Painful Vaso-occlusive Crises Research Articles

Brain network hypersensitivity underlies pain crises in sickle cell disease

Sickle cell disease (SCD) is a genetic disorder causing painful and unpredictable Vaso-occlusive crises (VOCs) through blood vessel blockages. In this study, we propose explosive synchronization (ES) as a novel approach to comprehend the hypersensitivity and occurrence of VOCs in the SCD brain network. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) as well as VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited lower alpha frequency than controls. SCD patients showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, stronger FDA was observed in SCD patients with a higher frequency of VOCs and EEG recording near VOC. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Our model demonstrated that a stronger FDA could be linked to increased sensitivity and frequency of VOCs. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.

Plant-Produced Therapeutic Crizanlizumab Monoclonal Antibody Binds P-Selectin to Alleviate Vaso-occlusive Pain Crises in Sickle Cell Disease.

Sickle Cell Disease (SCD) is a severe genetic disorder causing vascular occlusion and pain by upregulating the adhesion molecule P-selectin on endothelial cells and platelets. It primarily affects infants and children, causing chronic pain, circulatory problems, organ damage, and complications. Thus, effective treatment and management are crucial to reduce SCD-related risks. Anti-P-selectin antibody Crizanlizumab (Crimab) has been used to treat SCD. In this study, the heavy and light chain (HC and LC) genes of anti-P-Selectin antibody Crimab were cloned into a plant expression binary vector. The HC gene was under control of the duplicated 35S promoter and nopaline synthase (NOS) terminator, whereas the LC gene was under control of the potato proteinase inhibitor II (PIN2) promoter and PIN2 terminator. Agrobacterium tumefaciens LBA4404 was used to transfer the genes into the tobacco (Nicotiana tabacum cv. Xanthi) plant. In plants the genomic PCR and western blot confirmed gene presence and expression of HC and LC Crimab proteins in the plant, respectively. Crimab was successfully purified from transgenic plant leaf using protein A affinity chromatography. In ELISA, plant-derived Crimab (CrimabP) had similar binding activity to P-selectin compared to mammalian-derived Crimab (CrimabM). In surface plasmon resonance, the KD (dissociation binding constant) and response unit values were lower and higher than CrimabP, respectively. Taken together, these results demonstrate that the transgenic plant can be applied to produce biofunctional therapeutic monoclonal antibody.

Risk factors for acute chest syndrome among children with sickle cell anemia hospitalized for vaso-occlusive crises

Sickle cell anemia (SCA) is a globally prevalent inherited condition, with acute chest syndrome (ACS) being one of its most severe complications. ACS frequently leads to hospitalization, requires intensive care unit (ICU) admission, and can even result in death. This study aimed to discern the early indicators of impending ACS in children with SCA who were initially hospitalized due to painful vaso-occlusive crises (VOC). This was a retrospective, case‒control investigation of 120 patients aged 1–14 years seen at the King Saud Medical City in Riyadh, Saudi Arabia from January 2021 to December 2022. Patients were classified into cases and controls: those who developed and did not develop ACS during hospital stay, respectively. Demographic factors, laboratory results, vital and clinical signs, and treatment protocols were compared between these groups. The following were significant predictors of impending ACS: previous diagnosis of asthma, history of ACS, recent upper respiratory tract symptoms prior to admission, and need for a blood transfusion within the first 24 h of admission due to a drop in hemoglobin levels. Further regression analysis indicated that elevated steady-state mean corpuscular volume, leukocyte count, total bilirubin, and an increased absolute neutrophil count level 24 h after admission also foreshadowed impending ACS among patients admitted for VOC. The location of pain was also significant; the incidence of ACS was higher in patients with back pain, but lower in those with pain confined to the limbs. The ACS group had a longer average duration of hospital stay compared to those with VOC alone, (7.6 vs. 5.8 days). Among patients initially admitted for VOC, 15.7% were diagnosed with ACS. Most ACS cases were managed with transfusions and antibiotics, and nearly one-third of patients needed admission to an ICU or a high-dependency area.

