Abstract
Background
Vascular leakage is a major feature of acute respiratory distress syndrome (ARDS). We aimed to evaluate the efficacy of FX06, a drug under development that stabilizes ...interendothelial cell junctions, at reducing vascular leakage during SARS-CoV-2-induced ARDS.
Methods
This multicenter, double-blinded, randomized trial included adults with COVID-19-associated ARDS who had received invasive mechanical ventilation for < 5 days and were randomized to receive either intravenous FX06 (400 mg/d, for 5 days) or its vehicle as placebo. The primary endpoint was the lowering—from day 1 to day 7—of the transpulmonary thermodilution-derived extravascular lung-water index (EVLWi).
Results
Twenty-five patients were randomized to receive FX06 and 24 the placebo. Although EVLWi was elevated at baseline (median IQR 15.6 mL/kg 13.5; 18.5), its declines from day 1 to day 7 were comparable for FX06 recipients and controls (respectively, − 1.9 − 3.3; − 0.5 vs. − 0.8 − 5.5; − 1.1 mL/kg; estimated effect − 0.8 − 3.1; + 2.4,
p
= 0.51). Cardiac indexes, pulmonary vascular permeability indexes, and fluid balances were also comparable, as were PaO
2
/FiO
2
ratios and durations of mechanical ventilation. Adverse event rates were similar for the 2 groups, although more FX06 recipients developed ventilator-associated pneumonia (16/25 (64%) vs. 6/24 (24%),
p
= 0.009).
Conclusions
In this unique-dosing–regimen study, FX06 did not lower SARS-CoV-2-induced pulmonary vascular leakage. Future investigations will need to evaluate its efficacy at earlier times during the disease or using other regimens.
Trial registration
NCT04618042. Registered 5 November 2020.
There is an ongoing discussion whether
hyperoxia
, i.e. ventilation with high inspiratory O
2
concentrations (F
I
O
2
), and the consecutive
hyperoxaemia
, i.e. supraphysiological arterial O
2
...tensions (PaO
2
), have a place during the acute management of circulatory shock. This concept is based on experimental evidence that hyperoxaemia may contribute to the compensation of the imbalance between O
2
supply and requirements. However, despite still being common practice, its use is limited due to possible oxygen toxicity resulting from the increased formation of reactive oxygen species (ROS) limits, especially under conditions of ischaemia/reperfusion. Several studies have reported that there is a U-shaped relation between PaO
2
and mortality/morbidity in ICU patients. Interestingly, these mostly retrospective studies found that the lowest mortality coincided with PaO
2
~ 150 mmHg during the first 24 h of ICU stay, i.e. supraphysiological PaO
2
levels. Most of the recent large-scale retrospective analyses studied general ICU populations, but there are major differences according to the underlying pathology studied as well as whether medical or surgical patients are concerned. Therefore, as far as possible from the data reported, we focus on the need of mechanical ventilation as well as the distinction between the absence or presence of circulatory shock. There seems to be no ideal target PaO
2
except for avoiding prolonged exposure (> 24 h) to either hypoxaemia (PaO
2
< 55–60 mmHg) or supraphysiological (PaO
2
> 100 mmHg). Moreover, the need for mechanical ventilation, absence or presence of circulatory shock and/or the aetiology of tissue dysoxia, i.e. whether it is mainly due to impaired macro- and/or microcirculatory O
2
transport and/or disturbed cellular O
2
utilization, may determine whether any degree of hyperoxaemia causes deleterious side effects.
Abstract
Background
There is wide variability between intensivists in the decisions to forgo life-sustaining treatment (DFLST). Advance directives (ADs) allow patients to communicate their ...end-of-life wishes to physicians. We assessed whether ADs reduced variability in DFLSTs between intensivists.
Methods
We conducted a multicenter, prospective, simulation study. Eight patients expressed their wishes in ADs after being informed about DFLSTs by an intensivist-investigator. The participating intensivists answered ten questions about the DFLSTs of each patient in two scenarios, referring to patients’ characteristics without ADs (round 1) and then with (round 2). DFLST score ranged from 0 (no-DFLST) to 10 (DFLST for all questions). The main outcome was variability in DFLSTs between intensivists, expressed as relative standard deviation (RSD).
