Long-term effects of flexible visitation in the intensive care unit on family members’ mental health: 12-month results from a randomized clinical trial

Intensive Care Medicine, Published: 22 August 2024

Purpose

The aim of this study was to assess the effects of flexible intensive care unit (ICU) visitation on the 1-year prevalence of post-traumatic stress, anxiety and depression symptoms among family members of critically ill patients.

Methods

This is a long-term outcome analysis of a cluster-crossover randomized clinical trial that evaluated a flexible visitation model in the ICU (12 h/day) compared to a restrictive visitation model (median 1.5 h/day) in 36 Brazilian ICUs. In this analysis, family members were assessed 12 months after patient discharge from the ICU for the following outcomes: post-traumatic stress symptoms measured by the Impact Event Scale-6 and anxiety and depression symptoms measured by the Hospital Anxiety and Depression Scale.

Results

A total of 519 family members were analyzed (288 in the flexible visitation group and 231 in the restrictive visitation group). Three-hundred sixty-nine (71.1%) were women, and the mean age was 46.6 years. Compared to family members in the restrictive visitation group, family members in the flexible visitation group had a significantly lower prevalence of post-traumatic stress symptoms (21% vs. 30.5%; adjusted prevalence ratio [aPR], 0.91; 95% confidence interval [CI] 0.85–0.98; p = 0.01). The prevalence of anxiety (28.9% vs. 33.2%; aPR 0.93; 95% CI 0.72–1.21; p = 0.59) and depression symptoms (19.2% vs. 25%; aPR, 0.78; 95% CI 0.60–1.02; p = 0.07) did not differ significantly between the groups.

Conclusion

Flexible ICU visitation, compared to the restrictive visitation, was associated with a significant reduction in the 1-year prevalence of post-traumatic stress symptoms in family members.

 

Fluid balance control in critically ill patients: results from POINCARE-2 stepped wedge cluster-randomized trial

by Pierre-Edouard Bollaert, Alexandra Monnier, Francis Schneider, Laurent Argaud, Julio Badie, Claire Charpentier, Ferhat Meziani, Michel Bemer, Jean-Pierre Quenot, Marie Buzzi, Hervé Outin, Cédric Bruel, Laurent Ziegler, Sébastien Gibot, Jean-Marc Virion, Camille Alleyrat… 

Critical Care volume 27, Article number: 66 (2023)

Background

In critically ill patients, positive fluid balance is associated with excessive mortality. The POINCARE-2 trial aimed to assess the effectiveness of a fluid balance control strategy on mortality in critically ill patients.

Methods

POINCARE-2 was a stepped wedge cluster open-label randomized controlled trial. We recruited critically ill patients in twelve volunteering intensive care units from nine French hospitals. Eligible patients were ≥ 18 years old, under mechanical ventilation, admitted to one of the 12 recruiting units for > 48 and ≤ 72 h, and had an expected length of stay after inclusion > 24 h. Recruitment started on May 2016 and ended on May 2019. Of 10,272 patients screened, 1361 met the inclusion criteria and 1353 completed follow-up. The POINCARE-2 strategy consisted of a daily weight-driven restriction of fluid intake, diuretics administration, and ultrafiltration in case of renal replacement therapy between Day 2 and Day 14 after admission. The primary outcome was 60-day all-cause mortality. We considered intention-to-treat analyses in cluster-randomized analyses (CRA) and in randomized before-and-after analyses (RBAA).

Results

A total of 433 (643) patients in the strategy group and 472 (718) in the control group were included in the CRA (RBAA). In the CRA, mean (SD) age was 63.7 (14.1) versus 65.7 (14.3) years, and mean (SD) weight at admission was 78.5 (20.0) versus 79.4 (23.5) kg. A total of 129 (160) patients died in the strategy (control) group. Sixty-day mortality did not differ between groups [30.5%, 95% confidence interval (CI) 26.2–34.8 vs. 33.9%, 95% CI 29.6–38.2, p = 0.26]. Among safety outcomes, only hypernatremia was more frequent in the strategy group (5.3% vs. 2.3%, p = 0.01). The RBAA led to similar results.

Conclusion

The POINCARE-2 conservative strategy did not reduce mortality in critically ill patients. However, due to open-label and stepped wedge design, intention-to-treat analyses might not reflect actual exposure to this strategy, and further analyses might be required before completely discarding it.

 

Effect of high-flow oxygen versus T-piece ventilation strategies during spontaneous breathing trials on weaning failure among patients receiving mechanical ventilation: a randomized controlled trial

by Hong Yeul Lee, Jinwoo Lee and Sang-Min Lee 

 

Critical Care volume 26, Article number: 402 (2022)

 

Background

A spontaneous breathing trial (SBT) is used to determine whether patients are ready for extubation, but the best method for choosing the SBT strategy remains controversial. We investigated the effect of high-flow oxygen versus T-piece ventilation strategies during SBT on rates of weaning failure among patients receiving mechanical ventilation.

Methods

This randomized clinical trial was conducted from June 2019 through January 2022 among patients receiving mechanical ventilation for ≥ 12 h who fulfilled the weaning readiness criteria at a single-center medical intensive care unit. Patients were randomized to undergo either T-piece SBT or high-flow oxygen SBT. The primary outcome was weaning failure on day 2, and the secondary outcomes were weaning failure on day 7, ICU and hospital length of stay, and ICU and in-hospital morality.

