A three-step support strategy for relatives of patients dying in the intensive care unit: a cluster randomised trial.

BACKGROUND: In relatives of patients dying in intensive care units (ICUs), inadequate team support can increase the prevalence of prolonged grief and other psychological harm. We aimed to evaluate whether a proactive communication and support intervention would improve relatives' outcomes. METHODS: We undertook a prospective, multicentre, cluster randomised controlled trial in 34 ICUs in France, to compare standard care with a physician-driven, nurse-aided, three-step support strategy for families throughout the dying process, following a decision to withdraw or withhold life support. Inclusion criteria were relatives of patients older than 18 years with an ICU length of stay 2 days or longer. Participating ICUs were randomly assigned (1:1 ratio) into an intervention cluster and a control cluster. The randomisation scheme was generated centrally by a statistician not otherwise involved in the study, using permutation blocks of non-released size. In the intervention group, three meetings were held with relatives: a family conference to prepare the relatives for the imminent death, an ICU-room visit to provide active support, and a meeting after the patient's death to offer condolences and closure. ICUs randomly assigned to the control group applied their best standard of care in terms of support and communication with relatives of dying patients. The primary endpoint was the proportion of relatives with prolonged grief (measured with PG-13, score ≥30) 6 months after the death. Analysis was by intention to treat, with the bereaved relatives as the unit of observation. The study is registered with ClinicalTrials.gov, NCT02955992. FINDINGS: Between Feb 23, 2017, and Oct 8, 2019, we enrolled 484 relatives of ICU patients to the intervention group and 391 to the control group. 379 (78%) relatives in the intervention group and 309 (79%) in the control group completed the 6-month interview to measure the primary endpoint. The intervention significantly reduced the number of relatives with prolonged grief symptoms (66 [21%] vs 57 [15%]; p=0·035) and the median PG-13 score was significantly lower in the intervention group than in the control group (19 [IQR 14-26] vs 21 [15-29], mean difference 2·5, 95% CI 1·04-3·95). INTERPRETATION: Among relatives of patients dying in the ICU, a physician-driven, nurse-aided, three-step support strategy significantly reduced prolonged grief symptoms. FUNDING: French Ministry of Health.

Antibiotic Therapy in Comatose Mechanically Ventilated Patients Following Aspiration: Differentiating Pneumonia From Pneumonitis.

OBJECTIVES: To determine the proportion of patients with documented bacterial aspiration pneumonia among comatose ICU patients with symptoms suggesting either bacterial aspiration pneumonia or non-bacterial aspiration pneumonitis. DESIGN: Prospective observational study. SETTING: University-affiliated 30-bed ICU. PATIENTS: Prospective cohort of 250 patients admitted to the ICU with coma (Glasgow Coma Scale score ≤ 8) and treated with invasive mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the proportion of patients with microbiologically documented bacterial aspiration pneumonia. Patients meeting predefined criteria for aspiration syndrome routinely underwent telescopic plugged catheter sampling during bronchoscopy before starting probabilistic antibiotic treatment. When cultures were negative, the antibiotic treatment was stopped. Of 250 included patients, 98 (39.2%) had aspiration syndrome, including 92 before mechanical ventilation discontinuation. Telescopic plugged catheter in these 92 patients showed bacterial aspiration pneumonia in 43 patients (46.7%). Among the remaining 49 patients, 16 continued to receive antibiotics, usually for infections other than pneumonia; of the 33 patients whose antibiotics were discontinued, only two subsequently showed signs of lung infection. In the six patients with aspiration syndrome after mechanical ventilation, and therefore without telescopic plugged catheter, antibiotic treatment was continued for 7 days. Mechanical ventilation duration, ICU length of stay, and mortality did not differ between the 43 patients with bacterial aspiration pneumonia and the 49 patients with non-bacterial aspiration pneumonitis. The 152 patients without aspiration syndrome did not receive antibiotics. CONCLUSIONS: Among comatose patients receiving mechanical ventilation, those without clinical, laboratory, or radiologic evidence of bacterial aspiration pneumonia did not require antibiotics. In those with suspected bacterial aspiration pneumonia, stopping empirical antibiotic therapy when routine telescopic plugged catheter sampling recovered no microorganisms was nearly always effective. This strategy may be a valid alternative to routine full-course antibiotic therapy. Only half the patients with suspected bacterial aspiration pneumonia had this diagnosis confirmed by telescopic plugged catheter sampling.