Results
A total of 19,680 decisions made by 123 intensivists from 27 ICUs were analyzed. The DFLST score was higher with ADs than without (6.02 95% CI 5.85; 6.19 vs 4.92 95% CI 4.75; 5.10,
p
< 0.001). High inter-intensivist variability did not change with ADs (RSD: 0.56 (round 1) vs 0.46 (round 2),
p
= 0.84). Inter-intensivist agreement on DFLSTs was weak with ADs (intra-class correlation coefficient: 0.28). No factor associated with DFLSTs was identified. A qualitative analysis of ADs showed focus on end-of-life wills, unwanted things and fear of pain.
Conclusions
ADs increased the DFLST rate but did not reduce variability between the intensivists. In the decision-making process using ADs, the intensivist’s decision took priority. Further research is needed to improve the matching of the physicians’ decision with the patient’s wishes.
Trial registration
ClinicalTrials.gov Identifier: NCT03013530. Registered 6 January 2017;
https://clinicaltrials.gov/ct2/show/NCT03013530
.
Asfar and May discuss an experimental study of controlled hemorrhage in anesthetized pigs with a subcostal lobotomy, which mimics a penetrating injury. Libert et al examined the effects of treatment ...with a combination of norepinephrine with fluid versus fluid alone on renal microcirculatory perfusion, renal oxygenation, renal function, and renal histology 48 hours after hemorrhage. The main finding was that the combination of norepinephrine with fluids was as safe as fluid alone and reduced fluid requirements and therefore the degree of hemodilution. The strength of the study is that it examined a large animal model that is likely to be more clinically relevant than rodent models.
Introduction
Supplementation with increased inspired oxygen fractions has been suggested to alleviate the harmful effects of tissue hypoxia during hemorrhagic shock (HS) and traumatic brain injury. ...However, the utility of therapeutic hyperoxia in critical care is disputed to this day as controversial evidence is available regarding its efficacy. Furthermore, in contrast to its hypoxic counterpart, the effect of hyperoxia on the metabolism of circulating immune cells remains ambiguous. Both stimulating and detrimental effects are possible; the former by providing necessary oxygen supply, the latter by generation of excessive amounts of reactive oxygen species (ROS). To uncover the potential impact of increased oxygen fractions on circulating immune cells during intensive care, we have performed a
13
C-metabolic flux analysis (MFA) on PBMCs and granulocytes isolated from two long-term, resuscitated models of combined acute subdural hematoma (ASDH) and HS in pigs with and without cardiovascular comorbidity.
Methods
Swine underwent resuscitation after 2 h of ASDH and HS up to a maximum of 48 h after HS. Animals received normoxemia (P
a
O
2
= 80 – 120 mmHg) or targeted hyperoxemia (P
a
O
2
= 200 – 250 mmHg for 24 h after treatment initiation, thereafter P
a
O
2
as in the control group). Blood was drawn at time points T1 = after instrumentation, T2 = 24 h post ASDH and HS, and T3 = 48 h post ASDH and HS. PBMCs and granulocytes were isolated from whole blood to perform electron spin resonance spectroscopy, high resolution respirometry and
13
C-MFA. For the latter, we utilized a parallel tracer approach with 1,2-
13
C
2
glucose, U-
13
C glucose, and U-
13
C glutamine, which covered essential pathways of glucose and glutamine metabolism and supplied redundant data for robust Bayesian estimation. Gas chromatography-mass spectrometry further provided multiple fragments of metabolites which yielded additional labeling information. We obtained precise estimations of the fluxes, their joint credibility intervals, and their relations, and characterized common metabolic patterns with principal component analysis (PCA).
Results
13
C-MFA indicated a hyperoxia-mediated reduction in tricarboxylic acid (TCA) cycle activity in circulating granulocytes which encompassed fluxes of glutamine uptake, TCA cycle, and oxaloacetate/aspartate supply for biosynthetic processes. We further detected elevated superoxide levels in the swine strain characterized by a hypercholesterolemic phenotype. PCA revealed cell type-specific behavioral patterns of metabolic adaptation in response to ASDH and HS that acted irrespective of swine strains or treatment group.
