIV or high-flow nasal cannula (HFNC) in acute respiratory failure. METHODS: We searched multiple databases to identify RCTs and observational studies reporting on at least one of mortality, intubation, intensive care unit (ICU) length of stay, NIV duration, complications or comfort with NIV therapy. We assessed study risk of bias using the Cochrane Risk of Bias 2 tool for RCTs and the Ottawa-Newcastle Scale for observational studies, and rated certainty of pooled evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) framework. RESULTS: We separately pooled data from 16 RCTs (n=949) and eight observational studies (n=396). Compared to facemask NIV, based on low certainty of evidence, helmet NIV may reduce mortality (relative risk 0.56, 95% CI 0.33-0.95) and intubation (relative risk 0.35, 95% CI 0.22-0.56) in both hypoxic and hypercapnic respiratory failure, but may have no effect on duration of NIV. There was an uncertain effect of helmet NIV on ICU length of stay and development of pressure sores. Data from observational studies were consistent with the foregoing findings but of lower certainty. Based on low and very low certainty data, helmet NIV may reduce intubation compared to HFNC, but its effect on mortality is uncertain. CONCLUSIONS: Compared to facemask NIV, helmet NIV may reduce mortality and intubation; however, the effect of helmet NIV compared to HFNC remains uncertain.

Early intubation and patient-centered outcomes in septic shock: a secondary analysis of a prospective multicenter study.

PURPOSE: Despite the benefits of mechanical ventilation, its use in critically ill patients is associated with complications and had led to the growth of noninvasive techniques. We assessed the effect of early intubation (first 8 h after vasopressor start) in septic shock patients, as compared to non-early intubated subjects (unexposed), regarding in-hospital mortality, intensive care and hospital length of stay. METHODS: This study involves secondary analysis of a multicenter prospective study. To adjust for baseline differences in potential confounders, propensity score matching was carried out. In-hospital mortality was analyzed in a time-to-event fashion, while length of stay was assessed as a median difference using bootstrapping. RESULTS: A total of 735 patients (137 intubated in the first 8 h) were evaluated. Propensity score matching identified 78 pairs with similar severity and characteristics on admission. Intubation was used in all patients in the early intubation group and in 27 (35%) subjects beyond 8 h in the unexposed group. Mortality occurred in 35 (45%) and in 26 (33%) subjects in the early intubation and unexposed groups (hazard ratio 1.44 95% CI 0.86-2.39, p = 0.16). ICU and hospital length of stay were not different among groups [9 vs. 5 (95% CI 1 to 7) and 14 vs. 16 (95% CI - 7 to 8) days]. All sensitivity analyses confirmed the robustness of our findings. CONCLUSIONS: An early approach to invasive mechanical ventilation did not improve outcomes in this matched cohort of patients. The limited number of patients included in these analyses out the total number included in the study may limit generalizability of these findings. Trial registration NCT02780466. Registered on May 19, 2016.

Discordances Between Factors Associated With Withholding Extubation and Extubation Failure After a Successful Spontaneous Breathing Trial.

OBJECTIVES: To identify whether factors associated with withholding extubation in the ICU also predict the risk of extubation failure. DESIGN: Retrospective cohort study. SETTING: Eight medical-surgical ICUs in Toronto. PATIENTS: Adult patients receiving invasive mechanical ventilation, with a first successful spontaneous breathing trial within 28 days of initial ICU admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary end point had three mutually exclusive levels, including: 1) withholding extubation after a successful spontaneous breathing trial, 2) extubation failure within 48 hours, and 3) successful extubation. Among 9,910 patients, 38% of patients were not extubated within 24 hours of their first successful spontaneous breathing trial. A total of 12.9% of patients who were promptly extubated failed within the next 48 hours. Several discrepancies were evident in the association of factors with risk of withholding extubation and extubation failure. Specifically, both age and female sex were associated with withholding extubation (odds ratio, 1.07; 95% CI, 1.03-1.11; and odds ratio, 1.13; 95% CI, 1.02-1.26, respectively) but not a higher risk of failed extubation (odds ratio, 0.99; 95% CI, 0.93-1.05; and odds ratio, 0.93; 95% CI, 0.77-1.11, respectively). Conversely, both acute cardiovascular conditions and intubation for hypoxemic respiratory failure were associated with a higher risk of failed extubation (odds ratio, 1.32; 95% CI, 1.06-1.66; and odds ratio, 1.46; 95% CI, 1.16-1.82, respectively) but not a higher odds of a withheld extubation attempt (odds ratio, 0.79; 95% CI, 0.68-0.91; and odds ratio, 1.07; 95% CI, 0.93-1.23, respectively). CONCLUSIONS: Several factors showed discordance between the decision to withhold extubation and the risk of extubation failure. This discordance may lead to longer duration of mechanical ventilation or higher reintubation rates. Improving the decision-making behind extubation may help to reduce both exposure to invasive mechanical ventilation and extubation failure.