Results

Of 108 patients (mean age, 67.0 ± 11.1 years; 64.8% men), 54 received T-piece SBT and 54 received high-flow oxygen SBT. Weaning failure on day 2 occurred in 5 patients (9.3%) in the T-piece group and 3 patients (5.6%) in the high-flow group (difference, 3.7% [95% CI, − 6.1–13.6]; p = 0.713). Weaning failure on day 7 occurred in 13 patients (24.1%) in the T-piece group and 7 patients (13.0%) in the high-flow group (difference, 11.1% [95% CI, − 3.4–25.6]; p = 0.215). A post hoc subgroup analysis showed that high-flow oxygen SBT was significantly associated with a lower rate of weaning failure on day 7 (OR, 0.17 [95% CI, 0.04–0.78]) among those patients intubated because of respiratory failure (p for interaction = 0.020). The ICU and hospital length of stay and mortality rates did not differ significantly between the two groups. During the study, no serious adverse events were recorded.

Conclusions

Among patients receiving mechanical ventilation, high-flow oxygen SBT did not significantly reduce the risk of weaning failure compared with T-piece SBT. However, the study may have been underpowered to detect a clinically important treatment effect for the comparison of high-flow oxygen SBT versus T-piece SBT, and a higher percentage of patients with simple weaning and a lower weaning failure rate than expected should be considered when interpreting the findings.

 

Isoflurane vs. propofol for sedation in invasively ventilated patients with acute hypoxemic respiratory failure: an a priori hypothesis substudy of a randomized controlled trial

 

by Tobias Becher, Andreas Meiser, Ulf Guenther, Martin Bellgardt, Jan Wallenborn, Klaus Kogelmann, Hendrik Bracht, Andreas Falthauser, Jonas Nilsson, Peter Sackey and Patrick Kellner 

 

Annals of Intensive Care volume 12, Article number: 116 (2022) 

 

Background

Acute hypoxemic respiratory failure (AHRF) is a leading concern in critically ill patients. Experimental and clinical data suggest that early sedation with volatile anesthestics may improve arterial oxygenation and reduce the plasma and alveolar levels of markers of alveolar epithelial injury and of proinflammatory cytokines.

Methods

An a priori hypothesis substudy of a multicenter randomized controlled trial (The Sedaconda trial, EUDRA CT Number 2016-004551-67). In the Sedaconda trial, 301 patients on invasive mechanical ventilation were randomized to 48 h of sedation with isoflurane or propofol in a 1:1 ratio. For the present substudy, patients with a ratio of arterial pressure of oxygen (PaO2) to inspired fraction of oxygen (FiO2), PaO2/FiO2, of ≤ 300 mmHg at baseline were included (n = 162). The primary endpoint was the change in PaO2/FiO2 between baseline and the end of study sedation. A subgroup analysis in patients with PaO2/FiO2 ≤ 200 mmHg was performed (n = 82).

Results

Between baseline and the end of study sedation (48 h), oxygenation improved to a similar extent in the isoflurane vs. the propofol group (isoflurane: 199 ± 58 to 219 ± 76 mmHg (n = 70), propofol: 202 ± 62 to 236 ± 77 mmHg (n = 89); p = 0.185). On day seven after randomization, PaO2/FiO2 was 210 ± 79 mmHg in the isoflurane group (n = 41) and 185 ± 87 mmHg in the propofol group (n = 44; p = 0.411). In the subgroup of patients with PaO2/FiO2 ≤ 200 mmHg, PaO2/FiO2 increase between baseline and end of study sedation was 152 ± 33 to 186 ± 54 mmHg for isoflurane (n = 37), and 150 ± 38 to 214 ± 85 mmHg for propofol (n = 45; p = 0.029). On day seven, PaO2/FiO2 was 198 ± 69 mmHg in patients randomized to isoflurane (n = 20) and 174 ± 106 mmHg in patients randomized to propofol (n = 20; p = 0.933). Both for the whole study population and for the subgroup with PaO2/FiO2 ≤ 200 mmHg, no significant between-group differences were observed for PaCO2, pH and tidal volume as well as 30-day mortality and ventilator-free days alive.

Conclusions

In patients with AHRF, inhaled sedation with isoflurane for a duration of up to 48 h did not lead to improved oxygenation in comparison to intravenous sedation with propofol.

Trial registration The main study was registered in the European Medicines Agency’s EU Clinical Trial register (EudraCT), 2016-004551-67, before including the first patient. The present substudy was registered at German Clinical Trials Register (DRKS, ID: DRKS00018959) on January 7th, 2020, before opening the main study data base and obtaining access to study results.

 

 

 

Comparison of ultrasound-guided internal jugular vein and supraclavicular subclavian vein catheterization in critically ill patients: a prospective, randomized clinical trial

 

by Becem Trabelsi, Zied Hajjej, Dhouha Drira, Azza Yedes, Iheb Labbene, Mustapha Ferjani and Mechaal Ben Ali 

 

Annals of Intensive Care volume 12, Article number: 91 (2022) 

 

Background

The aim of this study was to compare the effectiveness and safety of ultrasound-guided out-of-plane internal jugular vein (OOP-IJV) and in-plane supraclavicular subclavian vein (IP-SSCV) catheterization in adult intensive care unit.

Methods

A total of 250 consecutive patients requiring central venous catheterization, were randomly assigned to undergo either ultrasound-guided OOP-IJV or IP-SSCV cannulation. All catheterizations were carried out by three physicians. The primary outcome was the first attempt success rate. Ultrasound scanning time, venous puncture time, insertion time, overall access time, number of puncture attempts, number of needle redirections, success rate, guidewire advancing difficulties, venous collapse and adverse events were also documented.

Results

The first attempt success rate was significantly higher in IP-SSCV group (83.2%) compared to OOP-IJV group (63.2%) (p = 0.001). The IP-SSCV group was associated with a longer ultrasound scanning time (16.54 ± 13.51 vs. 5.26 ± 4.05 s; p < 0.001) and a shorter insertion time (43.98 ± 26.77 vs. 53.12 ± 40.21 s; p = 0.038). In the IP-SCCV group, we recorded a fewer number of puncture attempts (1.16 ± 0.39 vs. 1.47 ± 0.71; p < 0.001), needle redirections (0.69 ± 0.58 vs. 1.17 ± 0.95; p < 0.001), difficulties in guidewire advancement (2.4% vs. 27.4%; p < 0.001), venous collapse (2.4%, vs. 18.4%; p < 0.001) and adverse events (8.8% vs. 13.6%; p = 0.22).