Conclusion
In a model of resuscitated porcine ASDH and HS, we saw that ventilation with increased inspiratory O
2
concentrations (P
a
O
2
= 200 – 250 mmHg for 24 h after treatment initiation) did not impact mitochondrial respiration of PBMCs or granulocytes. However, Bayesian
13
C-MFA results indicated a reduction in TCA cycle activity in granulocytes compared to cells exposed to normoxemia in the same time period. This change in metabolism did not seem to affect granulocytes’ ability to perform phagocytosis or produce superoxide radicals.
Background
Recent data suggest that hyperchloremia induced by fluid resuscitation is associated with acute kidney injury (AKI) and mortality, particularly in sepsis. Experimental studies showed that ...hyperchloremia could affect organ functions. In patients with septic shock, we examined the relationship between serum chloride concentration and both renal function and survival.
Methods
Post hoc analysis of the “HYPER2S” trial database (NCT01722422) including 434 patients with septic shock randomly assigned for resuscitation with 0.9% or 3% saline. Metabolic parameters were recorded up to 72 h. Metabolic effects of hyperchloremia (> 110 mmol/L) were studied stratified for hyperlactatemia (> 2 mmol/L). Cox models were constructed to assess the association between chloride parameters, day-28 mortality and AKI.
Results
413 patients were analysed. The presence of hyperlactatemia was significantly more frequent than hyperchloremia (62% versus 71% of patients, respectively,
p
= 0.006). Metabolic acidosis was significantly more frequent in patients with hyperchloremia, no matter the presence of hyperlactatemia,
p
< 0.001. Adjusted risk of AKI and mortality were not significantly associated with serum chloride, hyperchloremia, maximal chloremia and delta chloremia (maximal-H0 Cl).
Conclusions
Despite more frequent metabolic acidosis, hyperchloremia was not associated with an increased risk for AKI or mortality.
Trial registration
ClinicalTrials.gov, identifier: NCT01722422, registered 2 November 2012
OBJECTIVE:Hemorrhagic shock–induced tissue hypoxia induces hyperinflammation, ultimately causing multiple organ failure. Hyperoxia and hypothermia can attenuate tissue hypoxia due to increased oxygen ...supply and decreased demand, respectively. Therefore, we tested the hypothesis whether mild therapeutic hypothermia and hyperoxia would attenuate postshock hyperinflammation and thereby organ dysfunction.
DESIGN:Prospective, controlled, randomized study.
SETTING:University animal research laboratory.
SUBJECTS:Thirty-six Bretoncelles-Meishan-Willebrand pigs of either gender.
INTERVENTIONS:After 4 hours of hemorrhagic shock (removal of 30% of the blood volume, subsequent titration of mean arterial pressure at 35 mm Hg), anesthetized and instrumented pigs were randomly assigned to “control” (standard resuscitationretransfusion of shed blood, fluid resuscitation, norepinephrine titrated to maintain mean arterial pressure at preshock values, mechanical ventilation titrated to maintain arterial oxygen saturation > 90%), “hyperoxia” (standard resuscitation, but FIO2, 1.0), “hypothermia” (standard resuscitation, but core temperature 34°C), or “combi” (hyperoxia plus hypothermia) (n = 9 each).
MEASUREMENTS AND MAIN RESULTS:Before, immediately at the end of and 12 and 22 hours after hemorrhagic shock, we measured hemodynamics, blood gases, acid-base status, metabolism, organ function, cytokine production, and coagulation. Postmortem kidney specimen were taken for histological evaluation, immunohistochemistry (nitrotyrosine, cystathionine γ-lyase, activated caspase-3, and extravascular albumin), and immunoblotting (nuclear factor-κB, hypoxia-inducible factor-1α, heme oxygenase-1, inducible nitric oxide synthase, B-cell lymphoma-extra large, and protein expression of the endogenous nuclear factor-κB inhibitor). Although hyperoxia alone attenuated the postshock hyperinflammation and thereby tended to improve visceral organ function, hypothermia and combi treatment had no beneficial effect.
CONCLUSIONS:During resuscitation from near-lethal hemorrhagic shock, hyperoxia attenuated hyperinflammation, and thereby showed a favorable trend toward improved organ function. The lacking efficacy of hypothermia was most likely due to more pronounced barrier dysfunction with vascular leakage–induced circulatory failure.