Intravenous Hydration and Associated Outcomes in Patients With Sickle Cell Disease Admitted With Vaso-Occlusive Crises: A Systematic Review.

Acute painful vaso-occlusive crisis (VOC) is the common presentation of sickle cell disease (SCD) leading to emergency room visits, admissions, morbidity, mortality, and negative impacts on quality of life. Among various treatment approaches commonly employed to manage the condition, intravenous (IV) hydration is also frequently used in emergency and inpatient settings. Although helpful to overcome dehydration, IV hydration often leads to adverse outcomes like fluid overload, pulmonary edema, increased length of stay, transfer to intensive care unit, new oxygen requirement, etc. Small-scale retrospective studies are conducted to study the outcomes of IV hydration but have failed to conclusively demonstrate its benefits as well as choice of IV fluids, rate of IV fluid replacement, etc. We conduct this review as an attempt to summarize the available evidence on the role and utility of IV hydration in sickle cell crises along with reported adverse outcomes.

Incidence and risk factors of pain crisis after hematopoietic cell transplantation for sickle cell disease

AbstractVaso-occlusive episodes (VOC) or pain crises are the most common indications for hematopoietic cell transplantation (HCT) for sickle cell disease (SCD). Elimination of pain crisis after HCT is an important patient-centered outcome and may improve understanding of the natural history of pain syndromes in SCD. We examined deidentified records of 763 patients followed-up for a median of 36.7 months (range, 0.3-168.6 months), with 69.6% patient's age <18 years at HCT, 83.3% patient's Karnofsky-Lansky performance score (KPS) ≥90, overall survival 92.9%, event-free survival 72.4%, graft failure (GF) 22.4%, AGVHD 21.4%, CGVHD 27%, and pain crisis 8.65%. On unadjusted logistic regression, increased risk of pain crisis after HCT was observed in patient's aged >10 years at HCT (range, 11-17 years; OR, 9.43; 95% CI, 3.20-27.79; P < .0001), in age ≥18 years (OR, 16.62; 95% CI, 5.85-47.16; P < .0001), in those with history of pain crisis 2 years before HCT (OR, 13.16; 95% CI, 4.08-42.42; P < .0001), alternate donors (haploidentical [OR, 4.80; 95% CI, 2.48-9.31; P < .0001], unrelated matched [OR, 2.71; 95% CI, 1.23-5.97; P = .0132], and mismatched unrelated [OR, 3.19; 95% CI, 1.44-7.05; P = .0041], and those with GF (n = 41 [5.37%]; OR, 7.15; 95% CI, 4.20-12.18; P < .0001). Pain crisis was less frequent with KPS of ≥90 (OR, 0.31; 95% CI, 0.18-0.55; P < .0001). Multivariable logistic regression models confirmed age at HCT, KPS, graft type, donor type, history of VOC 2 years before HCT, and GF as independent predictors of pain crisis after HCT and generated predictive models and nomograms for pain crisis after HCT for SCD, which can support shared decision making.

Sickle Cell Health Awareness, Perspectives, and Experiences (SHAPE) Survey: Findings on the Burden of Sickle Cell Disease and Impact on the Quality of Life of Patients and Caregivers in Gulf Cooperation Council Countries

