In patients with acute respiratory distress syndrome (ARDS), the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network recommends a target partial pressure of arterial oxygen (Pao
) ...between 55 and 80 mm Hg. Prospective validation of this range in patients with ARDS is lacking. We hypothesized that targeting the lower limit of this range would improve outcomes in patients with ARDS.
In this multicenter, randomized trial, we assigned patients with ARDS to receive either conservative oxygen therapy (target Pao
, 55 to 70 mm Hg; oxygen saturation as measured by pulse oximetry Spo
, 88 to 92%) or liberal oxygen therapy (target Pao
, 90 to 105 mm Hg; Spo
, ≥96%) for 7 days. The same mechanical-ventilation strategies were used in both groups. The primary outcome was death from any cause at 28 days.
After the enrollment of 205 patients, the trial was prematurely stopped by the data and safety monitoring board because of safety concerns and a low likelihood of a significant difference between the two groups in the primary outcome. Four patients who did not meet the eligibility criteria were excluded. At day 28, a total of 34 of 99 patients (34.3%) in the conservative-oxygen group and 27 of 102 patients (26.5%) in the liberal-oxygen group had died (difference, 7.8 percentage points; 95% confidence interval CI, -4.8 to 20.6). At day 90, 44.4% of the patients in the conservative-oxygen group and 30.4% of the patients in the liberal-oxygen group had died (difference, 14.0 percentage points; 95% CI, 0.7 to 27.2). Five mesenteric ischemic events occurred in the conservative-oxygen group.
Among patients with ARDS, early exposure to a conservative-oxygenation strategy with a Pao
between 55 and 70 mm Hg did not increase survival at 28 days. (Funded by the French Ministry of Health; LOCO
ClinicalTrials.gov number, NCT02713451.).
Microcirculatory dysfunction has been well reported in clinical studies in septic shock. However, no clinical studies have investigated microcirculatory blood flow behavior in hemorrhagic shock. The ...main objective of this study was to assess the time course of sublingual microcirculation in traumatic hemorrhagic shock during the first 4 days after trauma.
Prospective observational study.
Eighteen traumatic hemorrhagic shock patients.
The sublingual microcirculation was estimated at the study inclusion after surgical or angiographic embolization to control bleeding (D1), and then three times at 24-hour intervals (D2, D3, and D4).
Sublingual microcirculation was impaired for 72 hours despite restoration of the macrovascular circulation after control of bleeding in traumatic hemorrhagic shock patients. Furthermore, we found significantly higher decreases in the microvascular flow index and proportion of perfused vessels in high Sequential Organ Failure Assessment score patients at D4 (Sequential Organ Failure Assessment score ≥ 6) compared to low Sequential Organ Failure Assessment score patients at D4 (Sequential Organ Failure Assessment score < 6) without any differences in global hemodynamics between these two groups. Finally, the initial proportion of perfused vessels at D1 appears to be a good predictor of high Sequential Organ Failure Assessment score at D4.
Alterations of microcirculation in traumatic hemorrhagic shock patients result from the interplay among hemorrhage-induced tissue hypoperfusion, trauma injuries, inflammatory response, and subsequent resuscitation interventions. Despite restoration of the macrocirculation, the sublingual microcirculation was impaired for at least 72 hours. The initial proportion of perfused vessels appears to be a good predictor of high Sequential Organ Failure Assessment score at D4. Further studies are required to firmly establish the link between microvascular alterations and organ dysfunction in traumatic hemorrhagic shock patients.
Inflammation is a cellular and molecular response to infection and/or tissues injury. While a suited inflammatory response in intensity and time allows for killing pathogens, clearing necrotic ...tissue, and healing injury; an excessive inflammatory response drives various diseases in which inflammation and tissues damages/stress self-sustain each other. Microbes have been poorly implied in non-resolving inflammation, emphasizing the importance of endogenous regulation of inflammation. Mitochondria have been historically identified as the main source of cellular energy, by coupling the oxidation of fatty acids and pyruvate with the production of high amount of adenosine triphosphate by the electron transport chain. Mitochondria are also the main source of reactive oxygen species. Interestingly, research in the last decade has highlighted that since its integration in eukaryote cells, this organelle of bacterial origin has not only been tolerated by immunity, but has also been placed as a central regulator of cell defense. In intact cells, mitochondria regulate cell responses to critical innate immune receptors engagement. Downstream intracellular signaling pathways interact with mitochondrial proteins and are tuned by mitochondrial functioning. Moreover, upon cell stress or damages, mitochondrial components are released into the cytoplasm or the extra cellular milieu, where they act as danger signals when recognized by innate immune receptors. Finally, by regulating the energetic state of immunological synapse between dendritic cells and lymphocytes, mitochondria regulate the inflammation fate toward immunotolerance or immunogenicity. As dysregulations of these processes have been recently involved in various diseases, the identification of the underlying mechanisms might open new avenues to modulate inflammation.
