Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA-2)

BACKGROUND: Nutritional support is crucial to the management of patients receiving invasive mechanical ventilation (IMV) and the most commonly prescribed treatment in intensive care units (ICUs). International guidelines consistently indicate that enteral nutrition (EN) should be preferred over parenteral nutrition (PN) whenever possible and started as early as possible. However, no adequately designed study has evaluated whether a specific nutritional modality is associated with decreased mortality. The primary goal of this trial is to assess the hypothesis that early first-line EN, as compared to early first-line PN, decreases day 28 all-cause mortality in patients receiving IMV and vasoactive drugs for shock. METHODS/DESIGN: The NUTRIREA-2 study is a multicenter, open-label, parallel-group, randomized controlled trial comparing early PN versus early EN in critically ill patients requiring IMV for an expected duration of at least 48 hours, combined with vasoactive drugs, for shock. Patients will be allocated at random to first-line PN for at least 72 hours or to first-line EN. In both groups, nutritional support will be started within 24 hours after IMV initiation. Calorie targets will be 20 to 25 kcal/kg/day during the first week, then 25 to 30 kcal/kg/day thereafter. Patients receiving PN may be switched to EN after at least 72 hours in the event of shock resolution (no vasoactive drugs for 24 consecutive hours and arterial lactic acid level below 2 mmol/L). On day 7, all patients receiving PN and having no contraindications to EN will be switched to EN. In both groups, supplemental PN may be added to EN after day 7 in patients with persistent intolerance to EN and inadequate calorie intake. We plan to recruit 2,854 patients at 44 participating ICUs. DISCUSSION: The NUTRIREA-2 study is the first large randomized controlled trial designed to assess the hypothesis that early EN improves survival compared to early PN in ICU patients. Enrollment started on 22 March 2013 and is expected to end in November 2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01802099 (registered 27 February 2013)

Effect of acetazolamide vs placebo on duration of invasive mechanical ventilation among patients with chronic obstructive pulmonary disease: A randomized clinical trial

International audienceImportance  Acetazolamide has been used for decades as a respiratory stimulant for patients with chronic obstructive pulmonary disease (COPD) and metabolic alkalosis, but no large randomized placebo-controlled trial is available to confirm this approach.Objective To determine whether acetazolamide reduces mechanical ventilation duration in critically ill patients with COPD and metabolic alkalosis.Design, Setting, and Participants The DIABOLO study, a randomized, double-blind, multicenter trial, was conducted from October 2011 through July 2014 in 15 intensive care units (ICUs) in France. A total of 382 patients with COPD who were expected to receive mechanical ventilation for more 24 hours were randomized to the acetazolamide or placebo group and 380 were included in an intention-to treat analysis.Interventions Acetazolamide (500-1000 mg, twice daily) vs placebo administered intravenously in cases of pure or mixed metabolic alkalosis, initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days.Main Outcomes and Measures The primary outcome was the duration of invasive mechanical ventilation via endotracheal intubation or tracheotomy. Secondary outcomes included changes in arterial blood gas and respiratory parameters, weaning duration, adverse events, use of noninvasive ventilation after extubation, successful weaning, the duration of ICU stay, and in-ICU mortality.Results Among 382 randomized patients, 380 (mean age, 69 years; 272 men [71.6%]; 379 [99.7%] with endotracheal intubation) completed the study. For the acetazolamide group (n = 187), compared with the placebo group (n = 193), no significant between-group differences were found for median duration of mechanical ventilation (−16.0 hours; 95% CI, −36.5 to 4.0 hours; P = .17), duration of weaning off mechanical ventilation (−0.9 hours; 95% CI, −4.3 to 1.3 hours; P = .36), daily changes of minute-ventilation (−0.0 L/min; 95% CI, −0.2 to 0.2 L/min; P = .72), or partial carbon-dioxide pressure in arterial blood (−0.3 mm Hg; 95% CI, −0.8 to 0.2 mm Hg; P = .25), although daily changes of serum bicarbonate (between-group difference, −0.8 mEq/L; 95% CI, −1.2 to −0.5 mEq/L; P \textless .001) and number of days with metabolic alkalosis (between-group difference, −1; 95% CI, −2 to −1 days; P \textless .001) decreased significantly more in the acetazolamide group. Other secondary outcomes also did not differ significantly between groups.Conclusions and Relevance Among patients with COPD receiving invasive mechanical ventilation, the use of acetazolamide, compared with placebo, did not result in a statistically significant reduction in the duration of invasive mechanical ventilation. However, the magnitude of the difference was clinically important, and it is possible that the study was underpowered to establish statistical significance.Trial Registration clinicaltrials.gov Identifier: NCT0162763

