Cost analysis of acute care resource utilization among individuals with sickle cell disease in a middle-income country

Abstract Background The costs associated with the treatment of sickle cell disease (SCD) are understudied in low and middle-income countries (LMIC). We evaluated the cost of treating SCD-related acute complications and the potential cost-savings of hydroxyurea in a specialized hematology center in Brazil. Methods The costs (US dollars) of emergency department (ED) and hospitalizations from SCD-related complications between 01.01.2018 and 06.30.2018 were ascertained using absorption and micro-costing approaches. The reasons for acute hospital visits were grouped as: 1) vaso-occlusive (VOC) pain, 2) infection, 3) anemia exacerbation, and 4) chronic organ damage complications. Hydroxyurea adherence was estimated by medication possession ratio (MPR) during the study period. Results In total, 1144 patients, median age 17 years (range 0–70), 903 (78.9%) with HbSS/HbSβ0-thalassemia, 441 (38.5%) prescribed hydroxyurea, visited the ED, of whom 381 (33%) were admitted. VOC accounted for 64% of all ED visits and 60% of all admissions. Anemia exacerbation was the most expensive reason for ED visit ($321.87/visit), while chronic organ damage carried the highest admission cost ($2176.40/visit). Compared with other genotypes, individuals with HbSS/HbSβ0-thalassemia were admitted more often (79% versus 21%, p < 0.0001), and their admission costs were higher ($1677.18 versus $1224.47/visit, p = 0.0001). Antibiotics and analgesics accounted for 43% and 42% of the total ED costs, respectively, while housing accounted for 46% of the total admission costs. Costs of ED visits not resulting in admissions were lower among HbSS/HbSβ0-thalassemia individuals with hydroxyurea MPR ≥65% compared with visits by patients with MPR <65% ($98.16/visit versus $182.46/visit, p = 0.0007). No difference in admission costs were observed relative to hydroxyurea use. Discussion In a LMIC hematology-specialized center, VOCs accounted for most acute visits from patients with SCD, but costs were highest due to anemia exacerbation. Analgesics, antibiotics, and housing drove most expenses. Hydroxyurea may reduce ED costs among individuals with HbSS/HbSβ0-thalassemia but is dependent on adherence level.

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Cost Analysis of ACUTE Care Resource Utilization Among Individuals with Sickle Cell Disease in a Middle-Income Country

Blood ◽

10.1182/blood-2021-149639 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2987-2987

Author(s):

Clarisse Lobo ◽

Jane S Hankins ◽

Nickhill Bhakta ◽

Emilia Nascimento ◽

Patricia Gomes Moura ◽

...

Keyword(s):