Conclusions

The IP-SSCV approach is an effective and a safe alternative to the classic OOP-IJV catheterization in critical adult patients.

 

 

 

Early administration of hydrocortisone, vitamin C, and thiamine in adult patients with septic shock: a randomized controlled clinical trial

 

by Qing-Quan Lyu, Rui-Qiang Zheng, Qi-Hong Chen, Jiang-Quan Yu, Jun Shao and Xiao-Hua Gu 

 

Critical Care volume 26, Article number: 295 (2022) 

 

Background

The combination therapy of hydrocortisone, vitamin C, and thiamine has been proposed as a potential treatment in patients with sepsis and septic shock. However, subsequent trials have reported conflicting results in relation to survival outcomes. Hence, we performed this randomized controlled trial (RCT) to evaluate the efficacy and safety of early combination therapy among adult patients with septic shock.

Methods

This single-center, double-blind RCT enrolled adult patients with diagnosis of septic shock within 12 h from Northern Jiangsu People's Hospital between February 2019 and June 2021. Recruited patients were randomized 1:1 to receive intervention (hydrocortisone 200 mg daily, vitamin C 2 g every 6 h, and thiamine 200 mg every 12 h) or placebo (0.9% saline) for 5 days or until ICU discharge. The primary endpoint was 90-day mortality. The secondary endpoints included mortality at day 28, ICU discharge, and hospital discharge; shock reversal; 72-h Delta SOFA score; ICU-free days, vasopressor-free days, and ventilator support -free days up to day 28; ICU length of stay (LOS) and hospital LOS.

Results

Among 426 patients randomized, a total of 408 patients with septic shock were included in the per-protocol (PP) analysis, of which 203 were assigned to the intervention group and 205 to the placebo group. In the PP population, the primary outcome of 90-day mortality was 39.9% (81/203) and 39.0% (80/205) in the intervention and the placebo groups, respectively, and was not significantly different (P = 0.86). There was no significant difference between two groups in 28-day mortality (36.5% vs. 36.1%, P = 0.94) or the ICU mortality (31.5% vs. 28.8%, P = 0.55) and hospital mortality (34.5% vs. 33.2%, P = 0.78). No other secondary outcomes showed significant differences between two groups, including shock reversal, vasopressor-free days, and ICU LOS. Intention-to-treat analysis included all the 426 patients and confirmed these results (all P > 0.05).

Conclusion

Among adult patients with septic shock, early use of hydrocortisone, vitamin C, and thiamine combination therapy compared with placebo did not confer survival benefits.

 

 

Daily Written Care Summaries for Families of Critically Ill Patients: A Randomized Controlled Trial

Greenberg, Jared A.; Basapur, Santosh; Quinn, Thomas V.; Bulger, Jeffrey L.; Schwartz, Nathaniel H.; Oh, Soo Kyung; Ritz, Ethan M.; Glover, Crystal M.; Shah, Raj C. 

Critical Care Medicine: May 23, 2022 - Volume - Issue - 10.1097

 

Objectives: 

To determine the effect of daily written updates on the satisfaction and psychologic symptoms of families of ICU patients.

Design: 

Randomized controlled trial.

Setting: 

Single, urban academic medical center.

Subjects: 

Surrogates of nondecisional, critically ill adults with high risk of mortality (n = 252) enrolled from June 2019 to January 2021.

Interventions: 

Usual communication with the medical team with or without written communication detailing the suspected cause and management approach of each ICU problem, updated each day.

Measurements and Main Results: 

Participants completed surveys at three time points during the ICU stay: enrollment (n = 252), 1 week (n = 229), and 2 weeks (n = 109) after enrollment. Satisfaction with care was measured using the Critical Care Family Needs Inventory (CCFNI). The presence of anxiety, depression, and acute stress were assessed using the Hospital Anxiety and Depression Scale (HADS) and Impact of Events Scale Revised (IES-R). CCFNI, HADS, and IES-R scores were similar among participants assigned to the intervention group and control group upon enrollment and during the first week after enrollment (p > 0.05). From enrollment to the second week after enrollment, there was an improvement in CCFNI and HADS scores among participants assigned to the intervention group versus the control group. At week 2, CCFNI scores were significantly lower among participants in the intervention group versus the control group, indicating greater satisfaction with care: 15.1 (95% CI, 14.2–16.0) versus 16.4, (95% CI, 15.5–17.3); p = 0.04. In addition, 2 weeks after enrollment, the odds of symptoms of anxiety, depression, and acute stress among participants assigned to the intervention versus control group were 0.16 (95% CI, 0.03–0.82; p = 0.03); 0.15 (95% CI, 0.01–1.87; p = 0.14); and 0.27 (95% CI, 0.06–1.27; p = 0.10), respectively.

Conclusions: 

Written communication improved satisfaction and the emotional well-being of families of critically ill patients, supporting its use as a supplement to traditional communication approaches.

 

Critical Care Bulletin - May 2022

Therapeutic Hyperthermia Is Associated With Improved Survival in Afebrile Critically Ill Patients With Sepsis: A Pilot Randomized Trial

 

by Drewry, Anne M.; Mohr, Nicholas M.; Ablordeppey, Enyo A.; Dalton, Catherine M.; Doctor, Rebecca J.; Fuller, Brian M.; Kollef, Marin H.; Hotchkiss, Richard S. 

 

Critical Care Medicine: June 2022 - Volume 50 - Issue 6 - p 924-934

 

OBJECTIVES: 

To test the hypothesis that forced-air warming of critically ill afebrile sepsis patients improves immune function compared to standard temperature management.

