OBJECTIVES:To determine whether early lactate reduction is associated with improved survival and good neurologic outcome in patients with out-of-hospital cardiac arrest.
DESIGN:Ad hoc data analysis ...of a prospective, multicenter observational study.
SETTING:Out-of-hospital cardiac arrest patients at 67 emergency hospitals in Kanto, Japan between January 2012 and March 2013.
PATIENTS:Adult patients with out-of-hospital cardiac arrest admitted to the hospital after successful resuscitation were identified.
INTERVENTIONS:Blood lactate concentrations were measured at hospital admission and 6 h after hospital admission. Early lactate clearance was defined as the percent change in lactate level 6 h after a baseline measurement.
MEASUREMENTS AND MAIN RESULTS:The 543 patients (mean age, 65 ± 16 yr; 72.6% male) had a mean lactate clearance of 42.4% ± 53.7%. Overall 30-day survival and good neurologic outcome were 47.1% and 27.4%, respectively. The survival proportion increased with increasing lactate clearance (quartile 1, 29.4%; quartile 2, 42.6%; quartile 3, 51.5%; quartile 4, 65.2%; p < 0.001). Multivariate logistic regression analysis showed that lactate clearance quartile was an independent predictor of the 30-day survival and good neurologic outcome. In the Cox proportional hazards model, the frequency of mortality during 30 days was significantly higher for patients with lactate clearance in quartile 1 (hazard ratio, 3.12; 95% CI, 2.14–4.53), quartile 2 (hazard ratio, 2.13; 95% CI, 1.46–3.11), and quartile 3 (hazard ratio, 1.49; 95% CI, 1.01–2.19) than those with lactate clearance in quartile 4. Furthermore, multivariate logistic regression analysis revealed that lactate clearance was a significant predictor of good neurologic outcome at 30 days after hospital admission.
CONCLUSIONS:Effective lactate reduction over the first 6 hours of postcardiac arrest care was associated with survival and good neurologic outcome independently of the initial lactate level.
To elucidate the clinical utility of the Clinical Frailty Scale score for predicting poor neurologic functions in patients resuscitated from out-of-hospital cardiac arrest (OHCA).
This was a ...prospective, multicenter, observational study conducted between 2019 and 2021. The study included adults with nontraumatic OHCA admitted to the intensive care unit after return of spontaneous circulation (ROSC). Pre-arrest high Clinical Frailty Scale score was defined as 5 or more. Favorable neurologic outcomes defined as a Cerebral Performance Category score of 2 or less at 30 days after admission were compared between patients with and without high Clinical Frailty Scale scores. Multivariable logistic regression analyses fitted with generalized estimating equations were performed to adjust for patient characteristics, out-of-hospital information, and resuscitation content and account for within-institution clustering.
Of 9,909 patients with OHCA during the study period, 1,216 were included, and 317 had a pre-arrest high Clinical Frailty Scale score. Favorable neurologic outcomes were fewer among patients with high Clinical Frailty Scale scores. The high Clinical Frailty Scale score group showed a lower percentage of favorable neurologic outcomes after OHCA than the low Clinical Frailty Scale score group (6.1% vs 24.4%; adjusted odds ratio, 0.45 95% confidence interval 0.22 to 0.93). This relationship remained in subgroups with cardiogenic OHCA, with ROSC after hospital arrival, and without a high risk of dying (Clinical Frailty Scale score of 7 or less), whereas the neurologic outcomes were comparable regardless of pre-arrest frailty in those with noncardiogenic OHCA and with ROSC before hospital arrival.
Pre-arrest high Clinical Frailty Scale score was associated with unfavorable neurologic functions among patients resuscitated from OHCA. The Clinical Frailty Scale score would help predict clinical consequences following intensive care after ROSC.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mortality of hemorrhagic shock primarily depends on whether or not the patients can endure the loss of circulating volume until radical treatment is applied. We investigated whether hydrogen (H2) gas ...inhalation would influence the tolerance to hemorrhagic shock and improve survival.
Hemorrhagic shock was achieved by withdrawing blood until the mean arterial blood pressure reached 30-35 mm Hg. After 60 minutes of shock, the rats were resuscitated with a volume of normal saline equal to four times the volume of shed blood. The rats were assigned to either the H2 gas (1.3% H2, 26% O2, 72.7% N2)-treated group or the control gas (26% O2, 74% N2)-treated group. Inhalation of the specified gas mixture began at the initiation of blood withdrawal and continued for 2 hours after fluid resuscitation.
The survival rate at 6 hours after fluid resuscitation was 80% in H2 gas-treated rats and 30% in control gas-treated rats (p < 0.05). The volume of blood that was removed through a catheter to induce shock was significantly larger in the H2 gas-treated rats than in the control rats. Despite losing more blood, the increase in serum potassium levels was suppressed in the H2 gas-treated rats after 60 minutes of shock. Fluid resuscitation completely restored blood pressure in the H2 gas-treated rats, whereas it failed to fully restore the blood pressure in the control gas-treated rats. At 2 hours after fluid resuscitation, blood pressure remained in the normal range and metabolic acidosis was well compensated in the H2 gas-treated rats, whereas we observed decreased blood pressure and uncompensated metabolic acidosis and hyperkalemia in the surviving control gas-treated rats.
