Mitochondrial Calcium Regulation of Cardiac Metabolism in Health and Disease.

Oxidative phosphorylation is regulated by mitochondrial calcium (Ca2+) in health and disease. In physiological states, Ca2+ enters via the mitochondrial Ca2+ uniporter and rapidly enhances NADH and ATP production. However, maintaining Ca2+ homeostasis is critical: insufficient Ca2+ impairs stress adaptation, and Ca2+ overload can trigger cell death. In this review, we delve into recent insights further defining the relationship between mitochondrial Ca2+ dynamics and oxidative phosphorylation. Our focus is on how such regulation affects cardiac function in health and disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, mitochondrial cardiomyopathies, Barth syndrome, and Friedreich's ataxia. Several themes emerge from recent data. First, mitochondrial Ca2+ regulation is critical for fuel substrate selection, metabolite import, and matching of ATP supply to demand. Second, mitochondrial Ca2+ regulates both the production and response to reactive oxygen species (ROS), and the balance between its pro- and antioxidant effects is key to how it contributes to physiological and pathological states. Third, Ca2+ exerts localized effects on the electron transport chain (ETC), not through traditional allosteric mechanisms but rather indirectly. These effects hinge on specific transporters, such as the uniporter or the Na+/Ca2+ exchanger, and may not be noticeable acutely, contributing differently to phenotypes depending on whether Ca2+ transporters are acutely or chronically modified. Perturbations in these novel relationships during disease states may either serve as compensatory mechanisms or exacerbate impairments in oxidative phosphorylation. Consequently, targeting mitochondrial Ca2+ holds promise as a therapeutic strategy for a variety of cardiac diseases characterized by contractile failure or arrhythmias.

Antipsychotics in the Treatment of Delirium in Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: To conduct a systematic review and meta-analysis assessing whether the use of antipsychotic medications in critically ill adult patients with delirium impacts patient-important outcomes. DATA SOURCES: A medical librarian searched Ovid MEDLINE, EMBASE, APA PsycInfo, and Wiley's Cochrane Library as well as clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform up to November 2023. STUDY SELECTION: Independently and in duplicate, reviewers screened abstracts and titles for eligibility, then full text of qualifying studies. We included parallel-group randomized controlled trials (RCTs) that included critically ill adult patients with delirium. The intervention group was required to receive antipsychotic medications at any dose, whereas the control group received usual care or placebo. DATA EXTRACTION: Reviewers extracted data independently and in duplicate using a piloted abstraction form. Statistical analyses were conducted using RevMan software (version 5.4). DATA SYNTHESIS: Five RCTs ( n = 1750) met eligibility criteria. The use of antipsychotic medications compared with placebo did not increase the number of delirium- or coma-free days (mean difference 0.90 d; 95% CI, -0.32 to 2.12; moderate certainty), nor did it result in a difference in mortality, duration of mechanical ventilation, ICU, or hospital length of stay. The use of antipsychotics did not result in an increased risk of adverse events (risk ratio 1.27; 95% CI, 0.71-2.30; high certainty). Subgroup analysis of typical versus atypical antipsychotics did not identify any subgroup effect for any outcome. CONCLUSIONS: In conclusion, our systematic review and meta-analysis demonstrated with moderate certainty that there is no difference in delirium- or coma-free days when delirious critically ill adults are treated with antipsychotic medications. Further studies in the subset of patients with hyperactive delirium may be of benefit.

2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia.

