Fluid overload due to intravenous fluid therapy for vaso-occlusive crisis in sickle cell disease: incidence and risk factors.
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ABSTRACT:
SUBMITTER: Gaartman AE
PROVIDER: S-EPMC8456906 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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
Project description:Acute vaso-occlusive crisis (VOC) in sickle cell disease (SCD) is an important cause of end-organ damage. It is estimated that 10-39% of VOC occurs with hepatic involvement. Current assessments of hepatic involvement during VOC are unsatisfactory. We investigated transient elastography (TE) as a marker of hepatic involvement, its relationship with histology, and biochemical markers during VOC. SCD patients were evaluated with biochemical markers and TE at steady-state and during VOC. Change in TE and biochemical markers were correlated with length of hospital stay. When available, liver biopsy and tricuspid regurgitation velocity (TRV) at steady-state were correlated with TE. Twenty-three patients were evaluated (mean age = 34.3 years, standard deviation = 7.96). In 15 patients with liver biopsies, TE correlated with fibrosis (P = 0.01) and TRV (P = 0.0063), but not hepatic iron. Hemolysis biomarkers changed during VOC (P < 0.022), but not alanine aminotransferase (ALT). Paired comparison of TE at steady-state and during VOC showed an increased from 6.2 to 12.3 kPa (P = 0.0029). Increasing TE during VOC associated with increasing ALT and alkaline phosphatase (P = 0.0088 and 0.0099, respectively). At steady-state, increasing inflammation on biopsy (P = 0.0037) and TRV (P = 0.0075) correlated with increasing TE during VOC. Increased hospital stay was associated with higher ALT (P = 0.041), lower albumin (P = 0.046), hemoglobin/hematocrit (P < 0.0021) but not TE. TE may identify patients with hepatic involvement during VOC independent of biochemical measures. Increase in TE may reflect both hepatic passive congestion and hepatic involvement during VOC. TE may serve as a physiological biomarker for hepatic features of VOC.
| S-EPMC3808506 | biostudies-literature
Project description:Heme, released from red blood cells in sickle cell disease (SCD), interacts with toll-like receptor 4 (TLR4) to activate NF-κB leading to the production of cytokines and adhesion molecules which promote inflammation, pain, and vaso-occlusion. In SCD, TLR4 inhibition has been shown to modulate heme-induced microvascular stasis and lung injury. We sought to delineate the role of endothelial verses hematopoietic TLR4 in SCD by developing a TLR4 null transgenic sickle mouse. We bred a global Tlr4-/- deficiency state into Townes-AA mice expressing normal human adult hemoglobin A and Townes-SS mice expressing sickle hemoglobin S. SS-Tlr4-/- had similar complete blood counts and serum chemistries as SS-Tlr4 +/+ mice. However, SS-Tlr4-/- mice developed significantly less microvascular stasis in dorsal skin fold chambers than SS-Tlr4 +/+ mice in response to challenges with heme, lipopolysaccharide (LPS), and hypoxia/reoxygenation (H/R). To define a potential mechanism for decreased microvascular stasis in SS-Tlr4-/- mice, we measured pro-inflammatory NF-κB and adhesion molecules in livers post-heme challenge. Compared to heme-challenged SS-Tlr4 +/+ livers, SS-Tlr4 -/- livers had lower adhesion molecule and cytokine mRNAs, NF-κB phospho-p65, and adhesion molecule protein expression. Furthermore, lung P-selectin and von Willebrand factor immunostaining was reduced. Next, to establish if endothelial or hematopoietic cell TLR4 signaling is critical to vaso-occlusive physiology, we created chimeric mice by transplanting SS-Tlr4 -/- or SS-Tlr4 +/+ bone marrow into AA-Tlr4 -/- or AA-Tlr4 +/+ recipients. Hemin-stimulated microvascular stasis was significantly decreased when the recipient was AA-Tlr4-/- . These data demonstrate that endothelial, but not hematopoietic, TLR4 expression is necessary to initiate vaso-occlusive physiology in SS mice.
