Browsing by Subject "Resuscitation"

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    Activation of the ATF6 (Activating Transcription Factor 6) Signaling Pathway in Neurons Improves Outcome After Cardiac Arrest in Mice.
    (Journal of the American Heart Association, 2021-06-11) Shen, Yuntian; Li, Ran; Yu, Shu; Zhao, Qiang; Wang, Zhuoran; Sheng, Huaxin; Yang, Wei
    Background Ischemia/reperfusion injury impairs proteostasis, and triggers adaptive cellular responses, such as the unfolded protein response (UPR), which functions to restore endoplasmic reticulum homeostasis. After cardiac arrest (CA) and resuscitation, the UPR is activated in various organs including the brain. However, the role of the UPR in CA has remained largely unknown. Here we aimed to investigate effects of activation of the ATF6 (activating transcription factor 6) UPR branch in CA. Methods and Results Conditional and inducible sATF6-KI (short-form ATF6 knock-in) mice and a selective ATF6 pathway activator 147 were used. CA was induced in mice by KCl injection, followed by cardiopulmonary resuscitation. We first found that neurologic function was significantly improved, and neuronal damage was mitigated after the ATF6 pathway was activated in neurons of sATF6-KI mice subjected to CA/cardiopulmonary resuscitation. Further RNA sequencing analysis indicated that such beneficial effects were likely attributable to increased expression of pro-proteostatic genes regulated by ATF6. Especially, key components of the endoplasmic reticulum-associated degradation process, which clears potentially toxic unfolded/misfolded proteins in the endoplasmic reticulum, were upregulated in the sATF6-KI brain. Accordingly, the CA-induced increase in K48-linked polyubiquitin in the brain was higher in sATF6-KI mice relative to control mice. Finally, CA outcome, including the survival rate, was significantly improved in mice treated with compound 147. Conclusions This is the first experimental study to determine the role of the ATF6 UPR branch in CA outcome. Our data indicate that the ATF6 UPR branch is a prosurvival pathway and may be considered as a therapeutic target for CA.
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    Association between Initial Fluid Choice and Subsequent In-hospital Mortality during the Resuscitation of Adults with Septic Shock.
    (Anesthesiology, 2015-12) Raghunathan, Karthik; Bonavia, Anthony; Nathanson, Brian H; Beadles, Christopher A; Shaw, Andrew D; Brookhart, M Alan; Miller, Timothy E; Lindenauer, Peter K
    BACKGROUND: Currently, guidelines recommend initial resuscitation with intravenous (IV) crystalloids during severe sepsis/septic shock. Albumin is suggested as an alternative. However, fluid mixtures are often used in practice, and it is unclear whether the specific mixture of IV fluids used impacts outcomes. The objective of this study is to test the hypothesis that the specific mixture of IV fluids used during initial resuscitation, in severe sepsis, is associated with important in-hospital outcomes. METHODS: Retrospective cohort study includes patients with severe sepsis who were resuscitated with at least 2 l of crystalloids and vasopressors by hospital day 2, patients who had not undergone any major surgical procedures, and patients who had a hospital length of stay (LOS) of at least 2 days. Inverse probability weighting, propensity score matching, and hierarchical regression methods were used for risk adjustment. Patients were grouped into four exposure categories: recipients of isotonic saline alone ("Sal" exclusively), saline in combination with balanced crystalloids ("Sal + Bal"), saline in combination with colloids ("Sal + Col"), or saline in combination with balanced crystalloids and colloids ("Sal + Bal + Col"). In-hospital mortality was the primary outcome, and hospital LOS and costs per day (among survivors) were secondary outcomes. RESULTS: In risk-adjusted Inverse Probability Weighting analyses including 60,734 adults admitted to 360 intensive care units across the United States between January 2006 and December 2010, in-hospital mortality was intermediate in the Sal group (20.2%), lower in the Sal + Bal group (17.7%, P < 0.001), higher in the Sal + Col group (24.2%, P < 0.001), and similar in the Sal + Bal + Col group (19.2%, P = 0.401). In pairwise propensity score-matched comparisons, the administration of balanced crystalloids by hospital day 2 was consistently associated with lower mortality, whether colloids were used (relative risk, 0.84; 95% CI, 0.76 to 0.92) or not (relative risk, 0.79; 95% CI, 0.70 to 0.89). The association between colloid use and in-hospital mortality was inconsistent, and survival was not uniformly affected, whereas LOS and costs per day were uniformly increased. Results were robust in sensitivity analyses. CONCLUSIONS: During the initial resuscitation of adults with severe sepsis/septic shock, the types of IV fluids used may impact in-hospital mortality. When compared with the administration of isotonic saline exclusively during resuscitation, the coadministration of balanced crystalloids is associated with lower in-hospital mortality and no difference in LOS or costs per day. When colloids are coadministered, LOS and costs per day are increased without improved survival. A large randomized controlled trial evaluating crystalloid choice is warranted. Meanwhile, the use of balanced crystalloids seems reasonable. (Anesthesiology 2015; 123:1385-93).
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    Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis.
    (The New England journal of medicine, 2017-06) PRISM Investigators; Rowan, Kathryn M; Angus, Derek C; Bailey, Michael; Barnato, Amber E; Bellomo, Rinaldo; Canter, Ruth R; Coats, Timothy J; Delaney, Anthony; Gimbel, Elizabeth; Grieve, Richard D; Harrison, David A; Higgins, Alisa M; Howe, Belinda; Huang, David T; Kellum, John A; Mouncey, Paul R; Music, Edvin; Peake, Sandra L; Pike, Francis; Reade, Michael C; Sadique, M Zia; Singer, Mervyn; Yealy, Donald M
    BACKGROUND:After a single-center trial and observational studies suggesting that early, goal-directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta-analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT. METHODS:We harmonized entry criteria, intervention protocols, outcomes, resource-use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol-based standard-therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90-day mortality. Secondary outcomes included 1-year survival, organ support, and hospitalization costs. We tested for treatment-by-subgroup interactions for 16 patient characteristics and 6 care-delivery characteristics. RESULTS:We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation. CONCLUSIONS:In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others; PRISM ClinicalTrials.gov number, NCT02030158 .).
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    Resuscitation in hip fractures: a systematic review.
    (BMJ open, 2017-05) Rocos, Brett; Whitehouse, Michael R; Kelly, Michael B
    To evaluate the evidence for the resuscitation of patients with hip fracture in the preoperative or perioperative phase of their treatment and its impact on mortality.

