Search

Excess mitochondrial reactive oxygen species (mROS) in sepsis is associated with organ failure, in part by generating inflammation through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. We determined the impact of a mitochondrial-targeted antioxidant (MitoTEMPO) on mitochondrial dysfunction in renal proximal tubular epithelial cells, peritoneal immune cell function ex vivo, and organ dysfunction in a rat model of sepsis.The effects of MitoTEMPO were assessed ex vivo using adenosine triphosphate and lipopolysaccharide-stimulated rat peritoneal immune cells and fresh rat kidney slices exposed to serum from septic rats. We assessed mROS production and phagocytotic capacity (flow cytometry), mitochondrial functionality (multiphoton imaging, respirometry), and NLRP3 inflammasome activation in cell culture. The effect of MitoTEMPO on organ dysfunction was evaluated in a rat model of faecal peritonitis.MitoTEMPO decreased septic serum-induced mROS (P0.001) and maintained normal reduced nicotinamide adenine dinucleotide redox state (P=0.02) and mitochondrial membrane potential (P0.001) in renal proximal tubular epithelial cells ex vivo. In lipopolysaccharide-stimulated peritoneal immune cells, MitoTEMPO abrogated the increase in mROS (P=0.006) and interleukin-1β (IL-1β) (P=0.03) without affecting non-mitochondrial oxygen consumption or the phagocytotic-induced respiratory burst (P0.05). In vivo, compared with untreated septic animals, MitoTEMPO reduced systemic IL-1β (P=0.01), reduced renal oxidative stress as determined by urine isoprostane levels (P=0.04), and ameliorated renal dysfunction (reduced serum urea (P0.001) and creatinine (P=0.05).Reduction of mROS by a mitochondria-targeted antioxidant reduced IL-1β, and protected mitochondrial, cellular, and organ functionality after septic insults.

Purpose Interleukin-6 (IL-6) levels discriminate between patients with mild and severe COVID-19, making IL-6 inhibition an attractive therapeutic strategy. We conducted a systematic review, meta-analysis, trial sequential analysis (TSA), and meta-regression of randomized-controlled trials to ascertain the benefit of IL-6 blockade with tocilizumab for COVID-19. Methods We included randomized-controlled trials (RCTs) allocating patients with COVID-19 to tocilizumab. Our control group included standard care or placebo. Trials co-administering other pharmacological interventions for COVID-19 were not excluded. Primary outcome was 2830day mortality. Secondary outcomes included progression-to-severe disease defined as need for mechanical ventilation, intensive-care unit (ICU) admission, or a composite. Results We identified 10 RCTs using tocilizumab, 9 of which reported primary outcome data (mortality), recruiting 6493 patients with 3358 (52.2%) allocated to tocilizumab. Tocilizumab may be associated with an improvement in mortality (24.4% vs. 29.0%; OR 0.87 [0.741.01]; p=0.07; I2=10%; TSA adjusted CI 0.661.14). Meta-regression suggested a relationship between treatment effect and mortality risk, with benefit at higher levels of risk (logOR vs %risk beta=0.018 [0.037 to 0.002]; p=0.07). Tocilizumab did reduce the need for mechanical ventilation and was associated with a benefit in the composite secondary outcome but did not reduce ICU admission. Conclusions For hospitalized COVID-19 patients, there is some evidence that tocilizumab use may be associated with a short-term mortality benefit, but further high-quality data are required. Its benefits may also lie in reducing the need for mechanical ventilation. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06416-z.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies, particularly those preventing interaction between the viral spike receptor-binding domain and the host angiotensin-converting enzyme 2 receptor, may prevent viral entry into host cells and disease progression. Methods We performed a systematic review, meta-analysis, trial sequential analysis (TSA), and meta-regression of RCTs to evaluate the benefit of convalescent plasma for COVID-19. The primary outcome was 28–30 day mortality. Secondary outcomes included need for mechanical ventilation and ICU admission. Data sources were PubMed, Embase, MedRxiv, and the Cochrane library on July 2, 2021. Results We identified 17 RCTs that recruited 15 587 patients with 8027 (51.5%) allocated to receive convalescent plasma. Convalescent plasma use was not associated with a mortality benefit (24.7% vs 25.5%; odds ratio [OR]=0.94 [0.85–1.04]; P=0.23; I2=4%; TSA adjusted confidence interval [CI], 0.84–1.05), or reduction in need for mechanical ventilation (15.7% vs 15.4%; OR=1.01 [0.92–1.11]; P=0.82; I2=0%; TSA adjusted CI, 0.91–1.13), or ICU admission (22.4% vs 16.7%; OR=0.80 [0.21–3.09]; P=0.75; I2=63%; TSA adjusted CI, 0.0–196.05). Meta-regression did not reveal association with titre of convalescent plasma, timing of administration, or risk of death and treatment effect (P>0.05). Risk of bias was high in most studies. Conclusions In patients with COVID-19, there was no clear mortality benefit associated with convalescent plasma treatment. In patients with mild disease, convalescent plasma did not prevent either the need for mechanical ventilation or ICU admission. Clinical trial registration CRD42021234201 (PROSPERO).