Patients liberated from invasive mechanical ventilation are at risk of extubation failure, including inability to breathe without a tracheal tube (airway failure) or without mechanical ventilation ...(non-airway failure). We sought to identify respective risk factors for airway failure and non-airway failure following extubation.
The primary endpoint of this prospective, observational, multicenter study in 26 intensive care units was extubation failure, defined as need for reintubation within 48 h following extubation. A multinomial logistic regression model was used to identify risk factors for airway failure and non-airway failure.
Between 1 December 2013 and 1 May 2015, 1514 patients undergoing extubation were enrolled. The extubation-failure rate was 10.4% (157/1514), including 70/157 (45%) airway failures, 78/157 (50%) non-airway failures, and 9/157 (5%) mixed airway and non-airway failures. By multivariable analysis, risk factors for extubation failure were either common to airway failure and non-airway failure: intubation for coma (OR 4.979 (2.797-8.864), P < 0.0001 and OR 2.067 (1.217-3.510), P = 0.003, respectively, intubation for acute respiratory failure (OR 3.395 (1.877-6.138), P < 0.0001 and OR 2.067 (1.217-3.510), P = 0.007, respectively, absence of strong cough (OR 1.876 (1.047-3.362), P = 0.03 and OR 3.240 (1.786-5.879), P = 0.0001, respectively, or specific to each specific mechanism: female gender (OR 2.024 (1.187-3.450), P = 0.01), length of ventilation > 8 days (OR 1.956 (1.087-3.518), P = 0.025), copious secretions (OR 4.066 (2.268-7.292), P < 0.0001) were specific to airway failure, whereas non-obese status (OR 2.153 (1.052-4.408), P = 0.036) and sequential organ failure assessment (SOFA) score ≥ 8 (OR 1.848 (1.100-3.105), P = 0.02) were specific to non-airway failure. Both airway failure and non-airway failure were associated with ICU mortality (20% and 22%, respectively, as compared to 6% in patients with extubation success, P < 0.0001).
Specific risk factors have been identified, allowing us to distinguish between risk of airway failure and non-airway failure. The two conditions will be managed differently, both for prevention and curative strategies.
ClinicalTrials.gov, NCT 02450669 . Registered on 21 May 2015.
Purpose
Investigate safety and tolerability of adrecizumab, a humanized monoclonal adrenomedullin antibody, in septic shock patients with high adrenomedullin.
Methods
Phase-2a, double-blind, ...randomized, placebo-controlled biomarker-guided trial with a single infusion of adrecizumab (2 or 4 mg/kg b.w.) compared to placebo. Patients with adrenomedullin above 70 pg/mL, < 12 h of vasopressor start for septic shock were eligible. Randomization was 1:1:2. Primary safety (90-day mortality, treatment emergent adverse events (TEAE)) and tolerability (drug interruption, hemodynamics) endpoints were recorded. Efficacy endpoints included the Sepsis Support Index (SSI, reflecting ventilator- and shock-free days alive), change in Sequential-related Organ Failure Assessment (SOFA) and 28-day mortality.
Results
301 patients were enrolled (median time of 8.5 h after vasopressor start). Adrecizumab was well tolerated (one interruption, no hemodynamic alteration) with no differences in frequency and severity in TEAEs between treatment arms (TEAE of grade 3 or higher: 70.5% in the adrecizumab group and 71.1% in the placebo group) nor in 90-day mortality. Difference in change in SSI between adrecizumab and placebo was 0.72 (CI −1.93–0.49,
p
= 0.24). Among various secondary endpoints, delta SOFA score (defined as maximum versus minimum SOFA) was more pronounced in the adrecizumab combined group compared to placebo difference at 0.76 (95% CI 0.18–1.35);
p
= 0.007. 28-day mortality in the adrecizumab group was 23.9% and 27.7% in placebo with a hazard ratio of 0.84 (95% confidence interval 0.53–1.31, log-rank
p
= 0.44).