Insulin therapy and blood glucose management in critically ill patients: a 1-day cross-sectional observational study in 69 French intensive care units.

BACKGROUND: Hyperglycaemia is common in critically ill patients, but blood glucose and insulin management may differ widely among intensive care units (ICUs). We aimed to describe insulin use practices and the resulting glycaemic control in French ICUs. We conducted a multicentre 1-day observational study on November 23, 2021, in 69 French ICUs. Adult patients hospitalized for an acute organ failure, severe infection or post-operative care were included. Data were recorded from midnight to 11:59 p.m. the day of the study by 4-h periods. RESULTS: Two ICUs declared to have no insulin protocol. There was a wide disparity in blood glucose targets between ICUs with 35 different target ranges recorded. In 893 included patients we collected 4823 blood glucose values whose distribution varied significantly across ICUs (P < 0.0001). We observed 1135 hyperglycaemias (> 1.8 g/L) in 402 (45.0%) patients, 35 hypoglycaemias (≤ 0.7 g/L) in 26 (2.9%) patients, and one instance of severe hypoglycaemia (≤ 0.4 g/L). Four hundred eight (45.7%) patients received either IV insulin (255 [62.5%]), subcutaneous (SC) insulin (126 [30.9%]), or both (27 [6.6%]). Among patients under protocolized intravenous (IV) insulin, 767/1681 (45.6%) of glycaemias were above the target range. Among patients receiving insulin, short- and long-acting SC insulin use were associated with higher counts of hyperglycaemias as assessed by multivariable negative binomial regression adjusted for the propensity to receive SC insulin: incidence rate ratio of 3.45 (95% confidence interval [CI] 2.97-4.00) (P < 0.0001) and 3.58 (95% CI 2.84-4.52) (P < 0.0001), respectively. CONCLUSIONS: Practices regarding blood glucose management varied widely among French ICUs. Administration of short or long-acting SC insulin was not unusual and associated with more frequent hyperglycaemia. The protocolized insulin algorithms used failed to prevent hyperglycaemic events.

Efficacy and safety of human soluble thrombomodulin (ART-123) for treatment of patients in France with sepsis-associated coagulopathy: post hoc analysis of SCARLET.

BACKGROUND: The phase 3 multinational SCARLET study evaluated the efficacy and safety of a recombinant human soluble thrombomodulin (ART-123) for treatment of sepsis-associated coagulopathy (SAC), which correlates with increased mortality risk in patients with sepsis. Although no significant reduction in mortality was observed with ART-123 compared with placebo in the full analysis set (FAS), an efficacy signal of ART-123 was observed in subgroups of patients who sustained coagulopathy until the first treatment and those not administered concomitant heparin. Post hoc analysis was performed of patients treated in France, the country with the largest enrollment (19% of the FAS) and consistent patient enrollment throughout the study duration. METHODS: Adult patients with SAC (international normalized ratio > 1.4; platelets > 30 × 109/L to < 150 × 109/L or platelet decrease > 30% within 24 h) and evidence of bacterial infection were included. The primary efficacy outcome was 28-day all-cause mortality. Safety outcomes included adverse, serious adverse, and major bleeding events. This analysis assessed patient characteristics and efficacy and safety outcomes in France compared with the rest of the world (ROW; excluding France). Mortality rates were assessed in patients in France or the ROW with characteristics previously associated with ART-123 efficacy. RESULTS: Baseline characteristics were similar between France and the ROW, but some measurements of disease severity were higher in patients in France. The 28-day all-cause mortality absolute risk reductions (ARRs) with ART-123 were 8.3% in France and 1.1% in the ROW. The greater ARR in France may be related to a higher rate of sustained coagulopathy and lower rate of heparin use. In France and the ROW, 84.6% and 78.0% of patients sustained coagulopathy from the time of initial SAC diagnosis to first treatment with the study drug, and 65.8% and 43.9% did not receive heparin, respectively. The ARRs for these subgroups of patients in France were 13.4% and 16.6%, respectively. Safety of ART-123 was comparable between France and the ROW. CONCLUSIONS: Results from this exploratory analysis suggest that patients with sustained SAC not receiving concomitant heparin may benefit from ART-123, a fact that should be confirmed in future studies with more restrictive inclusion criteria.