Introduction: Sickle cell disease (SCD) is an inherited disorder that adversely impacts the physical and emotional well-being of patients and caregivers, yet research on the impact of SCD on quality of life (QoL) is limited. In a systematic review the prevalence of SCD in Gulf Cooperation Council (GCC) countries ranged 0.24-5.8% (Abu-Shaheen et al. Expert Rev Hematol 2022). The 3 countries with the highest prevalence were Bahrain (1.2-2.1%, 2 studies), Saudi Arabia (0.24-4.5%, 15 studies), and Oman (5.8%, 1 study). The Sickle Cell Health Awareness, Perspectives, and Experiences (SHAPE) survey aimed to improve our understanding of the global burden of SCD. This analysis reports the experiences of patients with SCD and caregivers in GCC countries who participated in the SHAPE survey within the context of insights obtained globally. Methods: The SHAPE survey included patients and caregivers from Brazil, Canada, France, Germany, the UK, the US, and 4 countries in the GCC (Bahrain, Oman [patients only], Saudi Arabia, and the United Arab Emirates [UAE]). Participants completed a 12-minute face-to-face survey (GCC only) or online survey (other countries) comprising close-ended questions about their experiences with SCD. Patients with SCD aged ≥12 years and caregivers aged ≥18 years supporting a patient with SCD were eligible. Results: Of 919 patients and 207 caregivers globally who responded, 150 patients (16.3%; Saudi Arabia n=70, the UAE n=46, Bahrain n=19, and Oman n=15) and 50 caregivers (24.2%; Saudi Arabia n=25, the UAE n=17, and Bahrain n=8) were from GCC countries (Table). Symptoms experienced most frequently by patients in GCC countries and all surveyed patients, respectively, were fatigue/tiredness (91% vs 84%), bone aches (91% vs 69%), and vaso-occlusive crisis (VOC) pain (81% vs 71%). Compared with all surveyed patients, a significantly greater proportion of patients in GCC countries experienced fatigue/tiredness, bones aches, VOC pain, generalized pain, and signs of organ damage (Figure). Symptoms reported by a significantly smaller proportion of patients in GCC countries than by all surveyed patients were poor sleep/insomnia, poor appetite, memory/concentration issues, nausea, yellow eyes/nails/skin, vision difficulties/retinopathy, and leg ulcers. The top 3 symptoms patients in GCC countries reported as being most impactful in terms of the following categories were: (i) relationships/potential relationships (25% VOC pain, 19% low mood/feeling depressed, 16% bone aches); (ii) family (30% VOC pain, 12% bone aches, 11% low mood/feeling depressed); and (iii) long-term health prospects (29% bone aches, 23% VOC pain, 21% signs of organ damage). The average number of missed school/work days in the past month for patients was 3.9 in GCC countries and 7.5 globally. A smaller proportion of patients in GCC countries were optimistic about their future compared with all surveyed patients (35% vs 52%). The biggest concerns of caregivers of individuals with SCD were worsening of symptoms (54% in GCC countries vs 17% globally) and early loss of life (34% vs 39%). Approximately half of caregivers agreed that caring for a person with SCD had a big or noticeable impact on their family (52% in GCC countries vs 50% globally). The majority of caregivers agreed they were well-equipped to care for someone with SCD (80% in GCC countries vs 72% globally). A smaller proportion of caregivers in GCC countries were optimistic about the future of the person they care for with SCD compared with all surveyed caregivers (32% vs 62%). Conclusions: Findings from the SHAPE survey highlight the physical and emotional burden of SCD on patients and caregivers in GCC countries. Patients in GCC countries reported VOC pain, bone aches, and low mood/feeling depressed as symptoms that most affected their relationships/potential relationships and family. Caregivers in GCC countries expressed concerns about early loss of life and worsening SCD symptoms. Overall, these findings underline the need for effective treatments that alleviate symptoms and manage disease sequalae, and for additional resources to improve the QoL of patients and caregivers.

Steady-State Von Willebrand Factor Antigen Levels Predict Low Platelet Counts and Risk for Complications in Hospitalizations for Painful Sickle Cell Vaso-Occlusive Episodes

