Cytokine storm is an acute hyperinflammatory response that may be responsible for critical illness in many conditions including viral infections, cancer, sepsis, and multi-organ failure. The ...phenomenon has been implicated in critically ill patients infected with SARS-CoV-2, the novel coronavirus implicated in COVID-19. Critically ill COVID-19 patients experiencing cytokine storm are believed to have a worse prognosis and increased fatality rate. In SARS-CoV-2 infected patients, cytokine storm appears important to the pathogenesis of several severe manifestations of COVID-19: acute respiratory distress syndrome, thromboembolic diseases such as acute ischemic strokes caused by large vessel occlusion and myocardial infarction, encephalitis, acute kidney injury, and vasculitis (Kawasaki-like syndrome in children and renal vasculitis in adult). Understanding the pathogenesis of cytokine storm will help unravel not only risk factors for the condition but also therapeutic strategies to modulate the immune response and deliver improved outcomes in COVID-19 patients at high risk for severe disease. In this article, we present an overview of the cytokine storm and its implications in COVID-19 settings and identify potential pathways or biomarkers that could be targeted for therapy. Leveraging expert opinion, emerging evidence, and a case-based approach, this position paper provides critical insights on cytokine storm from both a prognostic and therapeutic standpoint.
Cardiovascular magnetic resonance myocardial feature tracking (CMR-FT) is a recently described method of post processing routine cine acquisitions which aims to provide quantitative measurements of ...circumferentially and radially directed ventricular wall strain. Inter-study reproducibility is important for serial assessments however has not been defined for CMR-FT.
16 healthy volunteers were imaged 3 times within a single day. The first examination was performed at 0900 after fasting and was immediately followed by the second. The third, non-fasting scan, was performed at 1400.CMR-FT measures of segmental and global strain parameters were calculated. Left ventricular (LV) circumferential and radial strain were determined in the short axis orientation (Ecc(SAX) and Err(SAX) respectively). LV and right ventricular longitudinal strain and LV radial strain were determined from the 4-chamber orientation (Ell(LV), Ell(RV), and Err(LAX) respectively). LV volumes and function were also analysed.Inter-study reproducibility and study sample sizes required to demonstrate 5% changes in absolute strain were determined by comparison of the first and second exams. The third exam was used to determine whether diurnal variation affected reproducibility.
CMR-FT strain analysis inter-study reproducibility was variable. Global strain assessment was more reproducible than segmental analysis. Overall Ecc(SAX) was the most reproducible measure of strain: coefficient of variation (CV) 38% and 20.3% and intraclass correlation coefficient (ICC) 0.68 (0.55-0.78) and 0.7 (0.32-0.89) for segmental and global analysis respectively. The least reproducible segmental measure was Ell(RV): CV 60% and ICC 0.56 (0.41-0.69) whilst the least reproducible global measure was Err(LAX): CV 33.3% and ICC 0.44 (0-0.77). Variable reproducibility was also reflected in the calculated sample sizes, which ranged from 11 (global Ecc(SAX)) to 156 subjects (segmental Ell(RV)). The reproducibility of LV volumes and function was excellent. There was no diurnal variation in global strain or LV volumetric measurements.
Inter-study reproducibility of CMR-FT varied between different parameters, as summarized above and was better for global rather than segmental analysis. It was not measurably affected by diurnal variation. CMR-FT may have potential for quantitative wall motion analysis with applications in patient management and clinical trials. However, inter-study reproducibility was relatively poor for segmental and long axis analyses of strain, which have yet to be validated, and may benefit from further development.
The Norwood surgical procedure restores functional systemic circulation in neonatal patients with single ventricle congenital heart defects, but this complex procedure carries a high mortality rate. ...In this study we address the need to provide an accurate patient specific risk prediction for one-year postoperative mortality or cardiac transplantation and prolonged length of hospital stay with the purpose of assisting clinicians and patients' families in the preoperative decision making process. Currently available risk prediction models either do not provide patient specific risk factors or only predict in-hospital mortality rates. We apply machine learning models to predict and calculate individual patient risk for mortality and prolonged length of stay using the Pediatric Heart Network Single Ventricle Reconstruction trial dataset. We applied a Markov Chain Monte-Carlo simulation method to impute missing data and then fed the selected variables to multiple machine learning models. The individual risk of mortality or cardiac transplantation calculation produced by our deep neural network model demonstrated 89 ± 4% accuracy and 0.95 ± 0.02 area under the receiver operating characteristic curve (AUROC). The C-statistics results for prediction of prolonged length of stay were 85 ± 3% accuracy and AUROC 0.94 ± 0.04. These predictive models and calculator may help to inform clinical and organizational decision making.