Nutrition During Targeted Temperature Management After Cardiac Arrest: Observational Study of Neurological Outcomes and Nutrition Tolerance.

BACKGROUND: Whether providing nutrition support is beneficial or deleterious during targeted temperature management (TTM) after cardiac arrest is unclear. We therefore performed a retrospective observational study to determine whether early nutrition was beneficial or deleterious during TTM. METHODS: We retrospectively studied patients admitted to our intensive care unit (ICU) between 2008 and 2014 after successfully resuscitated cardiac arrest. We compared the group given nutrition within 48 hours after ICU admission (E+ group) to the group given nutrition later on or not at all (E- group). RESULTS: Of the 203 included patients, 143 were in the E+ group and 60 in the E- group. The E+ group had a significantly higher proportion of patients with a good 3-month neurological outcome (42.7% vs 16.7%, P < 0.001). The difference remained significant after adjustment on a propensity score (odds ratio, 3.47; 95% confidence interval, 1.48-8.14; P = 0.004). The cumulative energy deficit for an energy goal of 20 kcal/kg/d from admission to day 7 was significantly lower in the E+ group (3304 ± 2863 kcal vs 5017 ± 2655 kcal, P < 0.001). Within the E+ group, the subgroups with nutrition initiation when body temperature was <36°C vs ≥36°C were not significantly different regarding the frequencies of early-onset pneumonia, ventilator-associated pneumonia, vomiting, and prokinetic drug use (all P-values > 0.05). CONCLUSIONS: Early nutrition after cardiac arrest during TTM appears safe and may be associated with better neurological outcomes. These findings warrant a randomized controlled trial to resolve the remaining issues.

Patient-related factors and circumstances surrounding decisions to forego life-sustaining treatment, including intensive care unit admission refusal.

OBJECTIVE: To assess decisions to forego life-sustaining treatment (LST) in patients too sick for intensive care unit (ICU) admission, comparatively to patients admitted to the ICU. DESIGN: Prospective observational cohort study. SETTING: A medical-surgical ICU. PATIENTS: Consecutive patients referred to the ICU during a one-yr period. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Of 898 triaged patients, 147 were deemed too well to benefit from ICU admission. Decisions to forego LST were made in 148 of 666 (22.2%) admitted patients and in all 85 patients deemed too sick for ICU admission. Independent predictors of decisions to forego LST at ICU refusal rather than after ICU admission were: age; underlying disease; living in an institution; preexisting cognitive impairment; admission for medical reasons; and acute cardiac failure, acute central neurologic illness, or sepsis. Hospital mortality after decisions to forego LST was not significantly different in refused and admitted patients (77.5% vs. 86.5%; p = .1). Decisions to forego LST were made via telephone in 58.8% of refused patients and none of the admitted patients. Nurses caring for the patient had no direct contact with the ICU physicians for 62.3% of the decisions in refused patients, whereas meetings between nurses and physicians occurred in 70.3% of decisions to forego LST in the ICU. Patients or relatives were involved in 28.2% of decisions to forego LST at ICU refusal compared with 78.4% of decisions to forego LST in ICU patients (p < .001). CONCLUSIONS: All patients deemed too sick for ICU admission had decisions to forego LST. These decisions were made without direct patient examination in two-thirds of refused patients (vs. none of admitted patients) and were associated with less involvement of nurses and relatives compared with decisions in admitted patients. Further work is needed to improve decisions to forego LST made under the distinctive circumstances of triage.