Supplemental Digital Content is available in the text., OBJECTIVES: Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. DESIGN: A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome. SETTING: University College London, a tertiary academic medical center in the United Kingdom. PATIENTS: Patients admitted to hospital with a diagnosis of coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-β, interferon-γ, interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-β, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable spike protein or nucleocapsid protein immunoglobulin G antibodies with equivalent levels between groups. Neutralization titers were higher among patients with severe disease. CONCLUSIONS: Some therapeutic and prognostic biomarkers may be useful in identifying coronavirus disease 2019 patients who may benefit from specific immunomodulatory therapies, particularly interleukin-6. However, biomarker absolute values often did not discriminate between patients with mild and severe disease or death, implying that these immunomodulatory treatments may be of limited benefit.

Patients with COVID-19 ARDS have distinct physiological and immunological phenotypes compared to patients with non-COVID ARDS. Patients with COVID-19 ARDS (n = 32) had a significant improvement in PaO2: FiO2 ratio (p = 0.046) following low-dose steroid treatment, unlike patients with non-COVID ARDS (n = 16) (p = 0.529). Patients with COVID-19 ARDS had a greater fall in CRP compared to patients with non-COVID ARDS, albeit not statistically significant (p = 0.07). Our novel findings highlight differences in the underlying physiological and immunological phenotypes between COVID-19 and non-COVID ARDS, with implications for future ARDS studies.

Introduction Acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality. We undertook a meta-analysis of randomized controlled trials (RCTs) to determine the mortality benefit of non-specialist therapeutic interventions for ARDS available to general critical care units. Evidence acquisition A systematic search of MEDLINE, Embase, and the Cochrane Central Register for RCTs investigating therapeutic interventions in ARDS including corticosteroids, fluid management strategy, high PEEP, low tidal volume ventilation, neuromuscular blockade, prone position ventilation, or recruitment maneuvers. Data was collected on demographic information, treatment strategy, duration and dose of treatment, and primary (28 or 30-day mortality) and secondary (PaO2:FiO2 ratio at 24-48 hours) outcomes. Evidence synthesis No improvement in 28-day mortality could be demonstrated in three RCTs investigating high PEEP (28.0% vs. 30.2% control; risk ratio [confidence interval] 0.93 [0.82-1.06]; eight assessing prone position ventilation (39.3% vs. 44.5%; RR 0.83 [0.68-1.01]; seven investigating neuromuscular blockade (37.8% vs. 42.0%; RR 0.91 [0.81-1.03]); ten investigating recruitment maneuvers (42.4% vs. 42.1%; RR 1.01 [0.91-1.12]); eight investigating steroids (34.8% vs. 41.1%; RR 0.81 [0.59-1.12]); and one investigating conservative fluid strategies (25.5% vs. 28.4%; RR 0.90 [0.73-1.10]). Three studies assessing low tidal volume ventilation (33.1% vs. 41.9 %; RR 0.79 (0.68-0.91); p=0.001), and subgroup analyses within studies investigating prone position ventilation greater than 12 hours (33.1% vs. 44.4%; RR 0.75 [0.59-0.95), p=0.02) did reveal outcome benefit. Conclusions Among non-specialist therapeutic strategies available to general critical care units, low tidal volumes and prone position ventilation for greater than 12 hours improve mortality in ARDS.

Objective: The objective of this study was to conduct a meta-analysis and trial sequential analysis (TSA) of published randomized controlled trials (RCTs) to determine whether mortality benefit exists for extracorporeal blood purification techniques in sepsis. Data Sources: A systematic search on MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for RCTs was performed. Study Selection: RCTs investigating the effect of extracorporeal blood purification device use on mortality among critically ill septic patients were selected. Data Extraction: Mortality was assessed using Mantel-Haenszel models, and I2 was used for heterogeneity. Data are presented as odds ratios (OR); 95% confidence intervals (CIs); p values; I2. Using the control event mortality proportion, we performed a TSA and calculated the required information size using an anticipated intervention effect of a 14% relative reduction in mortality. Data Synthesis: Thirty-nine RCTs were identified, with 2,729 patients. Fourteen studies used hemofiltration (n = 789), 17 used endotoxin adsorption devices (n = 1,363), 3 used nonspecific adsorption (n = 110), 2 were cytokine removal devices (n = 117), 2 used coupled plasma filtration adsorption (CPFA) (n = 207), 2 combined hemofiltration and perfusion (n = 40), and 1 used plasma exchange (n = 106). On conventional meta-analysis, hemofiltration (OR 0.56 [0.40–0.79]; p < 0.001; I2 = 0%), endotoxin removal devices (OR 0.40 [0.23–0.67], p < 0.001; I2 = 71%), and nonspecific adsorption devices (OR 0.32 [0.13–0.82]; p = 0.02; I2 = 23%) were associated with mortality benefit, but not cytokine removal (OR 0.99 [0.07–13.42], p = 0.99; I2 = 64%), CPFA (OR 0.50 [0.10–2.47]; p = 0.40; I2 = 64%), or combined hemofiltration and adsorption (OR 0.71 [0.13–3.79]; p = 0.69; I2 = 0%). TSA however revealed that based on the number of existing patients recruited for RCTs, neither hemofiltration (TSA-adjusted CI 0.29–1.10), endotoxin removal devices (CI 0.05–3.40), nor nonspecific adsorption devices (CI 0.01–14.31) were associated with mortality benefit. Conclusion: There are inadequate data at present to conclude that the use of extracorporeal blood purification techniques in sepsis is beneficial. Further adequately powered RCTs are required to confirm any potential mortality benefit, which may be most evident in patients at greatest risk of death.