Conclusions
Overall, we successfully completed a randomized trial evaluating selecting patients for enrolment who had a disease-related biomarker. There were no overt signals of harm with using two doses of the adrenomedullin antibody adrecizumab; however, further randomized controlled trials are required to confirm efficacy and safety of this agent in septic shock patients.
Purpose
The effect of the routine use of a stylet during tracheal intubation on first-attempt intubation success is unclear. We hypothesised that the first-attempt intubation success rate would be ...higher with tracheal tube + stylet than with tracheal tube alone.
Methods
In this multicentre randomised controlled trial, conducted in 32 intensive care units, we randomly assigned patients to tracheal tube + stylet or tracheal tube alone (i.e. without stylet). The primary outcome was the proportion of patients with first-attempt intubation success. The secondary outcome was the proportion of patients with complications related to tracheal intubation. Serious adverse events, i.e., traumatic injuries related to tracheal intubation, were evaluated.
Results
A total of 999 patients were included in the modified intention-to-treat analysis: 501 (50%) to tracheal tube + stylet and 498 (50%) to tracheal tube alone. First-attempt intubation success occurred in 392 patients (78.2%) in the tracheal tube + stylet group and in 356 (71.5%) in the tracheal tube alone group (absolute risk difference, 6.7; 95%CI 1.4–12.1; relative risk, 1.10; 95%CI 1.02–1.18;
P
= 0.01). A total of 194 patients (38.7%) in the tracheal tube + stylet group had complications related to tracheal intubation, as compared with 200 patients (40.2%) in the tracheal tube alone group (absolute risk difference, − 1.5; 95%CI − 7.5 to 4.6; relative risk, 0.96; 95%CI 0.83–1.12;
P
= 0.64). The incidence of serious adverse events was 4.0% and 3.6%, respectively (absolute risk difference, 0.4; 95%CI, − 2.0 to 2.8; relative risk, 1.10; 95%CI 0.59–2.06.
P
= 0.76).
Conclusions
Among critically ill adults undergoing tracheal intubation, using a stylet improves first-attempt intubation success.
Abstract
Patient reported outcomes measures (PROMS) are important endpoints to measure patient health status in the perioperative setting. However, there are no good tools to measure PROMS in the ...pediatric surgical population. Patients 7 to 17 years old undergoing surgery were included and followed up for 1 day after surgery (POD1). At POD1 the patients were asked to rate their overall postoperative recovery using a 100-mm visual analog scale (VAS). The primary outcome was the pediatric QoR-15 score on postoperative day 1 (POD1). 150 patients completed the study. The mean (SD) pediatric QoR-15F scores were 132.1 (14.1) and 111.0 (27.0), preoperatively and on POD1, respectively. Convergent validity confirmed with Pearson (r) correlation between the postoperative pediatric QoR-15F and the patient-rated global recovery assessment was 0.72 (95% confidence interval 0.63–0.79; p < 10
–16
). Concerning reliability, internal consistency of the pediatric QoR-15 assessed by Cronbach’s alpha was 0.90. The test–retest concordance correlation coefficient was 0.92; 95% CI 0.83–0.96. Split-half alpha was 0.74. The pictorial pediatric version of the QoR-15F showed good validity, reliability, responsiveness, acceptability and feasibility. This PROMS should be considered for clinical care and research in the perioperative pediatric patient setting.
Trial Registration:
NCT04453410 on clinicaltrials.gov.
Damage-associated molecular patterns (DAMPs) are a group of immunostimulatory molecules, which take part in inflammatory response after tissue injury. Kidney-specific DAMPs include Tamm-Horsfall ...glycoprotein, crystals, and uromodulin, released by tubular damage for example. Non-kidney-specific DAMPs include intracellular particles such as nucleus histones, high-mobility group box 1 protein (HMGB1) and cytosol parts. DAMPs trigger innate immunity by activating the NRLP3 inflammasome, G-protein coupled class receptors or the Toll-like receptor. Tubular necrosis leads to acute kidney injury (AKI) in either septic, ischemic or toxic conditions. Tubular necrosis releases DAMPs such as histones and HMGB1 and increases vascular permeability, which perpetuates shock and hypoperfusion via Toll Like Receptors. In acute tubular necrosis, intracellular abundance of NADPH may explain a chain reaction where necrosis spreads from cell to cell. The nature AKI in intensive care units does not have preclinical models that meet a variation of blood perfusion or a variation of glomerular filtration within hours before catecholamine infusion. However, the dampening of several DAMPs in AKI could provide organ protection. Research should be focused on the numerous pathophysiological pathways to identify the relative contribution to renal dysfunction. The therapeutic perspectives could be strategies to suppress side effect of DAMPs and to promote renal function regeneration.