High-flow nasal oxygen in patients with COVID-19-associated acute respiratory failure.

PURPOSE: Whether the use of high-flow nasal oxygen in adult patients with COVID-19 associated acute respiratory failure improves clinically relevant outcomes remains unclear. We thus sought to assess the effect of high-flow nasal oxygen on ventilator-free days, compared to early initiation of invasive mechanical ventilation, on adult patients with COVID-19. METHODS: We conducted a multicentre cohort study using a prospectively collected database of patients with COVID-19 associated acute respiratory failure admitted to 36 Spanish and Andorran intensive care units (ICUs). Main exposure was the use of high-flow nasal oxygen (conservative group), while early invasive mechanical ventilation (within the first day of ICU admission; early intubation group) served as the comparator. The primary outcome was ventilator-free days at 28 days. ICU length of stay and all-cause in-hospital mortality served as secondary outcomes. We used propensity score matching to adjust for measured confounding. RESULTS: Out of 468 eligible patients, a total of 122 matched patients were included in the present analysis (61 for each group). When compared to early intubation, the use of high-flow nasal oxygen was associated with an increase in ventilator-free days (mean difference: 8.0 days; 95% confidence interval (CI): 4.4 to 11.7 days) and a reduction in ICU length of stay (mean difference: - 8.2 days; 95% CI - 12.7 to - 3.6 days). No difference was observed in all-cause in-hospital mortality between groups (odds ratio: 0.64; 95% CI: 0.25 to 1.64). CONCLUSIONS: The use of high-flow nasal oxygen upon ICU admission in adult patients with COVID-19 related acute hypoxemic respiratory failure may lead to an increase in ventilator-free days and a reduction in ICU length of stay, when compared to early initiation of invasive mechanical ventilation. Future studies should confirm our findings.

Association of Noninvasive Oxygenation Strategies With All-Cause Mortality in Adults With Acute Hypoxemic Respiratory Failure: A Systematic Review and Meta-analysis.

Importance: Treatment with noninvasive oxygenation strategies such as noninvasive ventilation and high-flow nasal oxygen may be more effective than standard oxygen therapy alone in patients with acute hypoxemic respiratory failure. Objective: To compare the association of noninvasive oxygenation strategies with mortality and endotracheal intubation in adults with acute hypoxemic respiratory failure. Data Sources: The following bibliographic databases were searched from inception until April 2020: MEDLINE, Embase, PubMed, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science, and LILACS. No limits were applied to language, publication year, sex, or race. Study Selection: Randomized clinical trials enrolling adult participants with acute hypoxemic respiratory failure comparing high-flow nasal oxygen, face mask noninvasive ventilation, helmet noninvasive ventilation, or standard oxygen therapy. Data Extraction and Synthesis: Two reviewers independently extracted individual study data and evaluated studies for risk of bias using the Cochrane Risk of Bias tool. Network meta-analyses using a bayesian framework to derive risk ratios (RRs) and risk differences along with 95% credible intervals (CrIs) were conducted. GRADE methodology was used to rate the certainty in findings. Main Outcomes and Measures: The primary outcome was all-cause mortality up to 90 days. A secondary outcome was endotracheal intubation up to 30 days. Results: Twenty-five randomized clinical trials (3804 participants) were included. Compared with standard oxygen, treatment with helmet noninvasive ventilation (RR, 0.40 [95% CrI, 0.24-0.63]; absolute risk difference, -0.19 [95% CrI, -0.37 to -0.09]; low certainty) and face mask noninvasive ventilation (RR, 0.83 [95% CrI, 0.68-0.99]; absolute risk difference, -0.06 [95% CrI, -0.15 to -0.01]; moderate certainty) were associated with a lower risk of mortality (21 studies [3370 patients]). Helmet noninvasive ventilation (RR, 0.26 [95% CrI, 0.14-0.46]; absolute risk difference, -0.32 [95% CrI, -0.60 to -0.16]; low certainty), face mask noninvasive ventilation (RR, 0.76 [95% CrI, 0.62-0.90]; absolute risk difference, -0.12 [95% CrI, -0.25 to -0.05]; moderate certainty) and high-flow nasal oxygen (RR, 0.76 [95% CrI, 0.55-0.99]; absolute risk difference, -0.11 [95% CrI, -0.27 to -0.01]; moderate certainty) were associated with lower risk of endotracheal intubation (25 studies [3804 patients]). The risk of bias due to lack of blinding for intubation was deemed high. Conclusions and Relevance: In this network meta-analysis of trials of adult patients with acute hypoxemic respiratory failure, treatment with noninvasive oxygenation strategies compared with standard oxygen therapy was associated with lower risk of death. Further research is needed to better understand the relative benefits of each strategy.

Causes of acute respiratory failure in the immunocompromised host.