Sickle Cell Disease ◽

Cost Savings ◽

Organ Damage ◽

Cell Disease ◽

Middle Income ◽

Disease Modifying Therapies ◽

Ed Visits ◽

Disease Modifying ◽

The Cost ◽

Hydroxyurea Therapy

Abstract Background: The costs associated with the treatment of sickle cell disease (SCD) are understudied in low and middle-income countries (LMIC), where resources are scarcer and policy decisions about resource allocation rely on detailed cost data. Few studies have investigated the cost-savings of disease-modifying therapies in SCD in real-world setting. We evaluated the cost of treating SCD-related acute complications and the potential cost-savings of hydroxyurea therapy at HEMORIO, a specialized tertiary hematology center in Brazil. Methods: The costs (US dollars) of emergency department (ED) and hospitalizations from SCD-related complications between 01.01.2018 and 06.30.2018 were ascertained using absorption and micro-costing approaches. ED costs are presented as cost per each ED event and hospital admission costs are presented as cost per each admission event. ED and admission costs (separated and combined) were determined and compartmentalized into several inputs by fixed and variable categories for all patients over the period of the study [Falk JA et al, Atlas 2001]. The cause of ED or hospital admission visit was verified by a physician and abstracted via medical record review. All hospital admissions were evaluated in the ED. If an ED encounter resulted in an admission, the encounter was counted as an admission event only. The causes related to SCD were grouped and classified according to the discharge diagnosis: 1) VOC (acute pain crisis, priapism or dactylitis); 2) Infection (fever, sepsis, or acute chest syndrome); 3) Anemia exacerbation (acute hemolytic crisis, transient aplastic crisis, or acute splenic sequestration); 4) Chronic organ damage (overt stroke, chronic kidney disease, chronic liver disease or organ failure. Hydroxyurea adherence was estimated by medication possession ratio (MPR) during the study period [Shah N, et al. Health and quality of life outcomes. 2019]. The one-sample proportions test with continuity correction compared the differences in frequency of ED or admissions across discharge diagnoses and the Wilcoxon rank sum test with continuity correction was used to compare cost differences across the groups. Results: In total, 1144 patients, median age 17 years (range 0-70), 903 (78.9%) with HbSS/HbSβ 0-thalassemia, 441 (38.5%) prescribed hydroxyurea, visited the ED, of whom 381 (33%) were admitted. VOC accounted for 64% of all ED visits and 60% of all admissions (Table 1). Anemia exacerbation was the most expensive reason for ED visit ($321.87/visit), while chronic organ damage carried the highest admission cost ($2,176.40/visit) (Figure 1). Compared with other genotypes, individuals with HbSS/HbSβ 0-thalassemia were admitted more often (79% versus 21%, p<0.0001), and their admission costs were higher ($1,677.18 versus $1,224.47/visit, p=0.0001). Antibiotics and analgesics accounted for 43% and 42% of the total ED costs, respectively, while housing accounted for 46% of the total admission costs (Figure 2). In a regression tree analysis, costs of ED visits were lower among HbSS/HbSβ 0-thalassemia individuals with hydroxyurea MPR ≥65% compared with those with MPR<65% or untreated ($182.46 versus $98.16/visit, p=0.0007). No difference in admission costs were observed relative to hydroxyurea use. Discussion: It is estimated that between 60,000 to 100,000 individuals live with SCD in Brazil today [Lobo CL, et al. Pediatric blood & cancer. 2014]. In a LMIC hematology-specialized center, VOCs accounted for most acute visits from patients with SCD, but costs were highest due to anemia exacerbation. Analgesics, antibiotics, and housing drove most expenses. Our results confirm the lower acute health care resource utilization with hydroxyurea therapy (fewer ED visits and admissions among those prescribed this medication). Hydroxyurea therapy reduced ED costs among individuals with HbSS/HbSβ 0-thalassemia, however, was dependent on adherence level. A cost analysis of individuals with SCD has never been performed in Brazil previously. Our study will facilitate appropriate planning of allocation of funds and development of health policies for individuals with SCD and may serve as the benchmark against which new SCD disease-modifying therapies may be compared for cost-effectiveness and cost-savings estimation in LMIC, such as Brazil. Figure 1 Figure 1. Disclosures Lobo: Novartis: Consultancy. Hankins: Global Blood Therapeutics: Consultancy; UpToDate: Consultancy; Vindico Medical Education: Consultancy; Bluebird Bio: Consultancy.

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Drug Therapies for the Management of Sickle Cell Disease

F1000Research ◽

10.12688/f1000research.22433.1 ◽

2020 ◽

Vol 9 ◽

pp. 592

Author(s):

Parul Rai ◽

Kenneth I. Ataga

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Organ Damage ◽

The United States ◽

Cell Disease ◽

Multiple Agents ◽

Middle Income ◽

Hematopoietic Stem ◽

Rich Countries ◽

Low And Middle Income

Sickle cell disease (SCD) afflicts millions of people worldwide but is referred to as an orphan disease in the United States. Over the past several decades, there has been an increasing understanding of the pathophysiology of SCD and its complications. While most individuals with SCD in resource-rich countries survive into adulthood, the life expectancy of patients with SCD remains substantially shorter than for the general African-American population. SCD can be cured using hematopoietic stem cell transplantation and possibly gene therapy, but these treatment approaches are not available to most patients, the majority of whom reside in low- and middle-income countries. Until relatively recently, only one drug, hydroxyurea, was approved by the US Food and Drug Administration to ameliorate disease severity. Multiple other drugs (L-glutamine, crizanlizumab, and voxelotor) have recently been approved for the treatment of SCD, with several others at various stages of clinical testing. The availability of multiple agents to treat SCD raises questions related to the choice of appropriate drug therapy, combination of multiple agents, and affordability of recently approved products. The enthusiasm for new drug development provides opportunities to involve patients in low- and middle-income nations in the testing of potentially disease-modifying therapies and has the potential to contribute to capacity building in these environments. Demonstration that these agents, alone or in combination, can prevent or decrease end-organ damage would provide additional evidence for the role of drug therapies in improving outcomes in SCD.