In patients at risk of cancer therapy-related cardiac dysfunction (CTRCD), initiation of cardioprotective therapy (CPT) is constrained by the low sensitivity of ejection fraction (EF) for minor ...changes in left ventricular (LV) function. Global longitudinal strain (GLS) is a robust and sensitive marker of LV dysfunction, but existing observational data have been insufficient to support a routine GLS-guided strategy for CPT.
This study sought to identify whether GLS-guided CPT prevents reduction in LVEF and development of CTRCD in high-risk patients undergoing potentially cardiotoxic chemotherapy, compared with usual care.
In this international, multicenter, prospective, randomized controlled trial, 331 anthracycline-treated patients with another heart failure risk factor were randomly allocated to CPT initiation guided by either ≥12% relative reduction in GLS (n = 166) or >10% absolute reduction of LVEF (n = 165). Patients were followed for EF and development of CTRCD (symptomatic EF reduction of >5% or >10% asymptomatic to <55%) over 1 year.
Of 331 randomized patients, 2 died, and 22 withdrew consent or were lost to follow-up. Among 307 patients (age: 54 ± 12 years; 94% women; baseline LVEF: 59 ± 6%; GLS: –20.6 ± 2.4%) with a median (interquartile range) follow-up of 1.02 years (0.98 to 1.07 years), most (n = 278) had breast cancer. Heart failure risk factors were prevalent: 29% had hypertension, and 13% had diabetes mellitus. At the 1-year follow-up, although the primary outcome of change in LVEF was not significantly different between the 2 arms, there was significantly greater use of CPT, and fewer patients met CTRCD criteria in the GLS-guided than the EF-guided arm (5.8% vs. 13.7%; p = 0.02), and the 1-year EF was 57 ± 6% versus 55 ± 7% (p = 0.05). Patients who received CPT in the EF-guided arm had a larger reduction in LVEF at follow-up than in the GLS-guided arm (9.1 ± 10.9% vs. 2.9 ± 7.4%; p = 0.03).
Although the change in LVEF was not different between the 2 arms as a whole, when patients who received CPT were compared, those in the GLS-guided arm had a significantly lower reduction in LVEF at 1 year follow-up. Furthermore, GLS-guided CPT significantly reduced a meaningful fall of LVEF to the abnormal range. The results support the use of GLS in surveillance for CTRCD. (Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes SUCCOUR; ACTRN12614000341628)
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The aims of the study were to assess the prognostic significance of cardiac magnetic resonance myocardial feature tracking (CMR-FT) in a large multicenter study and to evaluate the most potent CMR-FT ...predictor of hard clinical events following myocardial infarction (MI).
CMR-FT is a new method that allows accurate assessment of global and regional circumferential, radial, and longitudinal myocardial strain. The prognostic value of CMR-FT in patients with reperfused MI is unknown.
The study included 1,235 MI patients (n = 795 with ST-segment elevation MI and 440 with non–ST-elevation MI) at 15 centers. All patients were reperfused by primary percutaneous coronary intervention. Central core laboratory–masked analyses were performed to determine left ventricular (LV) circumferential, radial, and longitudinal strain. The primary clinical endpoint of the study was the occurrence of major adverse cardiac events within 12 months after infarction.
Patients with cardiovascular events had significantly impaired CMR-FT strain values (p < 0.001 for all). Global longitudinal strain was identified as the strongest CMR-FT parameter of future cardiovascular events and emerged as an independent predictor of poor prognosis following MI even after adjustment for established prognostic markers. Global longitudinal strain provided an incremental prognostic value for all-cause mortality above LV ejection fraction (c-index increase from 0.65 to 0.73; p = 0.04) and infarct size (c-index increase from 0.60 to 0.78; p = 0.002).