H2 gas inhalation delays the progression to irreversible shock. Clinically, H2 gas inhalation is expected to stabilize the subject until curative treatment can be performed, thereby increasing the probability of survival after hemorrhagic shock.
As treatment of the early, inflammatory phase of sepsis improves, post-sepsis immunosuppression and secondary infection have increased in importance. How early inflammation drives immunosuppression ...remains unclear. Although IFN-γ typically helps microbial clearance, we found that increased plasma IFN-γ in early clinical sepsis was associated with the later development of secondary Candida infection. Consistent with this observation, we found that exogenous IFN-γ suppressed macrophage phagocytosis of zymosan in vivo, and antibody blockade of IFN-γ after endotoxemia improved survival of secondary candidemia. Transcriptomic analysis of innate lymphocytes during endotoxemia suggested that NKT cells drove IFN-γ production by NK cells via mTORC1. Activation of invariant NKT (iNKT) cells with glycolipid antigen drove immunosuppression. Deletion of iNKT cells in Cd1d-/- mice or inhibition of mTOR by rapamycin reduced immunosuppression and susceptibility to secondary Candida infection. Thus, although rapamycin is typically an immunosuppressive medication, in the context of sepsis, rapamycin has the opposite effect. These results implicated an NKT cell/mTOR/IFN-γ axis in immunosuppression following endotoxemia or sepsis. In summary, in vivo iNKT cells activated mTORC1 in NK cells to produce IFN-γ, which worsened macrophage phagocytosis, clearance of secondary Candida infection, and mortality.
Mechanical cardiopulmonary resuscitation (mCPR) devices have been developed to provide continuous high-quality CPR and help avoid interruption, compressor fatigue, and variations in compression ...depth, all of which have been associated poor outcomes 2. mCPR has largely been investigated in the out of hospital setting with uneven results 3, 4. All participating institutions were required to comply with local regulatory and privacy guidelines and, if required, to secure institutional review board approval. Because data were used primarily at the local site for quality improvement, sites were granted a waiver of informed consent under the common rule. Mechanical chest compressions and simultaneous defibrillation vs conventional cardiopulmonary resuscitation in out-of-hospital cardiac arrest: the LINC randomized trial.
In this single-center, retrospective cohort analysis of hospitalized coronavirus disease 2019 (COVID-19) patients, we investigate whether inflammatory biomarker levels predict respiratory decline in ...patients who initially present with stable disease. Examination of C-reactive protein (CRP) trends reveals that a rapid rise in CRP levels precedes respiratory deterioration and intubation, although CRP levels plateau in patients who remain stable. Increasing CRP during the first 48 h of hospitalization is a better predictor (with higher sensitivity) of respiratory decline than initial CRP levels or ROX indices (a physiological score of respiratory function). CRP, the proinflammatory cytokine interleukin-6 (IL-6), and physiological measures of hypoxemic respiratory failure are correlated, which suggests a mechanistic link. Our work shows that rising CRP predicts subsequent respiratory deterioration in COVID-19 and may suggest mechanistic insight and a potential role for targeted immunomodulation in a subset of patients early during hospitalization.
Display omitted
Rising CRP levels predict intubation in COVID-19 inpatients stable at admissionEarly CRP trend outperforms initial CRP level in prediction of respiratory failureCRP trend outperforms a physiological index (ROX) in prediction of respiratory failureCRP and IL-6 levels correlate with each other and with hypoxemia (PaO2/FiO2)
Mueller et al. demonstrate in hospitalized COVID-19 patients that trending C-reactive protein (CRP), an inflammatory biomarker, is a simple and accessible strategy for predicting respiratory deterioration. An early rise in CRP predicts intubation, and CRP levels correlate with IL-6 levels and physiological measures of hypoxemic respiratory failure.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract only Background: Molecular hydrogen gas (H 2 ) is known to alleviate ischemia-reperfusion injury; however, the mechanism of action involved remains unknown. Metabolome analysis of tissue ...subjected to ischemia-reperfusion injury has revealed xanthine oxidoreductase (XOR) as a candidate target molecule for H 2. Purpose: The effects of H 2 and the XOR inhibitor (XORi) on resuscitation after hemorrhagic shock (HS) were examined. Methods: Male Sprague-Dawley rats were subjected to HS by the withdrawal of blood to maintain a mean arterial pressure (MBP) of 35 mmHg for 60 minutes (T0 to T60). They were then resuscitated with lactated Ringer’s solution with 3 times the shed blood volume over 30 minutes (T60 to T90). The animals were randomly assigned into 3 groups: H 2 inhalation (1.3% H 2 ) from T30 (n=6), XORi administration (Topiroxostat 10 mg/kg, orally administered at 60 minutes before induction of HS) (n=5), and control (CTL) (n=5). The rats were observed until 2 hours after fluid resuscitation (T210). Results: Compared to that in the control group, the lactate level at 60 minutes after introduction of HS was lower in the XORi group, while the MBP after 2 hours of fluid resuscitation was higher in the H 2 group. XOR activity in the plasma, liver, kidney, and lung tissue was suppressed in the XORi group, but not in the H 2 group. Increased permeability of the pulmonary vasculature associated with increased levels of plasma inflammatory cytokines and plasma Syndecan-1 (a marker of endothelial glycocalyx degradation) after 2 hours of fluid resuscitation was ameliorated only in the H 2 group. Conclusion: The mechanisms of action possibly differ between H 2 and XORi. XORi confers resistance to ischemia by suppressing anaerobic glycolysis during ischemia. On the other hand, H 2 stabilizes hemodynamics via suppression of inflammation and vascular hyperpermeability after resuscitation.
Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent a novel therapeutic ...target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases.
We profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes.
Two shared clusters, CXCL10
CCL19
immune-interacting and SPARC
COL3A1
vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation.
This work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases.
Grant from F. Hoffmann-La Roche (Roche) AG.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Despite the importance of inflammation in chronic obstructive pulmonary disease (COPD), the immune cell landscape in the lung tissue of patients with mild-moderate disease has not been well ...characterized at the single-cell and molecular level.
To define the immune cell landscape in lung tissue from patients with mild-moderate COPD at single-cell resolution.
We performed single-cell transcriptomic, proteomic, and T-cell receptor repertoire analyses on lung tissue from patients with mild-moderate COPD (
= 5, Global Initiative for Chronic Obstructive Lung Disease I or II), emphysema without airflow obstruction (
= 5), end-stage COPD (
= 2), control (
= 6), or donors (
= 4). We validated in an independent patient cohort (
= 929) and integrated with the
murine model of COPD.
Mild-moderate COPD lungs have increased abundance of two CD8
T cell subpopulations: cytotoxic KLRG1
TIGIT
CX3CR1
TEMRA (T effector memory CD45RA
) cells, and DNAM-1
CCR5
T resident memory (T
) cells. These CD8
T cells interact with myeloid and alveolar type II cells via
and have hyperexpanded T-cell receptor clonotypes. In an independent cohort, the CD8
KLRG1
TEMRA cells are increased in mild-moderate COPD lung compared with control or end-stage COPD lung. Human CD8
KLRG1
TEMRA cells are similar to CD8
T cells driving inflammation in an aging-related murine model of COPD.
CD8
TEMRA cells are increased in mild-moderate COPD lung and may contribute to inflammation that precedes severe disease. Further study of these CD8
T cells may have therapeutic implications for preventing severe COPD.
Abstract only Background: Lymphopenia and elevated cytokine levels suggest a role for the systemic immune response after cardiac arrest (CA). However, little is known about the phenotypes and ...interactions of immune cells after CA. This study aimed to investigate the immunological network after CA and identify cell states correlating with poor neurological outcomes. Methods: Peripheral mononuclear blood cells of 11 post-out-of-hospital CA patients and 3 healthy subjects were analyzed by single-cell RNA-sequencing (scRNA-seq), with validation by flow cytometry, bulk RNA-seq of sorted cell subsets, plasma levels of cytokines, and the murine model of CA. Good and poor neurological outcomes at hospital discharge were defined by Cerebral Performance Category 1-2 and 3-5, respectively. Results: The scRNA-seq analysis of 96,179 cells revealed 6 major cell lineages with several subclusters. At 6h post-CA, cells of patients with good outcomes co-clustered with healthy subjects, while patients with poor outcomes formed distinct transcriptomic clusters. This distinction was lost by 48h post-CA. At 6h post-CA, we identified pro-inflammatory and hypoxia-responsive Tim-3 + NK cell and Nectin-2 + monocyte cell states specific to poor outcomes. In a validation cohort of post-CA patients, Tim-3 + NK cells and Nectin-2 + monocyte cell states were validated by flow cytometry. Bulk RNA-seq analysis of these sorted cells reproduced the transcriptomic profile determined by scRNA-seq. Interactome analysis identified NK cell-monocyte axes in poor outcomes, including IFNG-IFNGR2. Measurement of plasma cytokine levels revealed increased IFNγ levels at 6h post-CA that were associated with poor outcomes, but both poor and good outcomes had similarIFNγ levels by 48h. A murine model of CA demonstrated that IFNγ drives poor outcomes and mortality after CA. Conclusions: In clinical CA, transcriptomic analysis at single-cell resolution revealed hyperacute cell states of NK cells and monocytes associated with poor neurological outcomes. These hyperacute cell states interact by IFNγ-IFNγR2 axis, which is pathogenic in the murine model of CA. The immunophenotypes that distinguish patients with poor or good neurological outcomes are present at 6h but are no longer detectable by 48h post-CA.
PDF