| S-EPMC7851052 | biostudies-literature
Project description:Painful vaso-occlusive crisis (VOC) remains the most common reason for presenting to the Emergency Department and hospitalization in patients with sickle cell disease (SCD). Although two new agents have been approved by the Food and Drug Administration for treating SCD, they both target to reduce the frequency of VOC. Results from studies investigating various approaches to treat and shorten VOC have so far been generally disappointing. In this paper, we will summarize the complex pathophysiology and downstream events of VOC and discuss the likely reasons for the disappointing results using monotherapy. We will put forward the rationale for exploring some of the currently available agents to either protect erythrocytes un-involved in the hemoglobin polymerization process from sickling induced by the secondary events, or a multipronged combination approach that targets the complex downstream pathways of VOC.
| S-EPMC8454100 | biostudies-literature
Project description:The metabolomic profile of vaso-occlusive crisis, compared to the basal state of sickle cell disease, has never been reported to our knowledge. Using a standardized targeted metabolomic approach, performed on plasma and erythrocyte fractions, we compared these two states of the disease in the same group of 40 patients. Among the 188 metabolites analyzed, 153 were accurately measured in plasma and 143 in red blood cells. Supervised paired partial least squares discriminant analysis (pPLS-DA) showed good predictive performance for test sets with median area under the receiver operating characteristic (AUROC) curves of 99% and mean p-values of 0.0005 and 0.0002 in plasma and erythrocytes, respectively. A total of 63 metabolites allowed discrimination between the two groups in the plasma, whereas 61 allowed discrimination in the erythrocytes. Overall, this signature points to altered arginine and nitric oxide metabolism, pain pathophysiology, hypoxia and energetic crisis, and membrane remodeling of red blood cells. It also revealed the alteration of metabolite concentrations that had not been previously associated with sickle cell disease. Our results demonstrate that the vaso-occlusive crisis has a specific metabolomic signature, distinct from that observed at steady state, which may be potentially helpful for finding predictive biomarkers for this acute life-threatening episode.
| S-EPMC7230294 | biostudies-literature
Project description:Individuals with sickle cell disease (SCD) are living further into adulthood in high-resource countries. However, despite increased quantity of life, recurrent, acute painful episodes cause significant morbidity for affected individuals. These SCD-related painful episodes, also referred to as vaso-occlusive crises (VOCs), have multifactorial causes, and they often occur as a result of multicellular aggregation and vascular adherence of red blood cells, neutrophils, and platelets, leading to recurrent and unpredictable occlusion of the microcirculation. In addition to severe pain, long-term complications of vaso-occlusion may include damage to muscle and/or bone, in addition to vital organs such as the liver, spleen, kidneys, and brain. Severe pain associated with VOCs also has a substantial detrimental impact on quality of life for individuals with SCD, and is associated with increased health care utilization, financial hardship, and impairments in education and vocation attainment. Previous treatments have targeted primarily SCD symptom management, or were broad nontargeted therapies, and include oral or parenteral hydration, analgesics (including opioids), nonsteroidal anti-inflammatory agents, and various other types of nonpharmacologic pain management strategies to treat the pain associated with VOC. With increased understanding of the pathophysiology of VOCs, there are several new potential therapies that specifically target the pathologic process of vaso-occlusion. These new therapies may reduce cell adhesion and inflammation, leading to decreased incidence of VOCs and prevention of end-organ damage. In this review, we consider the benefits and limitations of current treatments to reduce the occurrence of VOCs in individuals with SCD and the potential impact of emerging treatments on future disease management.