Safety and tolerability of a single administration of AR-301, a human monoclonal antibody, in ICU patients with severe pneumonia caused by Staphylococcus aureus: first-in-human trial.

PURPOSE: Hospital-acquired bacterial pneumonia (HABP) is a critical concern in hospitals with ventilator-associated bacterial pneumonia (VABP) remaining the most common infection in the ICU, often due to Staphylococcus aureus, an increasingly difficult to treat pathogen. Anti-infective monoclonal antibodies (mAb) may provide new, promising treatment options. This randomized, double-blinded, placebo-controlled study aimed at assessing the safety and pharmacokinetics of AR-301, an S. aureus alpha toxin-neutralizing mAb, and exploring its clinical and microbiologic outcomes when used adjunctively with standard-of-care antibiotics. METHODS: Eligibility in this trial required microbiologically confirmed severe S. aureus pneumonia, including HABP, VABP or CABP, treated in the ICU and an APACHE II score ≤ 30. Standard-of-care antibiotics selected by the investigators were administered to all patients in the study following clinical and microbiologic confirmation of S. aureus pneumonia. Adjunctive treatment of AR-301 was to start < 36 h after onset of severe pneumonia. AR-301 was administered to four sequentially ascending dose cohorts. The placebo cohort received antibiotics and a placebo buffer. Clinical outcomes were adjudicated by a blinded committee. S. aureus eradication was declared based on a negative follow-up culture and presumed to be negative when no culture was obtained in the presence of clinical improvement. RESULTS: Thirteen ICUs enrolled 48 patients, with pneumonia attributable to MRSA in six subjects. The study drug displayed a favorable safety profile: Of 343 AEs reported, 8 (2.3%) were deemed related, none serious. In a post hoc subgroup analysis of VABP patients receiving AR-301, ventilation duration was shorter for AR-301-treated patients compared with the placebo group. Overall, there was a trend toward a better and faster microbiologic eradication at day 28. The PK profile of AR-301 is consistent with that of a human IgG1 mAb, with a plasma half-life of about 25 days. CONCLUSIONS: Adjunctive treatment of severe S. aureus HABP with anti-staphylococcal mAbs appears feasible and suggests some clinical benefits, but larger randomized studies are needed to better define its safety and efficacy.

Short-term effects of prone position in chronic obstructive pulmonary disease patients with severe acute hypoxemic and hypercapnic respiratory failure.

OBJECTIVE: To assess the short-term effects of prone positioning (PP) in chronic obstructive pulmonary disease (COPD) patients with severe hypoxemic and hypercapnic respiratory failure requiring invasive mechanical ventilation. DESIGN AND SETTING: Prospective observational study in the general intensive care unit of a university-affiliated hospital. PATIENTS: 11 consecutive COPD patients with persistent hypoxemia (PaO2/FIO2 < or = 200 mmHg with FIO2 > or = 0.6) and hypercapnia requiring invasive mechanical ventilation. Patients with adult respiratory distress syndrome or left ventricular failure were excluded. Mean age was 73+/-11 years, mean weight 86+/-31 kg, mean SAPS II 53+/-10, and ICU mortality 36%. INTERVENTIONS: Patients were turned every 6 h. MEASUREMENTS AND RESULTS: A response to PP (20% or greater PaO2/FIO2 increase) was noted in 9 (83%) patients. Blood gases were measured in the PP and supine (SP) positions 3 h after each turn, for 36 h, yielding six measurement sets (SP1, PP1, SP2, PP2, SP3, and PP3). PaO2/FIO2 was significantly better in PP: 190+/-26 vs. 113+/-9 mmHg for PP1/SP1, 175+/-22 vs. 135+/-16 mmHg for PP2/SP2, and 199+/-24 vs. 151+/-13 mmHg for PP3/SP3. After PP1 PaO2/FIO2 remained significantly improved, and the PaO2/FIO2 improvement from SP1 to SP2 was linearly related to PaO2/FIO2 during PP1 (r=0.8). The tracheal aspirate volume improved significantly from SP1 to PP1. PaCO2 was not significantly affected by position. CONCLUSIONS: PP was effective in treating severe hypoxemia in COPD patients. The first turn in PP was associated with increased tracheal aspirate.