DESIGN: 

Single-center, prospective, open-label, randomized controlled trial.

SETTING: 

One thousand two hundred-bed academic medical center.

PATIENTS: 

Eligible patients were mechanically ventilated septic adults with: 1) a diagnosis of sepsis within 48 hours of enrollment; 2) anticipated need for mechanical ventilation of greater than 48 hours; and 3) a maximum temperature less than 38.3°C within the 24 hours prior to enrollment. Primary exclusion criteria included: immunologic diseases, immune-suppressing medications, and any existing condition sensitive to therapeutic hyperthermia (e.g., brain injury). The primary outcome was monocyte human leukocyte antigen (HLA)-DR expression, with secondary outcomes of CD3/CD28-induced interferon gamma (IFN-γ) production, mortality, and 28-day hospital-free days.

INTERVENTIONS: 

External warming using a forced-air warming blanket for 48 hours, with a goal temperature 1.5°C above the lowest temperature documented in the previous 24 hours.

MEASUREMENTS AND MAIN RESULTS: 

We enrolled 56 participants in the study. No differences were observed between the groups in HLA-DR expression (692 vs 2,002; p = 0.396) or IFN-γ production (31 vs 69; p = 0.678). Participants allocated to external warming had lower 28-day mortality (18% vs 43%; absolute risk reduction, 25%; 95% CI, 2–48%) and more 28-day hospital-free days (difference, 2.6 d; 95% CI, 0–11.6).

CONCLUSIONS: 

Participants randomized to external forced-air warming did not have a difference in HLA-DR expression or IFN-γ production. In this pilot study, however, 28-day mortality was lower in the intervention group. Future research should seek to better elucidate the impact of temperature modulation on immune and nonimmune organ failure pathways in sepsis.

 

Effect of abdominal weight training with and without cough machine assistance on lung function in the patients with prolonged mechanical ventilation: a randomized trial

 

by Tsai-Yi Hung, Wen-Lan Wu, Ho-Chang Kuo, Shih-Feng Liu, Chia-Ling Chang, Hui-Chuan Chang, Yuh-Chyn Tsai and Jui-Fang Liu 

 

Critical Care volume 26, Article number: 153 (2022) Published: 25 May 2022

Purpose

The patients with prolonged mechanical ventilation (PMV) have the risk of ineffective coughing and infection due to diaphragm weakness. This study aimed to explore the effect of abdominal weight training (AWT) intervention with/without cough machine (CM) assistance on lung function, respiratory muscle strength and cough ability in these patients.

Methods

Forty patients with PMV were randomly assigned to three groups: AWT group (n = 12), AWT + CM group (n = 14) and control group (n = 14). Change of maximum inspiratory pressure (MIP), Maximum expiratory pressure (MEP) and peak cough flow (PCF) between 1 day before and 2 weeks after the intervention were compared among these three groups.

Results

MIP before and after intervention in AWT group (30.50 ± 11.73 vs. 36.00 ± 10.79; p < 0.05) and AWT + CM group (29.8 ± 12.14 vs. 36.14 ± 10.42; p < 0.05) compared with control group (28.43 ± 9.74 vs 26.71 ± 10.77; p > 0.05) was significantly improved. MEP before and after intervention in AWT group (30.58 ± 15.19 vs. 41.50 ± 18.33; p < 0.05) and AWT + CM group (27.29 ± 12.76 vs 42.43 ± 16.96; p < 0.05) compared with control group (28.86 ± 10.25 vs. 29.57 ± 14.21; p > 0.05) was significantly improved. PCF before and after intervention in AWT group in AWT group (105.83 ± 16.21 vs. 114.17 ± 15.20; p < 0.05) and AWT + CM group (108.57 ± 18.85 vs. 131.79 ± 38.96; p < 0.05) compared to control group (108.57 ± 19.96 vs. 109.86 ± 17.44; p > 0.05) showed significant improvements. AWT + CM group had significantly greater improvements than control group in MIP and peak cough flow than control group (13.71 ± 11.28 vs 19.64 ± 29.90, p < 0.05).

Conclusion

AWT can significantly improve lung function, respiratory muscle strength, and cough ability in the PMV patients. AWT + CM can further improve their expiratory muscle strength and cough ability.

 

TTCOV19: timing of tracheotomy in SARS-CoV-2-infected patients: a multicentre, single-blinded, randomized, controlled trial

by Måns Eeg-Olofsson, Nina Pauli, Louise Hafsten, Josephine Jacobsson, Christopher Lundborg, Magnus Brink, Helen Larsson, Ellen Lindell, Karin Löwhagen, Magnus Gisslén and Henrik Bergquist 

Critical Care volume 26, Article number: 142 (2022) Published: 18 May 2022

Background

Critically ill COVID-19 patients may develop acute respiratory distress syndrome and the need for respiratory support, including mechanical ventilation in the intensive care unit. Previous observational studies have suggested early tracheotomy to be advantageous. The aim of this parallel, multicentre, single-blinded, randomized controlled trial was to evaluate the optimal timing of tracheotomy.

Methods

SARS-CoV-2-infected patients within the Region Västra Götaland of Sweden who needed intubation and mechanical respiratory support were included and randomly assigned to early tracheotomy (≤ 7 days after intubation) or late tracheotomy (≥ 10 days after intubation). The primary objective was to compare the total number of mechanical ventilation days between the groups.