Cardiac troponins are the preferred biomarkers for diagnosing myocardial infarction (MI). High-sensitivity troponin T (hs-TnT) assays have increased sensitivity and enable more rapid diagnosis of infarction. We assessed the prognostic utility of admission hs-TnT to detect outcomes after primary angioplasty for ST-elevation/new left bundle branch block myocardial infarction (STEMI).Patients admitted to Auckland City Hospital for acute coronary catheterization with a diagnosis of STEMI between October 2010 and September 2011 were identified, and included if hs-TnT levels were measured at admission. Clinical characteristics and major adverse cardiovascular events (MACE: death, myocardial infarction and revascularization) at 30 days and 1 year were collected from national statistics and electronic medical records.Median admission hs-TnT level in the 173 STEMI patients studied was 59 ng/L (interquartile range (IQR) 19-310). Incidences of MACE at 30 days and 1 year were 10% (n=17) and 18% (n=31), respectively. C-statistics and 95% confidence interval (CI) (95% CI) for hs-TnT on admission at detecting MACE at 30 days and 1 year were 0.800 (0.696-0.904) and 0.750 (0.655-0.845) respectively, with the optimal cut-point of 225 ng/L giving sensitivities/specificities of 76.5%/75.6% and 64.5%/78.2% respectively. Admission log(hs-TnT) independently predicted both MACE at 30 days with hazards ratio 5.16, 95% CI (2.25-11.9) and 1 year with hazards ratio 2.88, 95% CI (1.79-4.63), as did age and cardiogenic shock. Age, Maori or Pacific ethnicity and chronic respiratory disease were independent predictors of hs-TnT225 ng/L.Admission hs-TnT measured in primary angioplasty is strongly prognostic of MACE at 30 days and 1 year, even following adjustment for potential confounding variables.

We present the case of a 33-year-old woman in her second pregnancy who was transferred to our unit following a one-month history of worsening fatigue and a three-day history of worsening symptoms of heart failure. Shortly after presentation she developed ventricular fibrillation and arrested. At an emergency caesarean section a placental abruption was noted and the baby was stillborn, unable to be resuscitated. The patient required a prolonged intensive and coronary care stay. Echocardiographic findings were consistent with dilated cardiomyopathy and as all investigations to ascertain a cause were negative she was diagnosed with peripartum cardiomyopathy. Her case highlights a potential fatal cause of breathlessness during pregnancy and the role of B-type natriuretic peptide to assist in the differential diagnosis of these cases.

These images are from the post-procedure transoesophageal echocardiogram of a 43-year-old female who was admitted to our unit for primary percutaneous coronary intervention (PCI) following diagnosis of an inferior ST-elevation myocardial infarction (MI). She had …

Predictors of Intervention in Acute Coronary Syndrome Patients with pre-Existing Bypass Grafts T.A.C. Snow ∗, T. Watson, P.N. Ruygrok, M.W. Webster, J.T. Stewart Green Lane Cardiovascular Service, Auckland City Hospital, New Zealand Background: The majority of patients who present to hospital with an acute coronary syndrome (ACS) undergo angiography with a view to revascularisation. However a large proportion of those with pre-existing coronary artery bypass grafts (CABG) have little scope for further intervention and are consequently treated medically. We investigated predictors of ability to offer percutaneous coronary intervention (PCI) in this cohort of patients. Methods: Case notes for all patients with previous CABG who presented to our unit with an ACS between May 2010 and February 2012 were reviewed. Clinical predictors for repeat revascularisationwere establishedusing binary logistic regression analysis. Results: 160 patients (mean age 70.2± 9.3 years, 82.5% male)were identified. Themeanduration sinceCABGwas 12.1± 6.6 years. The median number of grafts was three (range1–7)perpatient (90.6%hada left internalmammary, 80.3% had one or more saphenous venous and 26.3% had one or more radial artery grafts). Following angiography, PCI was undertaken in 66 (41.3%), 33 (50%) to the native c n