There is little descriptive data on Stenotrophomonas maltophilia hospital-acquired pneumonia (HAP) in critically ill patients. The optimal modalities of antimicrobial therapy remain to be determined. ...Our objective was to describe the epidemiology and prognostic factors associated with S. maltophilia pneumonia, focusing on antimicrobial therapy.
This nationwide retrospective study included all patients admitted to 25 French mixed intensive care units between 2012 and 2017 with hospital-acquired S. maltophilia HAP during intensive care unit stay. Primary endpoint was time to in-hospital death. Secondary endpoints included microbiologic effectiveness and antimicrobial therapeutic modalities such as delay to appropriate antimicrobial treatment, mono versus combination therapy, and duration of antimicrobial therapy.
Of the 282 patients included, 84% were intubated at S. maltophilia HAP diagnosis for duration of 11 5-18 days. The Simplified Acute Physiology Score II was 47 36-63, and the in-hospital mortality was 49.7%. Underlying chronic pulmonary comorbidities were present in 14.1% of cases. Empirical antimicrobial therapy was considered effective on S. maltophilia according to susceptibility patterns in only 30% of cases. Delay to appropriate antimicrobial treatment had, however, no significant impact on the primary endpoint. Survival analysis did not show any benefit from combination antimicrobial therapy (HR = 1.27, 95%CI 0.88; 1.83, p = 0.20) or prolonged antimicrobial therapy for more than 7 days (HR = 1.06, 95%CI 0.6; 1.86, p = 0.84). No differences were noted in in-hospital death irrespective of an appropriate and timely empiric antimicrobial therapy between mono- versus polymicrobial S. maltophilia HAP (p = 0.273). The duration of ventilation prior to S. maltophilia HAP diagnosis and ICU length of stay were shorter in patients with monomicrobial S. maltophilia HAP (p = 0.031 and p = 0.034 respectively).
S. maltophilia HAP occurred in severe, long-stay intensive care patients who mainly required prolonged invasive ventilation. Empirical antimicrobial therapy was barely effective while antimicrobial treatment modalities had no significant impact on hospital survival.
clinicaltrials.gov, NCT03506191.
Background
The first wave of the COVID-19 pandemic confronted healthcare systems around the world with unprecedented organizational challenges, particularly regarding the availability of intensive ...care unit (ICU) beds. One strategy implemented in France to alleviate healthcare pressure during the first COVID-19 wave was inter-hospital transfers of selected ICU patients from overwhelmed areas towards less saturated ones. At the time, the impact of this transfer strategy on patient mortality was unknown. We aimed to compare in-hospital mortality rates among ICU patients with COVID-19 who were transferred to another healthcare facility and those who remained in the hospital where they were initially admitted to.
Method
A prospective observational study was performed from 1 March to 21 June 2020. Data regarding hospitalized patients with COVID-19 were collected from the Ministry of Health-affiliated national SI-VIC registry. The primary endpoint was in-hospital mortality.
Results
In total, 93,351 hospital admissions of COVID-19 patients were registered, of which 18,348 (19.6%) were ICU admissions. Transferred patients (
n
= 2228) had a lower mortality rate than their non-transferred counterparts (
n
= 15,303), and the risk decreased with increasing transfer distance (odds ratio (OR) 0.7, 95% CI: 0.6–0.9,
p
= 0.001 for transfers between 10 and 50 km, and OR 0.3, 95% CI: 0.2–0.4,
p
< 0.0001 for transfer distance > 200 km). Mortality decreased overall over the 3-month study period.
Conclusions
Our study shows that the mortality rates were lower for patients with severe COVID-19 who were transferred between ICUs across regions, or internationally, during the first pandemic wave in France. However, the global mortality rate declined overall during the study. Transferring selected patients with COVID-19 from overwhelmed regions to areas with greater capacity may have improved patient access to ICU care, without compounding the short-term mortality risk of transferred patients.
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