Results

One hundred fifty patients (mean age 65 years, 79% males) were included. Seventy-two patients were assigned to early tracheotomy, and 78 were assigned to late tracheotomy. One hundred two patients (68%) underwent tracheotomy of whom sixty-one underwent tracheotomy according to the protocol. The overall median number of days in mechanical ventilation was 18 (IQR 9; 28), but no significant difference was found between the two treatment regimens in the intention-to-treat analysis (between-group difference: − 1.5 days (95% CI − 5.7 to 2.8); p = 0.5). A significantly reduced number of mechanical ventilation days was found in the early tracheotomy group during the per-protocol analysis (between-group difference: − 8.0 days (95% CI − 13.8 to − 2.27); p = 0.0064). The overall correlation between the timing of tracheotomy and days of mechanical ventilation was significant (Spearman’s correlation: 0.39, p < 0.0001). The total death rate during intensive care was 32.7%, but no significant differences were found between the groups regarding survival, complications or adverse events.

Conclusions

The potential superiority of early tracheotomy when compared to late tracheotomy in critically ill patients with COVID-19 was not confirmed by the present randomized controlled trial but is a strategy that should be considered in selected cases where the need for MV for more than 14 days cannot be ruled out.

 

Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial

 

by Klaus Stahl, Philipp Wand, Benjamin Seeliger, Pedro David Wendel-Garcia, Julius J. Schmidt, Bernhard M. W. Schmidt, Andrea Sauer, Felix Lehmann, Ulrich Budde, Markus Busch, Olaf Wiesner, Tobias Welte, Hermann Haller, Heiner Wedemeyer, Christian Putensen, Marius M. Hoeper

 

Critical Care volume 26, Article number: 134 (2022) Published: 12 May 2022

Background

Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy.

Methods

In the original RCT, patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 μg/kg/min received standard of care (SOC) or SOC + one single TPE. Here, we report all clinical and biological endpoints of this study. Multivariate mixed-effects modeling of NE reduction was performed to investigate characteristics that could be associated with clinical response to TPE.

Results

A continuous effect of TPE on the reduction in NE doses over the initial 24 h was observed (SOC group: estimated NE dose reduction of 0.005 µg/kg/min per hour; TPE group: 0.018 µg/kg/min per hour, p = 0.004). Similarly, under TPE, serum lactate levels, continuously decreased over the initial 24 h in the TPE group, whereas lactate levels increased under SOC (p = 0.001). A reduction in biomarkers and disease mediators (such as PCT (p = 0.037), vWF:Ag (p < 0.001), Angpt-2 (p = 0.009), sTie-2 (p = 0.005)) along with a repletion of exhausted protective factors (such as AT-III (p = 0.026), Protein C (p = 0.012), ADAMTS-13 (p = 0.008)) could be observed in the TPE but not in the SOC group. In a multivariate mixed effects model, increasing baseline lactate levels led to greater NE dose reduction effects with TPE as opposed to SOC (p = 0.004).

Conclusions

Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. We identified that baseline lactate concentration as a potential response predictor might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints.

 

 

Auxora vs. placebo for the treatment of patients with severe COVID-19 pneumonia: a randomized-controlled clinical trial

by Charles Bruen, Mukhtar Al-Saadi, Edward A. Michelson, Maged Tanios, Raul Mendoza-Ayala, Joseph Miller, Jeffrey Zhang, Kenneth Stauderman, Sudarshan Hebbar and Peter C. Hou 

Critical Care volume 26 Published: 08 April 2022

Background

Calcium release-activated calcium (CRAC) channel inhibitors block proinflammatory cytokine release, preserve endothelial integrity and may effectively treat patients with severe COVID-19 pneumonia.

Methods

CARDEA was a phase 2, randomized, double-blind, placebo-controlled trial evaluating the addition of Auxora, a CRAC channel inhibitor, to corticosteroids and standard of care in adults with severe COVID-19 pneumonia. Eligible patients were adults with ≥ 1 symptom consistent with COVID-19 infection, a diagnosis of COVID-19 confirmed by laboratory testing using polymerase chain reaction or other assay, and pneumonia documented by chest imaging. Patients were also required to be receiving oxygen therapy using either a high flow or low flow nasal cannula at the time of enrolment and have at the time of enrollment a baseline imputed PaO2/FiO2 ratio > 75 and ≤ 300. The PaO2/FiO2 was imputed from a SpO2/FiO2 determine by pulse oximetry using a non-linear equation. Patients could not be receiving either non-invasive or invasive mechanical ventilation at the time of enrolment. The primary endpoint was time to recovery through Day 60, with secondary endpoints of all-cause mortality at Day 60 and Day 30. Due to declining rates of COVID-19 hospitalizations and utilization of standard of care medications prohibited by regulatory guidance, the trial was stopped early.

Results

The pre-specified efficacy set consisted of the 261 patients with a baseline imputed PaO2/FiO2≤ 200 with 130 and 131 in the Auxora and placebo groups, respectively. Time to recovery was 7 vs. 10 days (P = 0.0979) for patients who received Auxora vs. placebo, respectively. The all-cause mortality rate at Day 60 was 13.8% with Auxora vs. 20.6% with placebo (P = 0.1449); Day 30 all-cause mortality was 7.7% and 17.6%, respectively (P = 0.0165). Similar trends were noted in all randomized patients, patients on high flow nasal cannula at baseline or those with a baseline imputed PaO2/FiO2 ≤ 100. Serious adverse events (SAEs) were less frequent in patients treated with Auxora vs. placebo and occurred in 34 patients (24.1%) receiving Auxora and 49 (35.0%) receiving placebo (P = 0.0616). The most common SAEs were respiratory failure, acute respiratory distress syndrome, and pneumonia.

Conclusions

Auxora was safe and well tolerated with strong signals in both time to recovery and all-cause mortality through Day 60 in patients with severe COVID-19 pneumonia. Further studies of Auxora in patients with severe COVID-19 pneumonia are warranted.