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Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Antioxidants ◽

10.3390/antiox10020296 ◽

2021 ◽

Vol 10 (2) ◽

pp. 296

Author(s):

Rosa Vona ◽

Nadia Maria Sposi ◽

Lorenza Mattia ◽

Lucrezia Gambardella ◽

Elisabetta Straface ◽

...

Keyword(s):

Oxidative Stress ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Globin Gene ◽

Organ Damage ◽

Cell Disease ◽

Vessel Occlusion ◽

Antioxidant Agents ◽

Oxidant Status

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

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Targeting pain at its source in sickle cell disease

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00021.2018 ◽

2018 ◽

Vol 315 (1) ◽

pp. R104-R112 ◽

Cited By ~ 8

Author(s):

Kanika Gupta ◽

Om Jahagirdar ◽

Kalpna Gupta

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Cell Activation ◽

Molecular Mechanisms ◽

Genetic Disorder ◽

Somatosensory System ◽

Organ Damage ◽

Mast Cell Activation ◽

Cell Disease ◽

Central Nervous Systems

Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

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The gut microbiome in sickle cell disease: Characterization and potential implications

PLoS ONE ◽

10.1371/journal.pone.0255956 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0255956

Author(s):

Hassan Brim ◽

James Taylor ◽

Muneer Abbas ◽

Kimberly Vilmenay ◽

Mohammad Daremipouran ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Gut Microbiome ◽

Tissue Injury ◽

Organ Damage ◽

Composition Analysis ◽

Cell Disease ◽

Blood Disorder ◽

Major Player ◽

Next Generation Sequencing Ngs

Background Sickle Cell Disease (SCD) is an inherited blood disorder that leads to hemolytic anemia, pain, organ damage and early mortality. It is characterized by polymerized deoxygenated hemoglobin, rigid sickle red blood cells and vaso-occlusive crises (VOC). Recurrent hypoxia-reperfusion injury in the gut of SCD patients could increase tissue injury, permeability, and bacterial translocation. In this context, the gut microbiome, a major player in health and disease, might have significant impact. This study sought to characterize the gut microbiome in SCD. Methods Stool and saliva samples were collected from healthy controls (n = 14) and SCD subjects (n = 14). Stool samples were also collected from humanized SCD murine models including Berk, Townes and corresponding control mice. Amplified 16S rDNA was used for bacterial composition analysis using Next Generation Sequencing (NGS). Pairwise group analyses established differential bacterial groups at many taxonomy levels. Bacterial group abundance and differentials were established using DeSeq software. Results A major dysbiosis was observed in SCD patients. The Firmicutes/Bacteroidetes ratio was lower in these patients. The following bacterial families were more abundant in SCD patients: Acetobacteraceae, Acidaminococcaceae, Candidatus Saccharibacteria, Peptostreptococcaceae, Bifidobacteriaceae, Veillonellaceae, Actinomycetaceae, Clostridiales, Bacteroidacbactereae and Fusobacteriaceae. This dysbiosis translated into 420 different operational taxonomic units (OTUs). Townes SCD mice also displayed gut microbiome dysbiosis as seen in human SCD. Conclusion A major dysbiosis was observed in SCD patients for bacteria that are known strong pro-inflammatory triggers. The Townes mouse showed dysbiosis as well and might serve as a good model to study gut microbiome modulation and its impact on SCD pathophysiology.

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Sickle Cell Disease Model Mice Lacking 2,3-Dpg Show Reduced RBC Sickling and Improvements in Markers of Hemolytic Anemia

Blood ◽

10.1182/blood-2020-142052 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-28

Author(s):

Kelly M. Knee ◽

Amey Barakat ◽

Lindsay Tomlinson ◽

Lila Ramaiah ◽

Zane Wenzel ◽

...

