Project description:Altered mitochondrial function occurs in sickle cell disease (SCD), due in part to low nitric oxide (NO) bioavailability. Arginine, the substrate for NO production, becomes acutely deficient in SCD patients with vaso-occlusive pain episodes (VOE). To determine if arginine improves mitochondrial function, 12 children with SCD-VOE (13.6 ± 3 years; 67% male; 75% hemoglobin-SS) were randomized to 1 of 3 arginine doses: (1) 100 mg/kg IV 3 times/day (TID); (2) loading dose (200 mg/kg) then 100 mg/kg TID; or (3) loading dose (200 mg/kg) followed by continuous infusion (300 mg/kg per day) until discharge. Platelet-rich plasma mitochondrial activity, protein expression, and protein-carbonyls were measured from emergency department (ED) presentation vs discharge. All VOE subjects at ED presentation had significantly decreased complex-V activity compared to a steady-state cohort. Notably, complex-V activity was increased at discharge in subjects from all 3 arginine-dosing schemes; greatest increase occurred with a loading dose (P < .001). Although complex-IV and citrate synthase activities were similar in VOE platelets vs steady state, enzyme activities were significantly increased in VOE subjects after arginine-loading dose treatment. Arginine also decreased protein-carbonyl levels across all treatment doses (P < .01), suggesting a decrease in oxidative stress. Arginine therapy increases mitochondrial activity and reduces oxidative stress in children with SCD/VOE. This trial was registered at www.clinicaltrials.gov as #NCT02536170.

| S-EPMC7498366 | biostudies-literature

Intravenous Fluid Administration and the Risk of Adverse Outcomes in Sickle Cell Disease Patients Hospitalized for Vaso-Occlusive Crisis.

Project description:Vaso-occlusive crisis (VOC) is the leading cause of hospitalization in sickle cell disease (SCD). Intravenous fluid (IVF) administration is the usual practice during VOC episodes to slow the sickling process. In the absence of an evidence-based, clear-cut consensus on the optimal choice, route, and rate of fluid administration, there has been a wide variability in the practice of IVF administration in the treatment of VOC. However, there are growing concerns about the safety of this practice. This systematic review summarized the current evidence on the risk of negative outcomes in SCD patients treated for VOC with IVFs. A database search of Medline/PubMed, EMBASE, Scopus, Web of Science, CINAHL, Wiley Cochrane Library, Clinicaltrials.gov, and conference proceedings of the European Hematology Association (EHA) and American Society of Hematology (ASH) were performed. The results were presented using narrative analysis of quantitative data. Of the 2,821 identified records, a total of three eligible retrospective cohort studies with a total demographic population of 549 SCD patients were included in this review. Normal saline, a frequently used IVF for VOC may be associated with adverse outcomes such as poor pain control and volume overload. Volume overload, new oxygen requirement, acute chest syndrome, and acute kidney injury are potential adverse outcomes of inappropriate IVF use in VOC. There is limited evidence supporting the current practice of IVF use in VOC. Randomized controlled trials are required to fully clarify the place and safety of IVF in the management of VOC.

| S-EPMC9635800 | biostudies-literature

Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial.

Project description:Sickle cell anaemia (SCA) is a progressive vascular disease characterized by episodic vaso-occlusive pain. Despite the broad impact of inflammation on acute and chronic clinical manifestations of SCA, no directed anti-inflammatory therapies currently exist. Statins are cholesterol-lowering agents shown to confer protection from vascular injury by suppressing inflammation. We previously documented a reduction in soluble biomarkers of inflammation in patients with sickle cell disease treated with simvastatin. To determine the potential clinical efficacy of simvastatin, we treated 19 SCA patients with single daily dose simvastatin for 3 months and assessed changes from baseline in the frequency and intensity of diary-reported pain and levels of circulating nitric oxide metabolites (NOx), high sensitivity C-reactive protein (hs-CRP), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), ICAM-3, E-selectin, and vascular endothelial growth factor (VEGF). Treatment with simvastatin resulted in a significant reduction in the frequency of pain (P = 0·0003), oral analgesic use (P = 0·003) and circulating hs-CRP (P = 0·003), soluble (s)E-selectin (P = 0·01), sICAM-1 (P = 0·02), sICAM-3 (P = 0·02) and sVEGF (P = 0·01). Simvastatin had no effect on pain intensity or levels of NOx, sP-selectin and sVCAM-1. The observed reductions in pain rate and markers of inflammation were greatest in subjects receiving hydroxycarbamide (HC), suggesting a synergistic effect of simvastatin. These results provide preliminary clinical data to support a larger trial of simvastatin in SCA.

| S-EPMC5435522 | biostudies-literature

Crizanlizumab for the Prevention of Vaso-Occlusive Pain Crises in Sickle Cell Disease.

Project description:Objective: To review the efficacy and safety of crizanlizumab (Adakveo) in the prevention of vaso-occlusive pain crises in sickle cell disease. Data Sources: An English-language literature search of PubMed, MEDLINE, and Ovid (1946 to January 2021) was completed using the terms crizanlizumab, SEG101, SelG1, and sickle cell disease. Manufacturer prescribing information, article bibliographies, and data from clinicaltrials.gov were incorporated in the reviewed data. Study Selection/Data Extraction: All studies registered on clinicaltrials.gov were incorporated in the reviewed data. Data Synthesis: Crizanlizumab is the first monoclonal antibody approved for sickle cell disease to reduce the frequency of vaso-occlusive crises. One phase 2 clinical trial and a post hoc analysis of the trial have been published. Relevance to Patient Care and Clinical Practice: Crizanlizumab is a monthly intravenous infusion approved by the Food and Drug Administration for patients with sickle cell disease 16 years of age and older to reduce the frequency of vaso-occlusive crises. Conclusion: Crizanlizumab appears to be an efficacious therapy for patients with sickle cell disease to reduce the frequency of vaso-occlusive crises. Concerns include drug cost and administration. Long-term benefits and risks have not been determined.

| S-EPMC8255978 | biostudies-literature

A polygenic score for acute vaso-occlusive pain in pediatric sickle cell disease.