Critical Care Bulletin - March 2022

 

Use of Airway Pressure Release Ventilation in Patients With Acute Respiratory Failure Due to COVID-19: Results of a Single-Center Randomized Controlled Trial*

 

by Ibarra-Estrada, Miguel Á.; García-Salas, Yessica; Mireles-Cabodevila, Eduardo; López-Pulgarín, José A.; Chávez-Peña, Quetzalcóatl; García-Salcido, Roxana; Mijangos-Méndez, Julio C.; Aguirre-Avalos, Guadalupe 

 

Critical Care Medicine: April 2022 - Volume 50 - Issue 4 - p 586-594

 

OBJECTIVES: 

Airway pressure release ventilation is a ventilatory mode characterized by a mandatory inverse inspiratory:expiratory ratio with a very short expiratory phase, aimed to avoid derecruitment and allow spontaneous breathing. Recent basic and clinical evidence suggests that this mode could be associated with improved outcomes in patients with acute respiratory distress syndrome. The aim of this study was to compare the outcomes between airway pressure release ventilation and traditional ventilation targeting low tidal volume, in patients with severe coronavirus disease 2019.

DESIGN: 

Single-center randomized controlled trial.

SETTING: 

ICU of a Mexican referral center dedicated to care of patients with confirmed diagnosis of coronavirus disease 2019.

PATIENTS: 

Ninety adult intubated patients with acute respiratory distress syndrome associated with severe coronavirus disease 2019.

INTERVENTIONS: 

Within 48 hours after intubation, patients were randomized to either receive ventilatory management with airway pressure release ventilation or continue low tidal volume ventilation.

MEASUREMENTS AND MAIN RESULTS: 

Forty-five patients in airway pressure release ventilation group and 45 in the low tidal volume group were included. Ventilator-free days were 3.7 (0–15) and 5.2 (0–19) in the airway pressure release ventilation and low tidal volume groups, respectively (p = 0.28). During the first 7 days, patients in airway pressure release ventilation had a higher Pao2/Fio2 (mean difference, 26 [95%CI, 13–38]; p < 0.001) and static compliance (mean difference, 3.7 mL/cm H2O [95% CI, 0.2–7.2]; p = 0.03), higher mean airway pressure (mean difference, 3.1 cm H2O [95% CI, 2.1–4.1]; p < 0.001), and higher tidal volume (mean difference, 0.76 mL/kg/predicted body weight [95% CI, 0.5–1.0]; p < 0.001). More patients in airway pressure release ventilation had transient severe hypercapnia, defined as an elevation of Pco2 at greater than or equal to 55 along with a pH less than 7.15 (42% vs 15%; p = 0.009); other outcomes were similar. Overall mortality was 69%, with no difference between the groups (78% in airway pressure release ventilation vs 60% in low tidal volume; p = 0.07).

CONCLUSIONS: 

In conclusion, when compared with low tidal volume, airway pressure release ventilation was not associated with more ventilator-free days or improvement in other relevant outcomes in patients with severe coronavirus disease 2019.

 

Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial*

 

by Tom, Jennifer; Bao, Min; Tsai, Larry; Qamra, Aditi; Summers, David; Carrasco-Triguero, Montserrat; McBride, Jacqueline; Rosenberger, Carrie M.; Lin, Celia J. F.; Stubbings, William; Blyth, Kevin G.; Carratalà, Jordi; François, Bruno; Benfield, Thomas; Haslem, Derrick; Bonfanti, Paolo; van der Leest, Cor H.; Rohatgi, Nidhi; Wiese, Lothar; Luyt, Charles Edouard; Kheradmand, Farrah; Rosas, Ivan O.; Cai, Fang 

 

Critical Care Medicine: March 2022 - Volume 50 - Issue 3 - p 398-409

 

OBJECTIVES: 

To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti–interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia.

DESIGN: 

Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial.

SETTING: 

Hospitals in North America and Europe.

PATIENTS: 

Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care.

INTERVENTION: 

Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo.

MEASUREMENTS AND MAIN RESULTS: 

Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo.

CONCLUSIONS: 

Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.

 

Randomized controlled trial: neostigmine for intra-abdominal hypertension in acute pancreatitis

 

by Wenhua He, Peng Chen, Yupeng Lei, Liang Xia, Pi Liu, Yong Zhu, Hao Zeng, Yao Wu, Huajing Ke, Xin Huang, Wenhao Cai, Xin Sun, Wei Huang, Robert Sutton, Yin Zhu and Nonghua Lu 

 

Critical Care volume 26, Article number: 52 (2022) Published: 03 March 2022

 

 

Background

Intra-abdominal hypertension (IAH) in acute pancreatitis (AP) is associated with deterioration in organ function. This trial aimed to assess the efficacy of neostigmine for IAH in patients with AP.

Methods

In this single-center, randomized trial, consenting patients with IAH within 2 weeks of AP onset received conventional treatment for 24 h. Patients with sustained intra-abdominal pressure (IAP) ≥ 12 mmHg were randomized to receive intramuscular neostigmine (1 mg every 12 h increased to every 8 h or every 6 h, depending on response) or continue conventional treatment for 7 days. The primary outcome was the percent change of IAP at 24 h after randomization.

Results

A total of 80 patients were recruited to neostigmine (n = 40) or conventional treatment (n = 40). There was no significant difference in baseline parameters. The rate of decrease in IAP was significantly faster in the neostigmine group compared to the conventional group by 24 h (median with 25th–75th percentile: −18.7% [− 28.4 to − 4.7%] vs. − 5.4% [− 18.0% to 0], P = 0.017). This effect was more pronounced in patients with baseline IAP ≥ 15 mmHg (P = 0.018). Per-protocol analysis confirmed these results (P = 0.03). Stool volume was consistently higher in the neostigmine group during the 7-day observational period (all P < 0.05). Other secondary outcomes were not significantly different between neostigmine and conventional treatment groups.