Neuromuscular blockade during therapeutic hypothermia after cardiac arrest: observational study of neurological and infectious outcomes.

INTRODUCTION: Neuromuscular blockade (NMB) is widely used during therapeutic hypothermia (TH) after cardiac arrest but its effect on patient outcomes is unclear. We compared the effects of NMB on neurological outcomes and frequency of early-onset pneumonia in cardiac-arrest survivors managed with TH. METHODS: We retrospectively studied consecutive adult cardiac-arrest survivors managed with TH in a tertiary-level intensive care unit between January 2008 and July 2013. Patients given continuous NMB for persistent shivering were compared to those managed without NMB. Cases of early-onset pneumonia and vital status at ICU discharge were recorded. To avoid bias due to between-group baseline differences, we adjusted the analysis on a propensity score. RESULTS: Of 311 cardiac-arrest survivors, 144 received TH, including 117 with continuous NMB and 27 without NMBs. ICU mortality was lower with NMB (hazard ratio [HR], 0.54 [0.32; 0.89], p=0.016) but the difference was not significant after adjustment on the propensity score (HR, 0.70 [0.39; 1.25], p=0.22). The proportion of patients with good neurological outcomes was not significantly different (36% with and 22% without NMB, p=0.16). Early-onset pneumonia was more common with NMB (HR, 2.36 [1.24; 4.50], p=0.009) but the difference was not significant after adjustment on the propensity score (HR, 1.68 [0.90; 3.16], p=0.10). CONCLUSIONS: Continuous intravenous NMB during TH after cardiac arrest has potential owns effects on ICU survival with a trend increase in the frequency of early-onset pneumonia. Randomised controlled trials are needed to define the role for NMB among treatments for TH-induced shivering.

Impact of not measuring residual gastric volume in mechanically ventilated patients receiving early enteral feeding: a prospective before-after study.

BACKGROUND: Monitoring of residual gastric volume (RGV) to prevent aspiration is standard practice in mechanically ventilated patients receiving early enteral nutrition (EN). No data are available to support a correlation between RGV and adverse event rates. We evaluated whether not measuring RGV affected EN delivery, vomiting, or risk of nosocomial pneumonia. METHODS: Two hundred and five eligible patients with nasogastric feeding within 48 hours after intubation were included in a 7-day prospective before-after study. Continuous 24-hour nutrition was started at 25 mL/h then increased by 25 mL/h every 6 hours, to 85 mL/h. In both groups, intolerance was treated with erythromycin (250 mg IV/6 h) and a delivery rate decrease to the previously well-tolerated rate. RGV monitoring was used during the first study period (n = 102), but not during the subsequent intervention period (n = 103). Intolerance was defined as RGV >250 mL/6 h or vomiting in the standard-practice group and as vomiting in the intervention group. RESULTS: Groups were similar for baseline characteristics. Median daily volume of enteral feeding was higher in the intervention group (1489; interquartile range [IQR], 1349-1647) than in the controls (1381; IQR, 1151-1591; P = .002). Intolerance occurred in 47 (46.1%) controls and 27 (26.2%) intervention patients (P = .004). The vomiting rate did not differ between controls and intervention group patients (24.5% vs 26.2%, respectively; P = .34), and neither was a difference found for ventilator-associated pneumonia (19.6% vs 18.4%; P = .86). CONCLUSION: Early EN without RGV monitoring in mechanically ventilated patients improves the delivery of enteral feeding and may not increase vomiting or ventilator-associated pneumonia.