Impact on 6-month outcomes of hospital trajectory in critically ill older patients: analysis of the ICE-CUB2 clinical trial

International audienceAbstract Background Little is known about the impact of hospital trajectory on survival and functional decline of older critically ill patients. We evaluate 6-month outcomes after admission to: intensive care units (ICU), intermediate care units (IMCU) or acute medical wards (AMW). Methods Data from the randomised prospective multicentre clinical trial ICE-CUB2 was secondarily analysed. Inclusion criteria were: presenting at emergency departments in critical condition; age ≥ 75 years; activity of daily living (ADL) ≥ 4; preserved nutritional status; and no active cancer. A Cox model was fitted to compare survival according to admission destination adjusting for patient characteristics. Sensitivity analysis using multiple imputation for missing data and propensity score matching were performed. Results Among 3036 patients, 1675 (55%) were women; median age was 85 [81–99] years; simplified acute physiology score (SAPS-3) 62 [55–69]; 1448 (47%) were hospitalised in an ICU, 504 in IMCU (17%), and 1084 (36%) in AMW. Six-month mortality was 629 (44%), 155 (31%) and 489 (45%) after admission in an ICU, IMCU and AMW ( p < 0.001), respectively. In multivariate analysis, AMW admission was associated with worse 6-month survival (HR 1.31, 95% CI 1.04–1.63) in comparison with IMCU admission, after adjusting for age, gender, comorbidities, ADL, SAPS-3 and diagnosis. Survival was not significantly different between patients admitted in an ICU and an IMCU (HR 1.17, 95% CI 0.95–1.46). Sensitivity analysis using multiple imputation for missing data and propensity score matching found similar results. Hospital destination was not significantly associated with the composite criterion loss of 1-point ADL or mortality. Physical and mental components of the 12-Item Short-Form Health Survey were significantly lower in the acute medical ward group (34.3 [27.5–41.7], p = 0.037 and 44.3 [38.6–48.6], p = 0.028, respectively) than in the ICU group (34.7 [28.4–45.3] and 45.5 [40.0–50.0], respectively) and IMCU group (35.7 [29.7–43.8] and 44.5 [39.7–48.4], respectively). Conclusions Admission in an AMW was associated with worse 6-month survival in older critically ill patients in comparison with IMCU admission, with no difference of survival between ICU and IMCU admission. There were no clinically relevant differences in quality of life in each group. These results should be confirmed in specific studies and raise the question of dedicated geriatric IMCUs

Impact on 6-month outcomes of hospital trajectory in critically ill older patients: analysis of the ICE-CUB2 clinical trial

International audienceAbstract Background Little is known about the impact of hospital trajectory on survival and functional decline of older critically ill patients. We evaluate 6-month outcomes after admission to: intensive care units (ICU), intermediate care units (IMCU) or acute medical wards (AMW). Methods Data from the randomised prospective multicentre clinical trial ICE-CUB2 was secondarily analysed. Inclusion criteria were: presenting at emergency departments in critical condition; age ≥ 75 years; activity of daily living (ADL) ≥ 4; preserved nutritional status; and no active cancer. A Cox model was fitted to compare survival according to admission destination adjusting for patient characteristics. Sensitivity analysis using multiple imputation for missing data and propensity score matching were performed. Results Among 3036 patients, 1675 (55%) were women; median age was 85 [81–99] years; simplified acute physiology score (SAPS-3) 62 [55–69]; 1448 (47%) were hospitalised in an ICU, 504 in IMCU (17%), and 1084 (36%) in AMW. Six-month mortality was 629 (44%), 155 (31%) and 489 (45%) after admission in an ICU, IMCU and AMW ( p < 0.001), respectively. In multivariate analysis, AMW admission was associated with worse 6-month survival (HR 1.31, 95% CI 1.04–1.63) in comparison with IMCU admission, after adjusting for age, gender, comorbidities, ADL, SAPS-3 and diagnosis. Survival was not significantly different between patients admitted in an ICU and an IMCU (HR 1.17, 95% CI 0.95–1.46). Sensitivity analysis using multiple imputation for missing data and propensity score matching found similar results. Hospital destination was not significantly associated with the composite criterion loss of 1-point ADL or mortality. Physical and mental components of the 12-Item Short-Form Health Survey were significantly lower in the acute medical ward group (34.3 [27.5–41.7], p = 0.037 and 44.3 [38.6–48.6], p = 0.028, respectively) than in the ICU group (34.7 [28.4–45.3] and 45.5 [40.0–50.0], respectively) and IMCU group (35.7 [29.7–43.8] and 44.5 [39.7–48.4], respectively). Conclusions Admission in an AMW was associated with worse 6-month survival in older critically ill patients in comparison with IMCU admission, with no difference of survival between ICU and IMCU admission. There were no clinically relevant differences in quality of life in each group. These results should be confirmed in specific studies and raise the question of dedicated geriatric IMCUs

Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial

International audienceEpidemiologic studies have documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). We assessed the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia

Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial

International audienceBackground: Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock.Methods: APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 μg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209).Findings: Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction).Interpretation: In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup.Funding: Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004

Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia The ANTICOVID Randomized Clinical Trial

International audienceImportance Given the high risk of thrombosis and anticoagulation-related bleeding in patients with hypoxemic COVID-19 pneumonia, identifying the lowest effective dose of anticoagulation therapy for these patients is imperative. OBJECTIVES To determine whether therapeutic anticoagulation (TA) or high-dose prophylactic anticoagulation (HD-PA) decreases mortality and/or disease duration compared with standard-dose prophylactic anticoagulation (SD-PA), and whether TA outperforms HD-PA; and to compare the net clinical outcomes among the 3 strategies. DESIGN, SETTINGS, AND PARTICIPANTS The ANTICOVID randomized clinical open-label trial included patients with hypoxemic COVID-19 pneumonia requiring supplemental oxygen and having no initial thrombosis on chest computer tomography with pulmonary angiogram at 23 health centers in France from April 14 to December 13, 2021. Of 339 patients randomized, 334 were included in the primary analysis-114 patients in the SD-PA group, 110 in the HD-PA, and 110 in the TA. At randomization, 90% of the patients were in the intensive care unit. Data analyses were performed from April 13, 2022, to January 3, 2023. INTERVENTIONS Patients were randomly assigned (1:1:1) to receive either SD-PA, HD-PA, or TA with low-molecular-weight or unfractionated heparin for 14 days. MAIN OUTCOMES AND MEASURES A hierarchical criterion of all-cause mortality followed by time to clinical improvement at day 28. Main secondary outcome was net clinical outcome at day 28 (composite of thrombosis, major bleeding, and all-cause death). RESULTS Among the study population of 334 individuals (mean [SD] age, 58.3 [13.0] years; 226 [67.7%] men and 108 [32.3%] women), use of HD-PA and SD-PA had similar probabilities of favorable outcome (47.3% [95%CI, 39.9% to 54.8%] vs 52.7%[95%CI, 45.2%to 60.1%]; P = .48), as did TA compared with SD-PA (50.9% [95%CI, 43.4%to 58.3%] vs 49.1% [95%CI, 41.7%to 56.6%]; P = .82) and TA compared with HD-PA (53.5%[95%CI 45.8% to 60.9%] vs 46.5% [95%CI, 39.1% to 54.2%]; P = .37). Net clinical outcome was met in 29.8% of patients receiving SD-PA (20.2%thrombosis, 2.6%bleeding, 14.0% death), 16.4% receiving HD-PA (5.5%thrombosis, 3.6%bleeding, 11.8%death), and 20.0% receiving TA (5.5% thrombosis, 3.6% bleeding, 12.7%death). Moreover, HD-PA and TA use significantly reduced thrombosis compared with SD-PA (absolute difference, -14.7 [95%CI -6.2 to -23.2] and -14.7 [95%CI -6.2 to -23.2], respectively). Use of HD-PA significantly reduced net clinical outcome compared with SD-PA (absolute difference, -13.5; 95%CI -2.6 to -24.3). CONCLUSIONS AND RELEVANCE This randomized clinical trial found that compared with SD-PA, neither HD-PAnor TAuse improved the primary hierarchical outcome of all-cause mortality or time to clinical improvement in patients with hypoxemicCOVID-19 pneumonia; however, HD-PA resulted in significantly better net clinical outcome by decreasing the risk of de novo thrombosis