Conclusion

Neostigmine reduced IAP and promoted defecation in patients with AP and IAH. These results warrant a larger, placebo-controlled, double-blind phase III trial.

Trial registration Clinical Trial No: NCT02543658 (registered August /27, 2015).

 

Effect of therapeutic drug monitoring-based dose optimization of piperacillin/tazobactam on sepsis-related organ dysfunction in patients with sepsis: a randomized controlled trial

 

Intensive Care Medicine: Published: 01 February 2022

 

Purpose

Insufficient antimicrobial exposure is associated with worse outcomes in sepsis. We evaluated whether therapeutic drug monitoring (TDM)-guided antibiotic therapy improves outcomes.

Methods

Randomized, multicenter, controlled trial from January 2017 to December 2019. Adult patients (n = 254) with sepsis or septic shock were randomly assigned 1:1 to receive continuous infusion of piperacillin/tazobactam with dosing guided by daily TDM of piperacillin or continuous infusion with a fixed dose (13.5 g/24 h if eGFR ≥ 20 mL/min). Target plasma concentration was four times the minimal inhibitory concentration (range ± 20%) of the underlying pathogen, respectively, of Pseudomonas aeruginosa in empiric situation. Primary outcome was the mean of daily total Sequential Organ Failure Assessment (SOFA) score up to day 10.

Results

Among 249 evaluable patients (66.3 ± 13.7 years; female, 30.9%), there was no significant difference in mean SOFA score between patients with TDM (7.9 points; 95% CI 7.1–8.7) and without TDM (8.2 points; 95% CI 7.5–9.0) (p = 0.39). Patients with TDM-guided therapy showed a lower 28-day mortality (21.6% vs. 25.8%, RR 0.8, 95% CI 0.5–1.3, p = 0.44) and a higher rate of clinical (OR 1.9; 95% CI 0.5–6.2, p = 0.30) and microbiological cure (OR 2.4; 95% CI 0.7–7.4, p = 0.12), but these differences did not reach statistical significance. Attainment of target concentration was more common in patients with TDM (37.3% vs. 14.6%, OR 4.5, CI 95%, 2.9–6.9, p < 0.001).

Conclusion

TDM-guided therapy showed no beneficial effect in patients with sepsis and continuous infusion of piperacillin/tazobactam with regard to the mean SOFA score. Larger studies with strategies to ensure optimization of antimicrobial exposure are needed to definitively answer the question.

 

 

Intravenous vitamin C administration to patients with septic shock: a pilot randomised controlled trial

 

by Patrice Rosengrave, Emma Spencer, Jonathan Williman, Jan Mehrtens, Stacey Morgan, Tara Doyle, Kymbalee Van Der Heyden, Anna Morris, Geoff Shaw and Anitra C. Carr 

 

Critical Care volume 26, Article number: 26 (2022) 

 

Background

Intravenous vitamin C administration in septic shock may have a sparing effect on vasopressor requirements, and vitamin C’s enzyme cofactor functions provide a mechanistic rationale. Our study aimed to determine the effect of intravenous vitamin C administration on vasopressor requirements and other outcomes in patients with septic shock.

Methods

This was a double-blind, randomised placebo-controlled trial in 40 patients with septic shock who were randomised (1:1) to receive intravenous vitamin C (at a dose of 25 mg/kg of body weight every 6 h) or placebo (intravenous 5% dextrose) for up to 96 h, or until death or discharge. The primary outcome was intravenous vasopressor requirements (dose and duration), and secondary outcomes included Sequential Organ Failure Assessment (SOFA) scores, intensive care unit (ICU) and hospital length of stay, and mortality. In addition, blood samples were collected to determine vitamin C kinetics and inflammatory marker concentrations.

Results

Median plasma vitamin C concentrations were deficient at baseline (9.2 [4.4, 12] µmol/L) and increased to 408 (227, 560) µmol/L following 72 h of intervention. The mean duration of intravenous vasopressor infusion in the vitamin C group was 48 (95% CI 35–62) hours and in the placebo group was 54 (95% CI 41–62) hours (p = 0.52). The dose of vasopressor delivered over time was comparable between the two groups, as were SOFA scores (p > 0.05). The median ICU length of stay in the intervention group was 3.8 (2.2, 9.8) days versus 7.1 (3.1, 20) days in the placebo group (p = 0.12). The median hospital length of stay for the vitamin C group was 18 (11, 35) days versus 22 (10, 52) days for the placebo group (p = 0.65). Mortality was comparable between the two groups (p > 0.05). Of the inflammatory markers, neutrophil counts were elevated in the vitamin C group relative to placebo by 72 h (p = 0.01). C-reactive protein and myeloperoxidase concentrations were elevated at baseline, however, the two groups were comparable over time (p > 0.05).

Conclusions

Our pilot study indicated that intravenous vitamin C did not provide significant decreases in the mean dose or duration of vasopressor infusion. Further research that takes into account the potential impact of intervention timing, dose and duration, and location of trial, may provide more definitive evidence.

 

 

Impact of rewarming rate on interleukin-6 levels in patients with shockable cardiac arrest receiving targeted temperature management at 33 °C: the ISOCRATE pilot randomized controlled trial

by Jean-Baptiste Lascarrou, Elie Guichard, Jean Reignier, Amélie Le Gouge, Caroline Pouplet, Stéphanie Martin, Jean-Claude Lacherade and Gwenhael Colin 

Critical Care volume 25, Article number: 434 (2021) Published: 17 December 2021

Purpose

While targeted temperature management (TTM) has been recommended in patients with shockable cardiac arrest (CA) and suggested in patients with non-shockable rhythms, few data exist regarding the impact of the rewarming rate on systemic inflammation. We compared serum levels of the proinflammatory cytokine interleukin-6 (IL6) measured with two rewarming rates after TTM at 33 °C in patients with shockable out-of-hospital cardiac arrest (OHCA).