Keyword(s):

Sickle Cell Disease ◽

Blood Cell ◽

Hemolytic Anemia ◽

Sickle Cell ◽

Red Blood Cell ◽

Organ Damage ◽

Complete Elimination ◽

Cell Disease ◽

The Impact ◽

2,3 Dpg

Sickle cell disease (SCD) is a severe genetic disorder caused by a mutation in hemoglobin (b6Glu-Val), which allows the mutant hemoglobin to assemble into long polymers when deoxygenated. Over time, these polymers build up and deform red blood cells, leading to hemolytic anemia, vaso-occlusion, and end organ damage. A number of recent therapies for SCD have focused on modulating the mutant hemoglobin directly, however, reduction or elimination of 2,3-DPG to reduce Hb S polymerization and RBC sickling has recently been proposed as a therapeutic strategy for SCD. Current clinical studies focus on activation of pyruvate kinase to reduce 2,3-DPG, however, direct targeting of the enzyme which produces 2,3-DPG; Bisphosphoglycerate Mutase (BPGM) may also be possible. In this study we evaluate the impact of elimination of 2,3-DPG on SCD pathology by complete knockout of BPGM in Townes model mice. Animals with complete knockout of BPGM (BPGM -/-) have no detectable 2,3-DPG, while animals that are heterozygous for BPGM (BPGM -/+) have 2,3-DPG levels comparable to Townes mice. Western Blot analysis confirms that BPGM -/- animals completely lack BPGM, while BPGM -/+ animals have BPGM levels that are nearly equivalent to Townes mice. As expected from the lack of 2,3-DPG, BPGM -/- animals have increased oxygen affinity, observed as a 39% decrease in p50 relative to Townes mice. Complete elimination of 2,3-DPG has significant effects on markers of hemolytic anemia in BPGM -/- mice. Mice lacking 2,3-DPG have a 60% increase in hemoglobin (3.7 g/dL), a 53% increase in red blood cell count, and a 29% increase in hematocrit relative to Townes mice. The BPGM -/- mice also have a 57% decrease in reticulocytes, and a 61% decrease in spleen weight relative to Townes animals, consistent with decreased extramedullary hematopoiesis. Consistent with the reduction in hemolysis, BPGM -/- animals had a 59% reduction in red blood cell sickling under robust hypoxic conditions. BPGM -/+ animals had hemoglobin, RBC, and hematocrit levels that were similar to Townes animals, and a similar degree of RBC sickling to Townes mice. Liver phenotype was similar across all variants, with areas of random necrosis observed in BPGM -/-, BPGM -/+ and Townes mice. Higher percentages of microcytic and/or hyperchromic RBCs were observed in BPGM -/- animals relative to BPGM -/+ or Townes animals. These results suggest that modulation of 2,3-DPG has a positive effect on RBC sickling and hemolytic anemia, which may have therapeutic benefits for SCD patients. However, the lack of improvement in organ damage suggests that modulation of 2,3-DPG alone may not be sufficient for complete elimination of SCD phenotypes, and further investigation of this therapeutic avenue may be necessary. Disclosures No relevant conflicts of interest to declare.

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Potential role of LSD1 inhibitors in the treatment of sickle cell disease: a review of preclinical animal model data

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00440.2017 ◽

2018 ◽

Vol 315 (4) ◽

pp. R840-R847 ◽

Cited By ~ 1

Author(s):

Angela Rivers ◽

Ramasamy Jagadeeswaran ◽

Donald Lavelle

Keyword(s):

Reactive Oxygen Species ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Globin Gene ◽