    Design

    We searched MEDLINE, EMBASE, CENTRAL and PROSPERO databases using a systematic search strategy for randomised trials and observational studies investigating the fluid resuscitation of any patient with hip fracture. No language limits were applied to the search, which was complemented by manually screening the reference lists of appropriate studies.

    Outcome measures

    Mortality at 1 week, 30 days and 1 year following surgery.

    Results

    Two hundred and ninety-eight citations were identified, and 12 full manuscripts were reviewed; no studies satisfied the inclusion criteria. The background literature showed that the mortality for these patients at 30 days is approximately 8.5% and that bone cement implantation syndrome is insufficient to explain this. The literature was explored to define the need for an interventional investigation into the preoperative resuscitation of patients with hip fracture.

    Conclusions

    Patients with hip fracture show similar physiological disturbance to major trauma patients. Nineteen per cent of patients presenting with hip fracture are hypoperfused and 50% show preoperative anaemia suggesting that under resuscitation is a common problem that has not been investigated. A properly conducted interventional trial could improve the outcome of these vulnerable patients.
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    Seven unconfirmed ideas to improve future ICU practice.
    (Crit Care, 2017-12-28) Marini, John J; De Backer, Daniel; Ince, Can; Singer, Mervyn; Van Haren, Frank; Westphal, Martin; Wischmeyer, Paul
    With imprecise definitions, inexact measurement tools, and flawed study execution, our clinical science often lags behind bedside experience and simply documents what appear to be the apparent faults or validity of ongoing practices. These impressions are later confirmed, modified, or overturned by the results of the next trial. On the other hand, insights that stem from the intuitions of experienced clinicians, scientists and educators-while often neglected-help place current thinking into proper perspective and occasionally point the way toward formulating novel hypotheses that direct future research. Both streams of information and opinion contribute to progress. In this paper we present a wide-ranging set of unproven 'out of the mainstream' ideas of our FCCM faculty, each with a defensible rationale and holding clear implications for altering bedside management. Each proposition was designed deliberately to be provocative so as to raise awareness, stimulate new thinking and initiate lively dialog.