CMR-FT is a superior measure of LV function and performance early after reperfused MI with incremental prognostic value for mortality over and above LV ejection fraction and infarct size. (Abciximab i.v. Versus i.c. in ST-segment elevation Myocardial Infarction AIDA STEMI; NCT00712101; Thrombus Aspiration in ThrOmbus Containing culpRIT Lesions in Non-ST-Elevation Myocardial Infarction TATORT-NSTEMI; NCT01612312)
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Abstract Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy, characterized by excess proliferation, apoptosis resistance, inflammation, fibrosis, and vasoconstriction. ...Although PAH therapies target some of these vascular abnormalities (primarily vasoconstriction), most do not directly benefit the right ventricle (RV). This is suboptimal because a patient's functional state and prognosis are largely determined by the success of the adaptation of the RV to the increased afterload. The RV initially hypertrophies but might ultimately decompensate, becoming dilated, hypokinetic, and fibrotic. A number of pathophysiologic abnormalities have been identified in the PAH RV, including: ischemia and hibernation (partially reflecting RV capillary rarefaction), autonomic activation (due to G protein receptor kinase 2-mediated downregulation and desensitization of β-adrenergic receptors), mitochondrial-metabolic abnormalities (notably increased uncoupled glycolysis and glutaminolysis), and fibrosis. Many RV abnormalities are detectable using molecular imaging and might serve as biomarkers. Some molecular pathways, such as those regulating angiogenesis, metabolism, and mitochondrial dynamics, are similarly deranged in the RV and pulmonary vasculature, offering the possibility of therapies that treat the RV and pulmonary circulation. An important paradigm in PAH is that the RV and pulmonary circulation constitute a unified cardiopulmonary unit. Clinical trials of PAH pharmacotherapies should assess both components of the cardiopulmonary unit.
Objective To identify clinical factors associated with pulmonary hypertension (PH) and mortality in patients with congenital diaphragmatic hernia (CDH). Study design A prospective cohort of neonates ...with a diaphragm defect identified at 1 of 7 collaborating medical centers was studied. Echocardiograms were performed at 1 month and 3 months of age and analyzed at a central core by 2 cardiologists independently. Degree of PH and survival were tested for association with clinical variables using Fischer exact test, χ2 , and regression analysis. Results Two hundred twenty patients met inclusion criteria. Worse PH measured at 1 month of life was associated with higher mortality. Other factors associated with mortality were need for extracorporeal membrane oxygenation, patients inborn at the treating center, and patients with a prenatal diagnosis of CDH. Interestingly, patients with right sided CDH did not have worse outcomes. Conclusions Severity of PH is associated with mortality in CDH. Other factors associated with mortality were birth weight, gestational age at birth, inborn status, and need for extracorporeal membrane oxygenation.
Background
Cardiac surgery-associated acute kidney injury (AKI) is associated with increased morbidity and mortality in both adults and children.
Objectives
This study aimed to identify clinical risk ...factors for AKI following cardiac surgery in the pediatric population.
Data sources
PubMed/MEDLINE, Embase, Scopus, and reference lists of relevant articles were searched for studies published by August 2020.
Study eligibility criteria
Studies were included if (1) the population consisted of pediatric patients (< 18 years old), (2) patients underwent cardiac surgery, (3) risk factors were compared between patients who developed AKI and those who did not, and (4) studies were prospective or retrospective observational studies or randomized controlled trials.
Participants and interventions
Children undergoing pediatric cardiac surgery.
Study appraisal and synthesis methods
Random-effects meta-analysis was performed, comparing potential risk factors between pediatric patients who developed CS-AKI and those who did not.
Results
Sixty-one publications including a total of 19,680 participants (AKI: 7257 participants; no AKI: 12,423 participants) were included from studies published between 2008 and 2020. The pooled estimated incidence of AKI was 34.3% (95% confidence interval 30.0–38.8%,
I
2
= 96.8%). Binary risk factors that were significantly and consistently associated with AKI were the presence of pulmonary hypertension, cyanotic heart disease, univentricular heart, risk adjustment for congenital heart surgery 1 (RACHS-1) score ≥ 3, vasopressor use, cardiopulmonary bypass use, reoperation, and sepsis. Significant continuous risk factors included younger age, lower body weight, lower preoperative creatinine, higher preoperative estimated glomerular filtration rate (eGFR), higher RACHS-1 score, longer surgery time, longer cardiopulmonary bypass time, longer aortic cross-clamp time, and higher red blood cell transfusion volume.
Limitations
Results are limited by heterogeneity and potential residual confounding.
Conclusions and implications of key findings
Our meta-analysis identified clinical risk factors that are associated with AKI in children undergoing cardiac surgery. This might help clinicians anticipate and manage more carefully this population and implement standardized preventive strategies.
Systematic review registration number
CRD42021262699.
Graphical abstract
A higher resolution version of the Graphical abstract is available as Supplementary information.