Methods

ISOCRATE was a single-center randomized controlled trial comparing rewarming at 0.50 °C/h versus 0.25 °C/h in patients coma after shockable OHCA in 2016–2020. The primary outcome was serum IL6 level 24–48 h after reaching 33 °C. Secondary outcomes included the day-90 Cerebral Performance Category (CPC) and the 48-h serum neurofilament light-chain (NF-L) level.

Results

We randomized 50 patients. The median IL6 area-under-the-curve was similar between the two groups (12,389 [7256–37,200] vs. 8859 [6825–18,088] pg/mL h; P = 0.55). No significant difference was noted in proportions of patients with favorable day-90 CPC scores (13/25 patients at 0.25 °C/h (52.0%; 95% CI 31.3–72.2%) and 13/25 patients at 0.50 °C/h (52.0%; 95% CI 31.3–72.2%; P = 0.99)). Median NF-L levels were not significantly different between the 0.25 °C/h and 0.50 °C/h groups (76.0 pg mL, [25.5–3074.0] vs. 192 pg mL, [33.6–4199.0]; P = 0.43; respectively).

Conclusion

In our RCT, rewarming from 33 °C at 0.25 °C/h, compared to 0.50 °C/h, did not decrease the serum IL6 level after shockable CA. Further RCTs are needed to better define the optimal TTM strategy for patients with CA.

Take-Home Message: Rewarming at a rate of 0.25 °C/h, compared to 0.50 °C, did not result in lower serum IL6 levels after achievement of hypothermia at 33 °C in patients who remained comatose after shockable cardiac arrest. No associations were found between the slower rewarming rate and day-90 functional outcomes or mortality.

140-character Tweet: Rewarming at 0.25 °C versus 0.50 °C did not decrease serum IL6 levels after hypothermia at 33 °C in patients comatose after shockable cardiac arrest.

Critical Care Bulletin: October 2021

 

Tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia: a randomized clinical trial

Intensive Care Medicine Published: 05 October 2021

Purpose

Trials of tocilizumab in patients with severe COVID-19 pneumonia have demonstrated mixed results, and the role of tocilizumab in combination with other treatments is uncertain. Here we evaluated whether tocilizumab plus remdesivir provides greater benefit than remdesivir alone in patients with severe COVID-19 pneumonia.

Methods

This randomized, double-blind, placebo-controlled, multicenter trial included patients hospitalized with severe COVID-19 pneumonia requiring > 6 L/min supplemental oxygen. Patients were randomly assigned (2:1 ratio) to receive tocilizumab 8 mg/kg or placebo intravenously plus ≤ 10 days of remdesivir. The primary outcome was time from randomization to hospital discharge or “ready for discharge” (defined as category 1, assessed by the investigator on a 7-category ordinal scale of clinical status) to day 28. Patients were followed for 60 days.

Results

Among 649 enrolled patients, 434 were randomly assigned to tocilizumab plus remdesivir and 215 to placebo plus remdesivir. 566 patients (88.2%) received corticosteroids during the trial to day 28. Median time from randomization to hospital discharge or “ready for discharge” was 14 (95% CI 12–15) days with tocilizumab plus remdesivir and 14 (95% CI 11–16) days with placebo plus remdesivir [log-rank P = 0.74; Cox proportional hazards ratio 0.97 (95% CI 0.78–1.19)]. Serious adverse events occurred in 128 (29.8%) tocilizumab plus remdesivir and 72 (33.8%) placebo plus remdesivir patients; 78 (18.2%) and 42 (19.7%) patients, respectively, died by day 28.

Conclusions

Tocilizumab plus remdesivir did not shorten time to hospital discharge or “ready for discharge” to day 28 compared with placebo plus remdesivir in patients with severe COVID-19 pneumonia.

 

Effect of oral chlorhexidine de-adoption and implementation of an oral care bundle on mortality for mechanically ventilated patients in the intensive care unit (CHORAL): a multi-center stepped wedge cluster-randomized controlled trial

Intensive Care Medicine Published: 05 October 2021

Purpose

Oral chlorhexidine is used widely for mechanically ventilated patients to prevent pneumonia, but recent studies show an association with excess mortality. We examined whether de-adoption of chlorhexidine and parallel implementation of a standardized oral care bundle reduces intensive care unit (ICU) mortality in mechanically ventilated patients.

Methods

A stepped wedge cluster-randomized controlled trial with concurrent process evaluation in 6 ICUs in Toronto, Canada. Clusters were randomized to de-adopt chlorhexidine and implement a standardized oral care bundle at 2-month intervals. The primary outcome was ICU mortality. Secondary outcomes were time to infection-related ventilator-associated complications (IVACs), oral procedural pain and oral health dysfunction. An exploratory post hoc analysis examined time to extubation in survivors.

Results

A total of 3260 patients were enrolled; 1560 control, 1700 intervention. ICU mortality for the intervention and control periods were 399 (23.5%) and 330 (21.2%), respectively (adjusted odds ratio [aOR], 1.13; 95% confidence interval [CI] 0.82 to 1.54; P = 0.46). Time to IVACs (adjusted hazard ratio [aHR], 1.06; 95% CI 0.44 to 2.57; P = 0.90), time to extubation (aHR 1.03; 95% CI 0.85 to 1.23; P = 0.79) (survivors) and oral procedural pain (aOR, 0.62; 95% CI 0.34 to 1.10; P = 0.10) were similar between control and intervention periods. However, oral health dysfunction scores (− 0.96; 95% CI − 1.75 to − 0.17; P = 0.02) improved in the intervention period.

Conclusion

Among mechanically ventilated ICU patients, no benefit was observed for de-adoption of chlorhexidine and implementation of an oral care bundle on ICU mortality, IVACs, oral procedural pain, or time to extubation. The intervention may improve oral health.