RATIONALE: New evidence is available examining the use of corticosteroids in sepsis, acute respiratory distress syndrome (ARDS) and community-acquired pneumonia (CAP), warranting a focused update of the 2017 guideline on critical illness-related corticosteroid insufficiency. OBJECTIVES: To develop evidence-based recommendations for use of corticosteroids in hospitalized adults and children with sepsis, ARDS, and CAP. PANEL DESIGN: The 22-member panel included diverse representation from medicine, including adult and pediatric intensivists, pulmonologists, endocrinologists, nurses, pharmacists, and clinician-methodologists with expertise in developing evidence-based Clinical Practice Guidelines. We followed Society of Critical Care Medicine conflict of interest policies in all phases of the guideline development, including task force selection and voting. METHODS: After development of five focused Population, Intervention, Control, and Outcomes (PICO) questions, we conducted systematic reviews to identify the best available evidence addressing each question. We evaluated the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach and formulated recommendations using the evidence-to-decision framework. RESULTS: In response to the five PICOs, the panel issued four recommendations addressing the use of corticosteroids in patients with sepsis, ARDS, and CAP. These included a conditional recommendation to administer corticosteroids for patients with septic shock and critically ill patients with ARDS and a strong recommendation for use in hospitalized patients with severe CAP. The panel also recommended against high dose/short duration administration of corticosteroids for septic shock. In response to the final PICO regarding type of corticosteroid molecule in ARDS, the panel was unable to provide specific recommendations addressing corticosteroid molecule, dose, and duration of therapy, based on currently available evidence. CONCLUSIONS: The panel provided updated recommendations based on current evidence to inform clinicians, patients, and other stakeholders on the use of corticosteroids for sepsis, ARDS, and CAP.

Comparative effectiveness of alternative spontaneous breathing trial techniques: a systematic review and network meta-analysis of randomized trials.

BACKGROUND: The spontaneous breathing trial (SBT) technique that best balance successful extubation with the risk for reintubation is unknown. We sought to determine the comparative efficacy and safety of alternative SBT techniques. METHODS: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to February 2023 for randomized or quasi-randomized trials comparing SBT techniques in critically ill adults and children and reported initial SBT success, successful extubation, reintubation (primary outcomes) and mortality (ICU, hospital, most protracted; secondary outcome) rates. Two reviewers screened, reviewed full-texts, and abstracted data. We performed frequentist random-effects network meta-analysis. RESULTS: We included 40 RCTs (6716 patients). Pressure Support (PS) versus T-piece SBTs was the most common comparison. Initial successful SBT rates were increased with PS [risk ratio (RR) 1.08, 95% confidence interval (CI) (1.05-1.11)], PS/automatic tube compensation (ATC) [1.12 (1.01 -1.25), high flow nasal cannulae (HFNC) [1.07 (1.00-1.13) (all moderate certainty), and ATC [RR 1.11, (1.03-1.20); low certainty] SBTs compared to T-piece SBTs. Similarly, initial successful SBT rates were increased with PS, ATC, and PS/ATC SBTs compared to continuous positive airway pressure (CPAP) SBTs. Successful extubation rates were increased with PS [RR 1.06, (1.03-1.09); high certainty], ATC [RR 1.13, (1.05-1.21); moderate certainty], and HFNC [RR 1.06, (1.02-1.11); high certainty] SBTs, compared to T-piece SBTs. There was little to no difference in reintubation rates with PS (vs. T-piece) SBTs [RR 1.05, (0.91-1.21); low certainty], but increased reintubation rates with PS [RR 2.84, (1.61-5.03); moderate certainty] and ATC [RR 2.95 (1.57-5.56); moderate certainty] SBTs compared to HFNC SBTs. CONCLUSIONS: SBTs conducted with pressure augmentation (PS, ATC, PS/ATC) versus without (T-piece, CPAP) increased initial successful SBT and successful extubation rates. Although SBTs conducted with PS or ATC versus HFNC increased reintubation rates, this was not the case for PS versus T-piece SBTs.

Spontaneous Breathing Trial Techniques for Extubating Adults and Children Who Are Critically Ill: A Systematic Review and Meta-Analysis.