Reactive Oxygen ◽

Organ Damage ◽

The United States ◽

Oxygen Species ◽

Cell Disease ◽

Hematopoietic Stem

Sickle cell disease (SCD) is caused by a mutation of the β-globin gene (Ingram VM. Nature 180: 326–328, 1957), which triggers the polymerization of deoxygenated sickle hemoglobin (HbS). Approximately 100,000 SCD patients in the United States and millions worldwide (Piel FB, et al. PLoS Med 10: e1001484, 2013) suffer from chronic hemolytic anemia, painful crises, multisystem organ damage, and reduced life expectancy (Rees DC, et al. Lancet 376: 2018–2031, 2010; Serjeant GR. Cold Spring Harb Perspect Med 3: a011783, 2013). Hematopoietic stem cell transplantation can be curative, but the majority of patients do not have a suitable donor (Talano JA, Cairo MS. Eur J Haematol 94: 391–399, 2015). Advanced gene-editing technologies also offer the possibility of a cure (Goodman MA, Malik P. Ther Adv Hematol 7: 302–315, 2016; Lettre G, Bauer DE. Lancet 387: 2554–2564, 2016), but the likelihood that these strategies can be mobilized to treat the large numbers of patients residing in developing countries is remote. A pharmacological treatment to increase fetal hemoglobin (HbF) as a therapy for SCD has been a long-sought goal, because increased levels of HbF (α2γ2) inhibit the polymerization of HbS (Poillin WN, et al. Proc Natl Acad Sci USA 90: 5039–5043, 1993; Sunshine HR, et al. J Mol Biol 133: 435–467, 1979) and are associated with reduced symptoms and increased lifespan of SCD patients (Platt OS, et al. N Engl J Med 330: 1639–1644, 1994; Platt OS, et al. N Engl J Med 325: 11–16, 1991). Only two drugs, hydroxyurea and l-glutamine, are approved by the US Food and Drug Administration for treatment of SCD. Hydroxyurea is ineffective at HbF induction in ~50% of patients (Charache S, et al. N Engl J Med 332: 1317–1322, 1995). While polymerization of HbS has been traditionally considered the driving force in the hemolysis of SCD, the excessive reactive oxygen species generated from red blood cells, with further amplification by intravascular hemolysis, also are a major contributor to SCD pathology. This review highlights a new class of drugs, lysine-specific demethylase (LSD1) inhibitors, that induce HbF and reduce reactive oxygen species.

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Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease

Therapeutic Advances in Hematology ◽

10.1177/2040620720955000 ◽

2020 ◽

Vol 11 ◽

pp. 204062072095500

Author(s):

Ifeyinwa Osunkwo ◽

Deepa Manwani ◽

Julie Kanter

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Severe Pain ◽

Management Strategies ◽

Organ Damage ◽

Care Utilization ◽

Cell Disease ◽

High Resource ◽

Emerging Treatments

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.

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Emergency Department Management of Children with Sickle Cell Disease.

Blood ◽

10.1182/blood.v104.11.1660.1660 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1660-1660

Author(s):

Melissa J. Frei-Jones ◽

Amy L. Baxter ◽

Charles T. Quinn ◽

George R. Buchanan

Keyword(s):

Emergency Department ◽

Steady State ◽

Sickle Cell Disease ◽

Hospital Admission ◽

Sickle Cell ◽

Admission Rate ◽

Categorical Variables ◽

Continuous Variables ◽

Cell Disease ◽

Ed Visits

Abstract Vaso-occlusive crises (VOC) are a common cause of emergency department (ED) visits for children with sickle cell disease (SCD). To better understand our patient population and compare with reports from other centers, we sought to describe the presentation, management, and disposition of children with VOC at our center’s ED. We also aimed to identify predictors of hospital admission. We retrospectively reviewed hospital records of all patients with SCD, age 8–19 years, who presented to our urban pediatric ED in 2003 with a chief complaint of pain. We identified all subjects diagnosed with VOC and not another cause of pain. We obtained the following data for each: SCD genotype; duration of VOC and treatment prior to ED presentation; the nature of analgesia and use of intravenous fluids (IVF) in the ED; hemoglobin (Hgb) concentration; and disposition (admitted, discharged, discharged with subsequent ED visit for same crisis). Categorical variables were evaluated by the χ2 and Fisher exact tests and continuous variables by the t-test. Odds ratios (OR) and 95% confidence intervals (CI) were calculated where appropriate. In 2003, there were 320 ED visits for patients with SCD and pain. Among these, there were 279 diagnoses of VOC in 105 individual patients: 45 had one visit, 25 two visits, and 16 ≥5 visits. Mean number of visits per patient was 2.7; 23 (22%) patients accounted for 145 (55%) visits. Homozygous sickle cell anemia (Hgb SS) was present in 73/105 patients, accounting for 222 (79%) ED visits. Overall admission rate was 179/279 (64%), with 167/179 admitted on their first visit and 12 on their return visit. Subjects with Hgb SS accounted for 147/179 (82%) admissions. Among those discharged who later returned to the ED during the same VOC, the admission rate was 86% (5 returned in 24 hours, 5 in 48 hours, 3 in 72 hours, and one 4 days later). Pre-ED home opioid use was reported in 75% of visits and was associated with increased likelihood of discharge (OR 1.63, CI 0.94–2.84, p=0.082). Duration of VOC before presentation did not significantly affect admission rate and averaged 53.2 hours for admitted patients and 49.7 hours for those discharged (p=0.689). Patients who received IVF in the ED (219/279; 79%) were less likely to be admitted (31% vs 56%, p<0.001). Hgb concentration was increased in 61%, decreased in 36% and unchanged in 3% of patients from steady-state values and was not associated with admission. After receiving 2 doses of morphine, 31 patients were discharged from the ED, while only 5 patients were discharged after receiving 3 or 4 doses of morphine. A departmental VOC protocol was followed for 25.4% of patients, with no impact on admission rate (p=0.290). In this retrospective analysis of a large series of pediatric sickle cell ED visits, patients presented later in their VOC, and admission rate was higher than previously reported. A small proportion of older patients with SCD accounted for most ED visits and hospitalizations. Hgb variation from steady-state was neither clinically significant nor predictive of admission or discharge. In contrast to previous studies, receiving IVF in the ED was associated with a greater likelihood of discharge. Home opioids prior to ED presentation seemed to decrease hospital admission. Adherence to our center’s VOC protocol did not appear to influence disposition from the ED.