We previously reported that a &amp;gt;20% decline in platelet counts from steady state to presentation predicted severe complications during hospitalization for vaso-occlusive pain crisis (VOC) in 130 adult sickle cell disease (SCD) patients. 1 Sharp platelet decline in acute chest syndrome was reported to be accompanied by large von Willebrand Factor (VWF) aggregates adherent to pulmonary vascular endothelium in SCD. 2 A prospective study of 24 SCD patients found a significant increase of VWF reactivity in VOC admissions relative to steady state, which correlated with low platelet counts and the development of acute chest syndrome. 3 We aimed to investigate the role of steady-state VWF antigen level and ADAMTS13 activity as predictors of platelet count decline and severe complications in VOC admissions. Plasma levels of VWF antigen and ADAMTS13 activity were measured 4 for 56 patients at steady-state outpatient visits (Baseline). VWF antigen was expressed as fold increase or decrease from the concentration in normal pooled plasma of 12.2 ug/ml; ADAMTS13 activity was expressed as fold of the value from normal pooled plasma which was considered 100% activity. Electronic records of VOC admission that occurred &amp;gt;21 days after Baseline were reviewed. Exclusion criteria included non-VOC admissions defined as elective admission for surgery, admission for accident or injury, admission for delivery of an infant, or admission with a pain score &amp;lt;8/10 at presentation. 5 A total of 98 qualifying admissions were identified. Severe complication during the admission was defined as having any of the following: 1) acute chest syndrome, new infiltrate on chest X-ray, or use of ventilator; 2) acute kidney injury; 6 3) acute liver injury; 7 4) thrombotic or hemorrhagic stroke; 5) venous thromboembolism including deep vein thrombosis, atrial thrombosis, and pulmonary embolism; 6) need for transfer to the intensive care unit; 7) need for exchange blood transfusion; 8) death during hospitalization. Platelet counts at presentation to the emergency room (ER) leading to the admissions under study were recorded, as well platelet counts at Baseline. The 56 patients had a median (range) age of 37 (21-66) years; 52% are female, 89% with hemoglobin SS or Sβ 0-thalassemia, and 57% on hydroxyrea (HU). Severe complication occurred in 35 (36%) of the 98 admissions involving 27 (48%) of the patients. Focusing on the first admissions, higher steady-state VWF antigen levels correlated strongly with lower ER platelet counts (ρ= -0.50, P=0.00011, Figure 1A) and higher steady-state ADAMTS13 activity correlated weakly with ER platelet counts (Spearman's ρ= 0.30, P=0.025). The ratio of VWF antigen to ADAMTS13 activity ratio also correlated strongly with lower ER platelet counts (ρ= -0.52, P=0.000052, Figure 1B). In contrast, steady-state VWF antigen level (ρ= -0.17, P=0.23), ADAMTS13 activity (ρ= 0.19, P=0.17), and VWF antigen to ADAMTS13 activity ratio (ρ= -0.23, P=0.098) showed no significant correlation with steady-state platelet counts. The correlations remained by adjusting for age, gender, Hb genotype severity, HU, and treatment of anticoagulant, aspirin, or non-steroidal anti-inflammatory drugs at VOC visits. In analyses restricted to admissions &amp;gt;1 year after Baseline, the correlation between steady-state VWF antigen level and ER platelet counts appeared to persist. Focusing on the 28 first admissions, steady-state VWF antigen level (ρ= -0.50, P=0.0071) and VWF antigen to ADAMTS13 activity ratio (ρ= -0.44, P=0.018) correlated negatively with ER platelet counts. Steady-state ADAMTS13 activity did not correlate with ER platelet counts in admissions that occurred &amp;gt;1 year after Baseline (ρ= 0.16, P=0.43). We further examined the association of steady-state VWF antigen level, ADAMTS13 activity, and their ratio with risk for severe complication in admission. Focusing on the first 56 admissions, which involved 23 complications, steady-state VWF antigen level in the top quartile (1.63) associated with risk for severe complications (OR=6.5, 95% CI 1.4-31, P=0.018, n=56), adjusting for age, gender, Hb genotype severity, and HU. Our observations suggest that steady-state VWF antigen level and the ratio of VWF antigen level to ADAMTS13 activity predict low platelet counts at presentation to VOC admissions, and that steady-state VWF antigen level in SCD patients may be a relatively stable marker for risk of severe VOC complications.