Importance: Considerable controversy exists regarding the best spontaneous breathing trial (SBT) technique to use. Objective: To summarize trials comparing alternative SBTs. Data Sources: Several databases (MEDLINE [from inception to February 2023], the Cochrane Central Register of Controlled Trials [in February 2023], and Embase [from inception to February 2023] and 5 conference proceedings (from January 1990 to April 2023) were searched in this systematic review and meta-analysis. Study Selection: Randomized trials directly comparing SBT techniques in critically ill adults or children and reporting at least 1 clinical outcome were selected. Data Extraction and Synthesis: Paired reviewers independently screened citations, abstracted data, and assessed quality for the systematic review and meta-analysis using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA guidelines). Data were pooled using random-effects models. Main Outcomes and Measures: Primary outcomes included SBT success, extubation success, and reintubation. Results: The systematic review and meta-analysis identified 40 trials that included 6716 patients. Low-quality evidence (14 trials [n = 4459]) suggested that patients were not more likely to pass a pressure support (PS) compared with a T-piece SBT (risk ratio [RR], 1.04; 95% CI, 0.97-1.11; P = .31; I2 = 73%), unless 1 outlier trial accounting for all heterogeneity was excluded (RR, 1.09; 95% CI, 1.06-1.12; P < .001; I2 = 0% [13 trials; n = 3939]; moderate-quality evidence), but were significantly more likely to be successfully extubated (RR, 1.07; 95% CI, 1.04-1.10; P < .001; I2 = 0%; 16 trials [n = 4462]; moderate-quality evidence). Limited data (5 trials [n = 502]) revealed that patients who underwent automatic tube compensation/continuous positive airway pressure compared with PS SBTs had a significantly higher successful extubation rate (RR, 1.10; 95% CI, 1.00-1.21; P = .04; I2 = 0% [low-quality evidence]). Compared with T-piece SBTs, high-flow oxygen SBTs (3 trials [n = 386]) had significantly higher successful extubation (RR, 1.06; 95% CI, 1.00-1.11; P = .04; I2 = 0%) and lower reintubation (RR, 0.37; 95% CI, 0.21-0.65; P = <.001; I2 = 0% [both low-quality evidence]) rates. Credible subgroup effects were not found. Conclusions and Relevance: In this systematic review and meta-analysis, the findings suggest that patients undergoing PS compared with T-piece SBTs were more likely to be extubated successfully and more likely to pass an SBT, after exclusion of an outlier trial. Pressure support SBTs were not associated with increased risk of reintubation. Future trials should compare SBT techniques that maximize differences in inspiratory support.

Corticosteroids in Sepsis and Septic Shock: A Systematic Review, Pairwise, and Dose-Response Meta-Analysis.

OBJECTIVES: To perform a systematic review and meta-analysis to assess the efficacy and safety of corticosteroids in patients with sepsis. DATA SOURCES: We searched PubMed, Embase, and the Cochrane Library, up to January 10, 2023. STUDY SELECTION: We included randomized controlled trials (RCTs) comparing corticosteroids with placebo or standard care with sepsis. DATA EXTRACTION: The critical outcomes of interest included mortality, shock reversal, length of stay in the ICU, and adverse events. DATA ANALYSIS: We performed both a pairwise and dose-response meta-analysis to evaluate the effect of different corticosteroid doses on outcomes. We used Grading of Recommendations Assessment, Development and Evaluation to assess certainty in pooled estimates. DATA SYNTHESIS: We included 45 RCTs involving 9563 patients. Corticosteroids probably reduce short-term mortality (risk ratio [RR], 0.93; 95% CI, 0.88-0.99; moderate certainty) and increase shock reversal at 7 days (RR, 1.24; 95% CI, 1.11-1.38; high certainty). Corticosteroids may have no important effect on duration of ICU stay (mean difference, -0.6 fewer days; 95% CI, 1.48 fewer to 0.27 more; low certainty); however, probably increase the risk of hyperglycemia (RR, 1.13; 95% CI, 1.08-1.18; moderate certainty) and hypernatremia (RR, 1.64; 95% CI, 1.32-2.03; moderate certainty) and may increase the risk of neuromuscular weakness (RR, 1.21; 95% CI, 1.01-1.45; low certainty). The dose-response analysis showed a reduction in mortality with corticosteroids with optimal dosing of approximately 260 mg/d of hydrocortisone (RR, 0.90; 95% CI, 0.83-0.98) or equivalent. CONCLUSIONS: We found that corticosteroids may reduce mortality and increase shock reversal but they may also increase the risk of hyperglycemia, hypernatremia, and neuromuscular weakness. The dose-response analysis indicates optimal dosing is around 260 mg/d of hydrocortisone or equivalent.

Adverse Effects Related to Corticosteroid Use in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia: A Systematic Review and Meta-Analysis.