Before-after study of a standardized ICU protocol for early enteral feeding in patients turned in the prone position.

BACKGROUNDS & AIMS: To evaluate an intervention for improving the delivery of early enteral nutrition (EN) in patients receiving mechanical ventilation with prone positioning (PP). METHODS: Eligible patients receiving EN and mechanical ventilation in PP were included within 48h after intubation in a before-after study. Patients were semi-recumbent when supine. Intolerance to EN was defined as residual gastric volume greater than 250ml/6h or vomiting. In the before group (n=34), the EN rate was increased by 500ml every 24h up to 2000ml/24h; patients were flat when prone and received erythromycin (250mgIV/6h) to treat intolerance. In the intervention group (n=38), the EN rate was increased by 25ml/h every 6h to 85ml/h, 25 degrees head elevation was used in PP, and prophylactic erythromycin was started at the first turn. RESULTS: Compared to the before group, larger feeding volumes were delivered in the intervention group (median volume per day with PP, 774ml [IQR 513-925] vs. 1170ml [IQR 736-1417]; P<0.001) without increases in residual gastric volume, vomiting, or ventilator-associated pneumonia. CONCLUSION: An intervention including PP with 25 degrees elevation, an increased acceleration to target rate of EN, and erythromycin improved EN delivery.

Early enteral nutrition in mechanically ventilated patients in the prone position.

OBJECTIVE: To assess the tolerance of early enteral nutrition in critically ill patients receiving invasive mechanical ventilation in the prone position. DESIGN: Prospective, comparative study. SETTING: General intensive care unit in a university-affiliated hospital. PATIENTS: A total of 71 consecutive patients receiving invasive mechanical ventilation with early nasogastric enteral nutrition were studied for 5 days while being treated continuously in the supine position (supine position group, n = 37) or with intermittent prone positioning for severe hypoxemia (prone position group, n = 34). INTERVENTIONS: Inclusion occurred within 24 hrs of mechanical ventilation initiation. Daily 18-hr enteral nutrition via a 14F gastric tube was initiated. Prone position patients were turned every 6 hrs as long as PaO2/FiO2 remained at <150, with a FiO2 of 0.6 and positive end-expiratory pressure of 10; the head was slightly elevated. When supine, patients in both groups were semirecumbent. Residual gastric volume was measured every 6 hrs, and enteral nutrition was discontinued if it exceeded 250 mL or vomiting occurred. MEASUREMENTS AND MAIN RESULTS: The groups were similar for age, sex, Simplified Acute Physiology Score II, mortality, and risk factors for enteral nutrition intolerance. At baseline, PaO2/FiO2 was lower in prone position patients than in supine position patients (127 +/- 55 vs. 228 +/- 102; p <.001). As compared with supine position patients, prone position patients had significantly greater residual gastric volumes on days 1, 2, and 4 and experienced more vomiting episodes (median, 1 [interquartile range, 0-2] vs. 0 [interquartile range, 0-1]; p <.05). Enteral nutrition was stopped in 82% of prone position patients and 49% of supine position patients (p <.01) so that daily enteral nutrition volumes were lower with prone position patients. In the prone position group, vomiting occurred more frequently in the prone than in the supine position (relative risk, 2.5; 95% confidence interval, 1.5-4.0; p <.001). CONCLUSION: In critically ill patients receiving invasive mechanical ventilation in the prone position, early enteral nutrition is poorly tolerated. Prokinetic agents or transpyloric feeding and semirecumbency should be considered to enhance gastric emptying and to prevent vomiting in patients receiving mechanical ventilation in the prone position.