Non-Traumatic Epidural Hematoma in Sickle Cell Disease

Non-traumatic epidural hematoma is an extremely rare finding in patients with sickle cell disease. Spontaneous intracranial epidural hemorrhage has been associated with coagulopathy, malignancy, and infection, but few cases secondary to sickle cell disease have been reported in the literature. The mechanism of hemorrhage in these patients is often unclear, although previous cases have suggested associations with vaso-occlusive pain crises, bone infarction, and/or vascular malformations. We report a 9 year old male with sickle cell disease type SS who presented with right shoulder pain, headaches, emesis, and no neurological deficits. CT head revealed large mixed density left frontoparietal epidural hematoma leading to complete left lateral ventricle effacement and 0.5 cm left to right midline shift. He subsequently underwent a left parietal craniotomy for evacuation of epidural hematoma from which he recovered well. The prevalence and proposed pathologic process behind this rare complication will be discussed.

Impact of Srs-CoV2 Infection on Pain Crises and Acute Chest Syndome in Patients with Sickle Cell Anemia: A Retrospective Multi-Cohort Study Based on USA Data from 2020-2022

Objective: To determine the impact of SARS-CoV-2 infection on vaso-occlusive pain crisis (VOC) and acute chest syndrome (ACS), incidence, and outcomes in sickle cell anemia (SCA) patients. Method: This retrospective study used the TriNetX USA health research network database to identify SCA patients (Hb-SS, Sβ0-thal) ages 1-50 with and without concomitant SARS-CoV-2 infection from May 2020 to May 2022. A total of 6 cohorts were created: pain crisis with/without SARS-CoV-2, ACS with/without SARS-CoV-2, and SARS-CoV-2 without pain crisis/ACS. Patients with SARS-CoV-2 and pain crisis/ACS were compared to 2 cohorts (SARS-CoV-2 without pain crisis/ACS) for demographic characteristics, baseline laboratory parameters, disease-modifying drug use, and influenza/COVID-19 vaccination status by t-tests. Pain crisis/ACS patients with SARS-CoV-2 were then compared to 2 cohorts (pain crisis/ACS without concomitant infection) for demographic characteristics, and relative risk for acute settings of care, pain control, laboratory parameters/outcomes (including hemolytic and inflammatory markers), procedures (blood transfusion) and mortality. Results : The incidence of pain crises and ACS in SCA patients following SARS-CoV-2 infection was 34 and 27 per 100 patients, respectively. The risk of developing ACS was significantly increased by SARS-CoV-2 infection (2.57% vs. 1.17%, RR 2.2), but not the risk of developing a pain crisis (RR 1.04). Pain crisis and ACS patients with concomitant SARS-CoV-2 infection had a greater risk for inpatient services, subsequent hospital visits, opioid and non-opioid analgesia, blood transfusions, and concerning hemolytic and inflammatory markers compared to those without the infection. Patients with SARS-CoV-2 who did not develop pain crises/ACS had higher baseline hemoglobin levels prior to infection compared to patients who developed pain crisis/ACS. There was a higher rate of COVID-19 and influenza vaccination in the cohorts who did not develop pain crisis/ACS and might have improved pain crisis rates (but not ACS) following SARS-CoV-2 infection. Conclusions: COVID-19 illness had an impact on the incidence of both pain crises and ACS, significantly increased the risk of developing ACS, and influenced morbidity outcomes for both pain crises and ACS. Prior vaccination against influenza and COVID-19 may represent a protective factor for developing pain crises.