OBJECTIVES: We postulate that corticosteroid-related side effects in critically ill patients are similar across sepsis, acute respiratory distress syndrome (ARDS), and community-acquired pneumonia (CAP). By pooling data across all trials that have examined corticosteroids in these three acute conditions, we aim to examine the side effects of corticosteroid use in critical illness. DATA SOURCES: We performed a comprehensive search of MEDLINE, Embase, Centers for Disease Control and Prevention library of COVID research, CINAHL, and Cochrane center for trials. STUDY SELECTION: We included randomized controlled trials (RCTs) that compared corticosteroids to no corticosteroids or placebo in patients with sepsis, ARDS, and CAP. DATA EXTRACTION: We summarized data addressing the most described side effects of corticosteroid use in critical care: gastrointestinal bleeding, hyperglycemia, hypernatremia, superinfections/secondary infections, neuropsychiatric effects, and neuromuscular weakness. DATA SYNTHESIS: We included 47 RCTs (n = 13,893 patients). Corticosteroids probably have no effect on gastrointestinal bleeding (relative risk [RR], 1.08; 95% CI, 0.87-1.34; absolute risk increase [ARI], 0.3%; moderate certainty) or secondary infections (RR, 0.97; 95% CI, 0.89-1.05; absolute risk reduction, 0.5%; moderate certainty) and may have no effect on neuromuscular weakness (RR, 1.22; 95% CI, 1.03-1.45; ARI, 1.4%; low certainty) or neuropsychiatric events (RR, 1.19; 95% CI, 0.82-1.74; ARI, 0.5%; low certainty). Conversely, they increase the risk of hyperglycemia (RR, 1.21; 95% CI, 1.11-1.31; ARI, 5.4%; high certainty) and probably increase the risk of hypernatremia (RR, 1.59; 95% CI, 1.29-1.96; ARI, 2.3%; moderate certainty). CONCLUSIONS: In ARDS, sepsis, and CAP, corticosteroids are associated with hyperglycemia and probably with hypernatremia but likely have no effect on gastrointestinal bleeding or secondary infections. More data examining effects of corticosteroids, particularly on neuropsychiatric outcomes and neuromuscular weakness, would clarify the safety of this class of drugs in critical illness.

Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.

The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart, however the rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the final myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation can blunt hypertrophy. We hypothesized this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. Post-I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψ), and Ca2+, increased pyruvate entry to TCA cycle, increased oxygen consumption, improved myocardial salvage and functional outcomes following I/R. Our data suggests normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.

Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury.

The established clinical therapy for the treatment of acute myocardial infarction is primary percutaneous coronary intervention (PPCI) to restore blood flow to the ischemic myocardium. PPCI is effective at reperfusing the ischemic myocardium, however the rapid re-introduction of oxygenated blood also can cause ischemia-reperfusion (I/R) injury. Reperfusion injury is the culprit for up to half of the final myocardial damage, but there are no clinical interventions to reduce I/R injury. We previously demonstrated that inhibiting the lactate exporter, monocarboxylate transporter 4 (MCT4), and re-directing pyruvate towards oxidation can blunt isoproterenol-induced hypertrophy. Based on this finding, we hypothesized that the same pathway might be important during I/R. Here, we establish that the pyruvate-lactate metabolic axis plays a critical role in determining myocardial salvage following injury. Post-I/R injury, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium following I/R injury. MPC loss in cardiomyocytes caused more cell death with less myocardial salvage, which was associated with an upregulation of MCT4 in the myocardium at risk of injury. We deployed a pharmacological strategy of MCT4 inhibition with a highly selective compound (VB124) at the time of reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (Δψ), and Ca 2+ , increased pyruvate entry to TCA cycle, and improved myocardial salvage and functional outcomes following I/R injury. Altogether, our data suggest that normalizing the pyruvate-lactate metabolic axis via MCT4 inhibition is a promising pharmacological strategy to mitigate I/R injury.

Sex and gender-based analysis and diversity metric reporting in acute care trials published in high-impact journals: a systematic review.