Hepatic dysfunction is a recognized complication after Fontan palliation of congenital heart disease. We sought to quantitatively measure hepatic stiffness and vascular Doppler indices using ...ultrasound (US) and shear wave elastography (SWE) in a Fontan cohort. Subjects were prospectively recruited for echocardiography and real‐time hepatic duplex US with SWE for hepatic stiffness (kPa). Doppler peak velocities, velocity time integral, resistive, pulsatility, acceleration indices (RI, PI, AI), and flow volume were measured in celiac artery, superior mesenteric artery, and main portal vein (MPV). A subset underwent cardiac catheterizations with liver biopsy. Correlations were explored between SWE, duplex, hemodynamic, and histopathologic data. In all, 106 subjects were studied including 41 patients with Fontan physiology (age 13.8 ± 6 years, weight 45.4 ± 23 kg) and 65 controls (age 15.0 ± 8.4 years, weight 47.9 ± 22 kg). Patients with Fontan physiology had significantly higher hepatic stiffness (15.6 versus 5.5 kPa, P < 0.0001), higher celiac RI (0.78 versus 0.73, P = 0.04) superior mesenteric artery RI (0.89 versus 0.84, P = 0.005), and celiac PI (1.87 versus 1.6, P = 0.034); while MPV flow volume (287 versus 420 mL/min in controls, P = 0.007) and SMA AI (829 versus 1100, P = 0.002) were lower. Significant correlation was seen for stiffness with ventricular end‐diastolic pressure (P = 0.001) and pulmonary artery wedge pressure (P = 0.009). Greater stiffness correlated with greater degrees of histopathologic fibrosis. No significant change was seen in stiffness or other duplex indices with age, gender, time since Fontan, or ventricular morphology. Conclusion: Elevated hepatic afterload in Fontan, manifested by high ventricular end‐diastolic pressures and pulmonary arterial wedge pressures, is associated with remarkably increased hepatic stiffness, abnormal vascular flow patterns, and fibrotic histologic changes. The MPV is dilated and carries decreased flow volume, while the celiac and superior mesenteric arterial RI is increased. SWE is feasible in this population and shows promise as a means for predicting disease severity on liver biopsy. (Hepatology 2014;58:251–260)
Acute kidney injury (AKI) occurs frequently after cardiac surgery in children. Although current diagnostic criteria rely on serum creatinine and urine output, changes occur only after considerable ...loss of kidney function. This meta-analysis aimed to synthesize the knowledge on novel biomarkers and compare their ability to predict AKI. PubMed/MEDLINE, Embase, Scopus, and reference lists were searched for relevant studies published by March 2021. Diagnostic accuracy parameters were extracted and analyzed using hierarchical summary receiver operating characteristic (HSROC) method. Pooled estimates of the area under the curve (AUC) were calculated using conventional random-effects meta-analysis. Fifty-six articles investigating 49 biomarkers in 8617 participants fulfilled our eligibility criteria. Data from 37 studies were available for meta-analysis. Of the 10 biomarkers suitable for HSROC analysis, urinary neutrophil gelatinase-associated lipocalin (uNGAL) to creatinine (Cr) ratio yielded the highest diagnostic odds ratio (91.0, 95% CI 90.1–91.9), with a sensitivity of 91.3% (95% CI 91.2–91.3%) and a specificity of 89.7% (95% CI 89.6–89.7%). These results were confirmed in pooled AUC analysis, as uNGAL-to-Cr ratio and uNGAL were the only elaborately studied biomarkers (> 5 observations) with pooled AUCs ≥ 0.800. Liver fatty acid-binding protein (L-FABP), serum cystatin C (sCysC), serum NGAL (sNGAL), and interleukin-18 (IL-18) all had AUCs ≥ 0.700.
Conclusion
: A variety of biomarkers have been proposed as predictors of cardiac surgery-associated AKI in children, of which uNGAL was the most prominent with excellent diagnostic qualities. However, more consolidatory evidence will be required before these novel biomarkers may eventually help realize precision medicine in AKI management.
What is Known:
• Acute kidney injury (AKI) occurs in about 30–60% of children undergoing cardiac surgery and is associated with increased in-hospital mortality and adverse short-term outcomes. However, in current clinical practice, AKI definitions and detection often rely on changes in serum creatinine and urine output, which are late and insensitive markers of kidney injury.
• Although various novel biomarkers have been studied for the diagnosis of AKI in children after cardiac surgery, it remains unclear how these compare to one another in terms of diagnostic accuracy.
What is New:
• Pooled analyses suggest that for the diagnosis of AKI in children who underwent cardiac surgery, NGAL is the most accurate among the most frequently studied biomarkers.
• A number of other promising biomarkers have been reported, although they will require further research into their diagnostic accuracy and clinical applicability.
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