Background
Recent studies identified coronavirus disease 2019 (COVID-19) as a risk factor for invasive pulmonary aspergillosis (IPA) but produced conflicting data on IPA incidence and impact on ...patient outcomes. We aimed to determine the incidence and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA) in mechanically ventilated patients.
Methods
We performed a multicenter retrospective observational cohort study in consecutive adults admitted to 15 French intensive care units (ICUs) in 2020 for COVID-19 requiring mechanical ventilation. CAPA was diagnosed and graded according to 2020 ECMM/ISHAM consensus criteria. The primary objective was to determine the incidence of proven/probable CAPA, and the secondary objectives were to identify risk factors for proven/probable CAPA and to assess associations between proven/probable CAPA and patient outcomes.
Results
The 708 included patients (522 73.7% men) had a mean age of 65.2 ± 10.8 years, a median mechanical ventilation duration of 15.0 8.0–27.0 days, and a day-90 mortality rate of 28.5%. Underlying immunosuppression was present in 113 (16.0%) patients. Corticosteroids were used in 348 (63.1%) patients. Criteria for probable CAPA were met by 18 (2.5%) patients; no patient had histologically proven CAPA. Older age was the only factor significantly associated with probable CAPA (hazard ratio HR, 1.04; 95% CI 1.00–1.09;
P
= 0.04). Probable CAPA was associated with significantly higher day-90 mortality (HR, 2.07; 95% CI 1.32–3.25;
P
= 0.001) but not with longer mechanical ventilation or ICU length of stay.
Conclusion
Probable CAPA is a rare but serious complication of severe COVID-19 requiring mechanical ventilation and is associated with higher day-90 mortality.
Graphical Abstract
Cigarette smoking (CS) aggravates post-traumatic acute lung injury and increases ventilator-induced lung injury due to more severe tissue inflammation and apoptosis. Hyper-inflammation after chest ...trauma is due to the physical damage, the drop in alveolar PO2, and the consecutive hypoxemia and tissue hypoxia. Therefore, we tested the hypotheses that 1) CS exposure prior to blunt chest trauma causes more severe post-traumatic inflammation and thereby aggravates lung injury, and that 2) hyperoxia may attenuate this effect. Immediately after blast wave-induced blunt chest trauma, mice (n=32) with or without 3-4 weeks of CS exposure underwent 4 hours of pressure-controlled, thoraco-pulmonary compliance-titrated, lung-protective mechanical ventilation with air or 100% O2. Hemodynamics, lung mechanics, gas exchange, and acid-base status were measured together with blood and tissue cytokine and chemokine concentrations, heme oxygenase-1 (HO-1), activated caspase-3, and hypoxia-inducible factor 1-α (HIF-1α) expression, nuclear factor-κB (NF-κB) activation, nitrotyrosine formation, purinergic receptor 2X4 (P2XR4) and 2X7 (P2XR7) expression, and histological scoring. CS exposure prior to chest trauma lead to higher pulmonary compliance and lower PaO2 and Horovitz-index, associated with increased tissue IL-18 and blood MCP-1 concentrations, a 2-4-fold higher inflammatory cell infiltration, and more pronounced alveolar membrane thickening. This effect coincided with increased activated caspase-3, nitrotyrosine, P2XR4, and P2XR7 expression, NF-κB activation, and reduced HIF-1α expression. Hyperoxia did not further affect lung mechanics, gas exchange, pulmonary and systemic cytokine and chemokine concentrations, or histological scoring, except for some patchy alveolar edema in CS exposed mice. However, hyperoxia attenuated tissue HIF-1α, nitrotyrosine, P2XR7, and P2XR4 expression, while it increased HO-1 formation in CS exposed mice. Overall, CS exposure aggravated post-traumatic inflammation, nitrosative stress and thereby organ dysfunction and injury; short-term, lung-protective, hyperoxic mechanical ventilation have no major beneficial effect despite attenuation of nitrosative stress, possibly due to compensation of by regional alveolar hypoxia and/or consecutive hypoxemia, resulting in down-regulation of HIF-1α expression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