| S-EPMC7534097 | biostudies-literature
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
Project description:IntroductionSickle cell disease (SCD) is an inherited hemoglobinopathy disorder. The main consequence is synthesis of hemoglobin S leading to chronic hemolysis associated with morbidity. The aim of this study was to investigate Thrombin Generation Assay (TGA) to assess hypercoagulability in SCD and TGA parameters as biomarkers of vaso-occlusive crisis (VOC) risk and hospitalization within 1 year.Materials and methodsWe performed TGA in platelet poor plasma (PPP) with 1 pM of tissue factor and 4 μM of phospholipid-standardized concentration, in duplicate for patients and controls. We measured thrombomodulin (TM), soluble endothelial Protein C Receptor and Tissue Factor Pathway Inhibitor (TFPI).ResultsA total of 113 adult patients with SCD, 83 at steady state and 30 during VOC, and 25 healthy controls matched on age and gender were included. Among the 83 patients at steady state, (36 S/S-1 S/β0, 20 S/Sα3.7, and 19 S/C-7 S/β+) 28 developed a VOC within 1 year (median: 4 months [2.25-6]). We observed an increase of peak and velocity associated with a shortening of lagtime and time to peak (TTP) and no difference of endogenous thrombin potential (ETP) in patients compared to controls. TFPI (p < 0.001) and TM (p = 0.006) were significantly decreased. TGA confirmed hypercoagulability in all SCD genotypes and clinical status. The association of ETP > 1,207 nM.min and peak >228.5 nM presented a sensitivity of 73.5% and a specificity of 93.9% to predict VOC development within 1 year.ConclusionWe have demonstrated a hypercoagulable state in SCD associated with chronic hemolysis. These preliminary findings suggest that TGA parameters, as ETP and peak, could be used to predict VOC development within 1 year.
| S-EPMC9579298 | biostudies-literature
Project description:IntroductionVaso-occlusive crisis (VOC) is one of the main causes of hospital admission in patients with sickle cell disease (SCD). Ketamine is often used as an adjuvant to opioids to control sickle cell crisis; however, there is a lack of evidence about its safety and efficacy for VOC in SCD patients.ObjectiveTo synthesize evidence from published reports about the efficacy and safety of ketamine in the management of acute painful VOC in both pediatric and adult SCD patients.MethodsA systematic literature search of PubMed, Scopus, Web of Science, EBSCO and Cochrane Library was conducted, up to March 2019. Studies reporting the analgesic effects and side effects of ketamine in the management of acute painful VOC in pediatric and adult SCD patients were included. The primary outcome measure was improvement in pain scale, and the secondary outcomes were reduction in opioid utilization and side effects. Studies were narratively summarized in this review.ResultsFourteen studies (with a total of 604 patients) were included in the final analysis. Several case reports and case series showed that ketamine significantly reduced pain scales and opioid utilization in both populations. The only randomized controlled trial available showed that ketamine was noninferior to morphine in reducing pain scores, but had a higher incidence of nonlife-threatening, reversible adverse effects. However, a retrospective study of 33 patients showed a higher pain score in the ketamine group with an acceptable short-term adverse effect.ConclusionKetamine has a potentially comparable efficacy with other opioids in reducing the pain during VOC in SCD patients. However, it also likely has a higher rate of transient adverse events. Owing to the lack of published randomized controlled trials, current evidence is not sufficient to confirm the safety and efficacy of ketamine. Future well-designed randomized controlled trials are strongly recommended.
| S-EPMC7839575 | biostudies-literature
Project description:Pain is an hallmark of sickle-cell-related acute clinical manifestations as part of acute vaso-occlusive crisis (VOC). In SCD pain has different origins such as vascular or neuropathic pain, which requires multimodal analgesia. This is based on the administration of drugs with different pharmacological mechanisms of action, maximizing analgesia and minimizing their adverse events and the risk of drug-addition in patients experiencing acute-recurrent pain events as in SCD. Ketorolac is a potent non-narcotic analgesic, being relatively safe and effective during pain-management in children and adults. Up to now, there is a lack of safety information on continuous infusion ketorolac as used to control acute pain in patients with SCD, and the benefits/risks ratio needs to be investigated. Here, we report for the first time the safety profile of ketorolac in the special population of patients with SCD. We confirmed that ketorolac in combination with tramadol, an opioid like molecule, is effective in pain control of adult patients with SCD experiencing acute severe VOCs defined by pain visual analog scale. Our study shows that short term (72 h) continuous infusion of ketorolac plus tramadol is not associated with adverse events such as liver or kidney acute disfunction or abnormalities in coagulation parameters during patients' hospitalization and within 30 days after patients discharge. This is extremely important for patients with SCD, who should have access to multimodal therapy to control recurrent acute pain crisis in order to limit central sensitization a fearsome issue of undertreated recurrent acute pain and of chronic pain.
| S-EPMC10801952 | biostudies-literature