Project description:Individuals with monogenic disorders can experience variable phenotypes that are influenced by genetic variation. To investigate this in sickle cell disease (SCD), we performed whole-genome sequencing (WGS) of 722 individuals with hemoglobin HbSS or HbSβ0-thalassemia from Baylor College of Medicine and from the St. Jude Children's Research Hospital Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort study. We developed pipelines to identify genetic variants that modulate sickle hemoglobin polymerization in red blood cells and combined these with pain-associated variants to build a polygenic score (PGS) for acute vaso-occlusive pain (VOP). Overall, we interrogated the α-thalassemia deletion -α3.7 and 133 candidate single-nucleotide polymorphisms (SNPs) across 66 genes for associations with VOP in 327 SCCRIP participants followed longitudinally over 6 years. Twenty-one SNPs in 9 loci were associated with VOP, including 3 (BCL11A, MYB, and the β-like globin gene cluster) that regulate erythrocyte fetal hemoglobin (HbF) levels and 6 (COMT, TBC1D1, KCNJ6, FAAH, NR3C1, and IL1A) that were associated previously with various pain syndromes. An unweighted PGS integrating all 21 SNPs was associated with the VOP event rate (estimate, 0.35; standard error, 0.04; P = 5.9 × 10-14) and VOP event occurrence (estimate, 0.42; standard error, 0.06; P = 4.1 × 10-13). These associations were stronger than those of any single locus. Our findings provide insights into the genetic modulation of VOP in children with SCD. More generally, we demonstrate the utility of WGS for investigating genetic contributions to the variable expression of SCD-associated morbidities.

| S-EPMC8341359 | biostudies-literature

Intravenous magnesium for pediatric sickle cell vaso-occlusive crisis: methodological issues of a randomized controlled trial.

Project description:Multiple recent Sickle Cell Disease studies have been terminated due to poor enrollment. We developed methods to overcome past barriers and utilized these to study the efficacy and safety of intravenous magnesium for vaso-occlusive crisis (VOC). We describe the methods of the Intravenous Magnesium in Sickle Vaso-occlusive Crisis (MAGiC) trial and discuss methods used to overcome past barriers. MAGiC was a multi-center randomized double-blind placebo-controlled trial of intravenous magnesium versus normal saline for treatment of VOC. The study was a collaboration between Pediatric Hematologists and Emergency Physicians in the Pediatric Emergency Care Applied Research Network (PECARN). Eligible patients were randomized within 12 hours of receiving intravenous opioids in the Emergency Department (ED) and administered study medication every 8 hours. The primary outcome was hospital length of stay. Associated plasma studies elucidated magnesium's mechanism of action and the pathophysiology of VOC. Health-related quality of life was measured. Site-, protocol-, and patient-related barriers from prior studies were identified and addressed. Limited study staff availability, lack of collaboration with the ED, and difficulty obtaining consent were previously identified barriers. Leveraging PECARN resources, forging close collaborations between Sickle Cell Centers and EDs of participating sites, and approaching eligible patients for prior consent helped overcome these barriers. Participation in the PECARN network and establishment of collaborative arrangements between Sickle Cell Centers and their affiliated EDs are major innovative features of the MAGiC study that allowed improved subject capture. These methods could serve as a model for future studies of VOCs.

| S-EPMC3995128 | biostudies-literature

Impact of PCA strategies on pain intensity and functional assessment measures in adults with sickle cell disease during hospitalized vaso-occlusive episodes.

Project description: Not available

| S-EPMC3533241 | biostudies-literature

Opioid Use in Adults With Sickle Cell Disease Hospitalized During Vaso-Occlusive Crisis: A Systematic Review.

Project description:BackgroundWhile pain is the hallmark of sickle cell disease (SCD), healthcare personnel are often ill-equipped to adequately treat patients who present in vaso-occlusive crisis (VOC). Although symptom severity varies from individual to individual, SCD is characterized by intervallic pain as a result of oxygen deprivation in tissues and organs. Regardless of pain severity, SCD patients are often viewed as drug seekers by healthcare personnel who have concerns regarding patients' dependence on opioids which may lead to addiction. The objective was to assess the types and amount of opioids used to treat VOC in comparison to Centers for Disease Control opioid prescription guidelines.MethodsLiterature search was conducted using CINAHL, PubMed, the Cochrane Library, Web of Science and hand search. Data were analyzed from 1999 to 2018. Randomized trials, observational, and case studies involved hospitalized adults with SCD who were prescribed opioids to treat VOC. Quality assessment was conducted using Downs and Black checklist. Meta-analysis was not conducted.ResultsFive studies were conducted in the USA, Arabia and the Netherlands, and the USA and Canada were included. Participants were treated with either morphine or morphine milligram equivalent (MME). No study used the same method of opioid administration.ConclusionsPatients with SCD who are hospitalized secondary to VOC mostly received opioids for pain well within the Centers for Disease Control and Prevention prescription guidelines. No uniform method exists. Additional research is warranted.

| S-EPMC8110229 | biostudies-literature

Haptoglobin genotype predicts severe acute vaso-occlusive pain episodes in children with sickle cell anemia.

Project description: Not available

| S-EPMC7343605 | biostudies-literature