OBJECTIVE: To characterise sex and gender-based analysis (SGBA) and diversity metric reporting, representation of female/women participants in acute care trials and temporal changes in reporting before and after publication of the 2016 Sex and Gender Equity in Research guideline. DESIGN: Systematic review. DATA SOURCES: We searched MEDLINE for trials published in five leading medical journals in 2014, 2018 and 2020. STUDY SELECTION: Trials that enrolled acutely ill adults, compared two or more interventions and reported at least one clinical outcome. DATA ABSTRACTION AND SYNTHESIS: 4 reviewers screened citations and 22 reviewers abstracted data, in duplicate. We compared reporting differences between intensive care unit (ICU) and cardiology trials. RESULTS: We included 88 trials (75 (85.2%) ICU and 13 (14.8%) cardiology) (n=111 428; 38 140 (34.2%) females/women). Of 23 (26.1%) trials that reported an SGBA, most used a forest plot (22 (95.7%)), were prespecified (21 (91.3%)) and reported a sex-by-intervention interaction with a significance test (19 (82.6%)). Discordant sex and gender terminology were found between headings and subheadings within baseline characteristics tables (17/32 (53.1%)) and between baseline characteristics tables and SGBA (4/23 (17.4%)). Only 25 acute care trials (28.4%) reported race or ethnicity. Participants were predominantly white (78.8%) and male/men (65.8%). No trial reported gendered-social factors. SGBA reporting and female/women representation did not improve temporally. Compared with ICU trials, cardiology trials reported significantly more SGBA (15/75 (20%) vs 8/13 (61.5%) p=0.005). CONCLUSIONS: Acute care trials in leading medical journals infrequently included SGBA, female/women and non-white trial participants, reported race or ethnicity and never reported gender-related factors. Substantial opportunity exists to improve SGBA and diversity metric reporting and recruitment of female/women participants in acute care trials. PROSPERO REGISTRATION NUMBER: CRD42022282565.

Comparison of analgesic effects of pericapsular nerve group block and fascia iliaca compartment block during hip arthroplasty: A systematic review and meta-analysis of randomised controlled trials.

Background and Aims: Postoperative pain for patients having hip arthroplasty ranges from moderate to severe. Many regional anaesthesia procedures treat postoperative pain to improve functional ability and quality of life. Evidence comparing the analgesic effects of the pericapsular nerve group (PENG) block and fascia iliaca compartment block (FICB) remains unclear. The analgesic efficacies of PENG and FICB in hip arthroplasty were compared to determine which technique is associated with superior analgesia. Methods: The electronic databases (PubMed, Cochrane Library, Google Scholar and Web of Sciences) were searched for published randomised controlled trials (RCTs) till 5 April 2023 comparing PENG block vs. FICB following hip arthroplasty. The primary outcome was pain scores [numerical rating scale (NRS) or visual analogue scale (VAS)] between 0 and 10 at rest and during movement at 24 h. Secondary outcomes included pain scores at rest and during movement within 30 min, at 6 h and 12 h, time to first rescue analgesia and cumulative postoperative opioid use in 24 h. We assessed the risk of bias using the Cochrane Collaboration Risk-of-Bias 2 tool. Using Grading of Recommendations Assessment, Development, and Evaluation (GRADE), the certainty of the evidence was assessed. Subgroup analysis was performed to explore the source of heterogeneity. Results: We included 12 RCTs examining 644 patients. Pain scores at rest at 24 h (standardised mean differences (SMDs): 0.17; 95% confidence interval (CI): -0.90 to 1.23; P = 0.76, moderate certainty) and during movement at 24 h (SMD: -0.58, 95% CI: -1.53 to 0.38, P = 0.24, moderate certainty) were not different in both PENG block and FICB. Pain scores at rest and during movement within 30 min may be lower with PENG block than FICB. However, the pain score at rest and during movement at 6 h and the time to first rescue analgesia were not different between the two treatment arms. The mean opioid consumption in oral morphine equivalents (mg) in 24 h may be lower with PENG than FICB. Conclusion: We observed no difference between the PENG block and the FICB at 24 h for pain at rest and movement with a moderate degree of certainty. However, PENG block showed improved analgesia within 30 min at rest and during movement, and reduce postoperative opioid consumption in 24 h with moderate certainty of evidence. Further large-scale and high-quality RCTs are required to supplement the present findings.