Effects of Standard-Dose Prophylactic, High-Dose Prophylactic, and Therapeutic Anticoagulation in Patients With Hypoxemic COVID-19 Pneumonia The ANTICOVID Randomized Clinical Trial

International audienceIMPORTANCE Given the high risk of thrombosis and anticoagulation-related bleeding in patients with hypoxemic COVID-19 pneumonia, identifying the lowest effective dose of anticoagulation therapy for these patients is imperative. OBJECTIVES To determine whether therapeutic anticoagulation (TA) or high-dose prophylactic anticoagulation (HD-PA) decreases mortality and/or disease duration compared with standard-dose prophylactic anticoagulation (SD-PA), and whether TA outperforms HD-PA; and to compare the net clinical outcomes among the 3 strategies. DESIGN, SETTINGS, AND PARTICIPANTS The ANTICOVID randomized clinical open-label trial included patients with hypoxemic COVID-19 pneumonia requiring supplemental oxygen and having no initial thrombosis on chest computer tomography with pulmonary angiogram at 23 health centers in France from April 14 to December 13, 2021. Of 339 patients randomized, 334 were included in the primary analysis-114 patients in the SD-PA group, 110 in the HD-PA, and 110 in the TA. At randomization, 90% of the patients were in the intensive care unit. Data analyses were performed from April 13, 2022, to January 3, 2023. INTERVENTIONS Patients were randomly assigned (1:1:1) to receive either SD-PA, HD-PA, or TA with low-molecular-weight or unfractionated heparin for 14 days. MAIN OUTCOMES AND MEASURES A hierarchical criterion of all-cause mortality followed by time to clinical improvement at day 28. Main secondary outcome was net clinical outcome at day 28 (composite of thrombosis, major bleeding, and all-cause death). RESULTS Among the study population of 334 individuals (mean [SD] age, 58.3 [13.0] years; 226 [67.7%] men and 108 [32.3%] women), use of HD-PA and SD-PA had similar probabilities of favorable outcome (47.3% [95%CI, 39.9% to 54.8%] vs 52.7%[95%CI, 45.2%to 60.1%]; P = .48), as did TA compared with SD-PA (50.9% [95%CI, 43.4%to 58.3%] vs 49.1% [95%CI, 41.7%to 56.6%]; P = .82) and TA compared with HD-PA (53.5%[95%CI 45.8% to 60.9%] vs 46.5% [95%CI, 39.1% to 54.2%]; P = .37). Net clinical outcome was met in 29.8% of patients receiving SD-PA (20.2%thrombosis, 2.6%bleeding, 14.0% death), 16.4% receiving HD-PA (5.5%thrombosis, 3.6%bleeding, 11.8%death), and 20.0% receiving TA (5.5% thrombosis, 3.6% bleeding, 12.7%death). Moreover, HD-PA and TA use significantly reduced thrombosis compared with SD-PA (absolute difference, -14.7 [95%CI -6.2 to -23.2] and -14.7 [95%CI -6.2 to -23.2], respectively). Use of HD-PA significantly reduced net clinical outcome compared with SD-PA (absolute difference, -13.5; 95%CI -2.6 to -24.3). CONCLUSIONS AND RELEVANCE This randomized clinical trial found that compared with SD-PA, neither HD-PAnor TAuse improved the primary hierarchical outcome of all-cause mortality or time to clinical improvement in patients with hypoxemicCOVID-19 pneumonia; however, HD-PA resulted in significantly better net clinical outcome by decreasing the risk of de novo thrombosis

Relationship between the Clinical Frailty Scale and short-term mortality in patients ≥ 80 years old acutely admitted to the ICU: a prospective cohort study

Background: The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. Methods: We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient’s age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. Results: The median age in the sample of 7487 consecutive patients was 84 years (IQR 81–87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p < 0.001). The relationship between the CFS score and mortality was nonlinear (p < 0.01). Conclusion: Knowledge about a patient’s frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2