PURPOSE OF REVIEW: A wide spectrum of heterogeneous conditions can render a patient immunocompromised. Recent years have seen an increase in the number of immunocompromised patients given the earlier detection of conditions that require immunosuppressive therapies, changes in immunosuppressive regimens leading to increased survival or novel therapeutic advancements in oncologic care. Acute respiratory failure (ARF) is the leading cause of critical illness and mortality in this population. This review highlights the spectrum of causes of ARF in immunocompromised patients with a particular focus on acute toxicities of novel oncologic treatments. RECENT FINDINGS: Recent years have seen improved survival amongst critically ill immunocompromised patients with ARF. This is likely attributable to patient selection of immunosuppressive therapy, improved noninvasive microbiologic diagnostic techniques, improved antimicrobial prophylaxis, treatment, stewardship, and advancements in supportive care including intensive care. Infectious complications remain the leading cause of ARF in this population. However, one of the greatest challenges physicians continue to face is accurate identification of the cause of ARF, given the vast (and increasing) noninfectious causes of ARF across these patients. Emerging therapies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell therapy (CAR T-cell) have contributed to this problem. Finally, undetermined ARF is reported in approximately 13% of immunocompromised and is associated with a worse prognosis. SUMMARY: Infectious complications are still the leading cause of ARF in immunocompromised patients. However, noninfectious complications, derived from the underlying disease or treatment, should be always considered, including novel therapies, such as ICIs and CAR T cells. Further research should focus in improving the diagnostic rate in this subgroup.

Outcomes of hematopoietic cell transplant recipients requiring invasive mechanical ventilation: a two-centre retrospective cohort study.

PURPOSE: Outcomes of critically ill, hematopoietic cell transplant patients who require prolonged mechanical ventilation are not well studied. We describe the baseline characteristics, critical care management, and outcomes of this population and explore potential predictors of mortality. METHODS: We performed a retrospective cohort study in two critical care units in Ontario. We included adult intensive care unit patients who required invasive mechanical ventilation within 90 days of receiving a hematopoietic cell transplant. The primary outcome was mortality at 90 days. Using logistic regression, we explored predictors of mortality including type of transplant (allogeneic vs autologous), severity of illness (assessed using the Sequential Organ Failure Assessment [SOFA] score), and baseline characteristics (such as age and sex). RESULTS: We included 70 patients from two study sites. Ninety-day mortality was 73% (n = 51) in the entire cohort, 58% (15/26) in patients post-autologous transplant, and 82% (36/44) in those post-allogeneic transplant. Ninety-one percent (10/11) of patients who required invasive mechanical ventilation for more than 21 days died. Independent predictors of all-cause mortality included allogeneic transplant, higher SOFA score, the presence of acute hypoxemic respiratory failure, and a longer interval between receiving the transplant and initiation of mechanical ventilation. CONCLUSIONS: Our study shows high rates of mortality among hematopoietic cell transplant recipients that require invasive mechanical ventilation, particularly in those post-allogeneic transplant and in those who require prolonged ventilation for more than 21 days.

Effect of angiotensin 2 receptor blockers on chronic obstructive lung disease mortality: A retrospective cohort study.

INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) is the fifth cause of mortality worldwide. Systemic inflammation is a crucial element in its physiopathology. As Renin-Angiotensin System is one of the main components of this inflammatory neurohumoral cascade, Angiotensin Receptor Blockers (ARBs) might have an effect on mortality in COPD patients. GOAL: To evaluate the association between ARBs treatment and mortality in COPD patients. METHODS: Retrospective cohort of patients with diagnosis of COPD from 2003 to 2013. COPD cases were detected according to the diagnosis by treating physicians in any field of the electronic clinical health records by controlled vocabulary in patients older than 18 years affiliated to the Hospital Italiano de Buenos Aires (HIBA) Health Plan. Patients were classified in two groups depending on their use of ARBs according to the hospital pharmacy records. The mortality registry of the HIBA was used to obtain the event of death. The 8 year survival experience was described using Kaplan Meier estimator and survival curve comparisons were calculated with the Cox Mantel test. Hazard Ratios (HR) were estimated using a Cox proportional risk model. A propensity score (PS) was developed for the use of ARBs. RESULTS: 1140 deaths were detected, 1063 in the no exposure group and 77 in the ARBs exposure group. The 8 year survival was 71% (CI 95% 69-72%). The survival in the non exposed group was 71% (CI 95% 69-73%) and 76% (CI 95% 0,69-0,81) in the ARBs exposed group. The unadjusted HR for mortality was 0.85 (CI 95% 0.67-1.07, p = 0.17) and the adjusted HR by PS was 0.63 (CI 95% 0.50-0.80, p < 0.001). DISCUSSION: ARBs use seems to be associated to a lower mortality in patients with COPD. Additional studies are needed to corroborate this finding.