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Reduced Oxidative Stress and Enhanced Nitric Oxide (NO) Bioavailability in Transgenic-Knockout Sickle Mice Expressing Fetal Hemoglobin (HbF) Is Mediated by Decreased Sickling and Hemolysis.

Blood ◽

10.1182/blood.v110.11.842.842 ◽

2007 ◽

Vol 110 (11) ◽

pp. 842-842

Author(s):

Trisha Dasgupta ◽

Mary E. Fabry ◽

Dhananjay K. Kaul

Keyword(s):

Oxidative Stress ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Genetic Manipulation ◽

Fetal Hemoglobin ◽

Organ Damage ◽

Multiple Organ ◽

Protective Effects ◽

Cell Disease ◽

No Bioavailability

Abstract The primary event in the vaso-occlusive pathophysiology of sickle cell disease (SCD) is polymerization of hemoglobin S under deoxygenated conditions. In SCD, sub-clinical transient vaso-occlusive events caused by red cell sickling are likely to be more frequent resulting in “reperfusion injury” that generates reactive oxygen species and results in chronic oxidative stress that will contribute to multiple organ damage. In fact, previous studies have suggested that sickling is etiologic to repefusion injury and oxidative stress (Kaul and Hebbel, JCI, 2000), although the effect of antisickling therapy on oxidative stress has not been evaluated. Increasing the levels of antisickling fetal hemoglobin (HbF) by hydroxyurea therapy markedly reduces polymer formation. HbF exerts an ameliorating effect in sickle cell disease patients both on red cells and in the prevention of multiple organ damage. Here, we hypothesize that induction of HbF by genetic manipulation (in the absence of pharmacological manipulation) will reduce organ oxidative stress by reducing sickling and hemolysis, and thereby increase NO bioavailability. To test our hypothesis, we measured activity of selected antioxidants and lipid peroxidation (LPO) in BERK mice expressing exclusively human α- and βS-globins and varying levels of HbF, i.e., BERK (<1% HbF), BERKγM (20% HbF) and BERKγH (40% HbF). Percent sickled cells in venous samples (drawn in 2.5% glutaraldehyde solution in 0.1M cacodylate buffer) showed a distinct decrease with increased %HbF (P<0.05, multiple comparisons). Consistent with maximal sickling, BERK mice showed 5.4–6.9-fold increase in LPO in various tissues (muscle, kidney and liver) compared with C57BL controls (P<0.001). In contrast, BERKγM and BERKγH mice showed a marked decrease (73% and 80%, respectively) in LPO compared with BERK mice (P<0.001). Also, activity/levels of antioxidants (superoxide dismutase [SOD], catalase, glutathione peroxidase [GPx] and reduced glutathione [GSH]) showed significant decreases in BERK mice (P<0.001–0.00001). On the other hand, BERKγM and BERKγH mice showed significant increases in antioxidant activity (P<0.05–0.0001). Induction of HbF was associated with increased levels of NO metabolites (NOx) and reduced hemolysis; the latter is in agreement with our previous observations in BERKγM mice (Kaul et al. JCI, 2004). These results strongly suggest that reduced sickling and hemolysis in the presence of HbF cause increased NO bioavailability. NO is well known to exert antioxidative effects. Thus, we show for the first time that the induction of antisickling HbF leads to an increase in NO bioavailability and a decrease in oxidative stress, and that these protective effects are mediated primarily by reduced intravascular sickling.

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