Clinical Results of a Randomized Placebo Controlled Trial of Inhaled Mometasone to Promote Reduction in Vaso-Occlusive Events (IMPROVE-II)

Introduction: A subset of patients living with sickle cell disease (SCD) who do not meet diagnostic criteria for asthma exhibit episodic cough or wheeze (ECW), and this is associated with higher rates of vaso-occlusive pain crisis and acute chest syndrome. ECW may be caused by pulmonary inflammation from SCD. In the former IMPROVE trial, 54 patients with SCD and ECW were randomized to receive 16 weeks of placebo or mometasone furoate, an inhaled corticosteroid used to treat pulmonary inflammation. Treatment with mometasone was associated with significant reductions in daily pain, markers of hemolysis, and soluble vascular cell adhesion molecule (sVCAM) (a biomarker of disease severity in SCD) compared to placebo. The IMPROVE-II trial evaluated whether treatment with mometasone over a longer period could improve clinical and biological endpoints in non-asthmatic patients with SCD and ECW. We report here the clinical outcomes from the IMPROVE-II trial. Methods: We conducted a randomized, placebo-controlled, single-center interventional trial. Patients with SCD without asthma were randomized to receive either mometasone furoate 220 mcg or placebo inhaled powder for 48 weeks followed by a 4-week wash out. Key inclusion criteria included age &amp;gt; 18 years with SCD genotype HbSS/HbSβ0 at stable baseline who endorsed ECW. Patients were excluded if they had &amp;gt;15 emergency department (ED) visits for vaso-occlusive pain crisis in the past 12 months or if other treatments for SCD (i.e. hydroxyurea, L-glutamine) were being titrated. The primary outcome was the change in soluble vascular cell adhesion molecule (sVCAM) level with treatment. Clinical outcomes included ED visits and hospitalizations for any reason, and health care visits for acute chest syndrome, pneumonia, stroke, or transient ischemic attack, as well as daily pain (self-report 1-10 scale), and 6 Minute Walk. Adaptive covariate randomization was used to balance covariates including hydroxyurea use (yes/no), age, and previous rate of ED use. Results: A total of 80 patients were randomized and 77 received study treatment; 40 were assigned to mometasone and 37 to placebo (Figure 1). There were no significant differences between treatment groups in patient demographics (Table 1). Treatment with mometasone was associated with higher rates of acute care visits for vaso-occlusive crisis (4 (2/19) vs 1 (1/3) /patient year (50%(25%/75%), p&amp;lt;0.001), hospitalization for acute chest syndrome (mean 0.2 vs 0.1/patient year, p=0.05) and ED utilization (2 (1/5) vs 2 (1/4) /patient year (50%(25%/75%), p0.01). Laboratory outcomes including sVCAM are not yet resulted. Adverse events that were reported by more than 5% of patients are listed in Table 1; there was no difference between rates of adverse (&amp;lt;5%) events between mometasone and placebo. There were no deaths during the study. Conclusions: In individuals with SCD and ECW who do not have asthma, long-term treatment with inhaled corticosteroids did not improve clinical outcomes and may be harmful as they were associated with higher rates of acute care visits for pain crisis, ED visits, and acute chest syndrome. Further analyses of biological endpoints and clinical laboratory data are needed to fully elucidate the effects of inhaled corticosteroids in SCD.

Omega-3 Fatty Acid Supplements in Reducing Vaso-Occlusive Crisis Hospitalizations in Patients with Sickle Cell Disease: A Systemic Review and Meta-Analysis

Introduction Omega-3 fatty acids (O3FA) have been evaluated in various clinical settings for sickle cell disease (SCD) patients with promising results. This study aims to assess the efficacy and safety of O3FA supplements in preventing SCD complications. Methods We systematically searched Embase, PubMed, and Cochrane Register of Controlled Trials from inception to May 26 th, 2023. Studies that met the following criteria were included: (1) randomized controlled trials (RCTs) or nonrandomized studies of interventions; (2) comparing O3FA supplements to the standard of care (with or without hydroxyurea treatment); (3) patients with sickle cell disease; (4) and reporting at least one clinical outcomes of interest. We excluded studies (1) with unstable treatment history 3-6 months before the beginning of the studies; or (2) with patients on regular blood transfusion. Our outcomes of interest included (1) the frequency of painful vaso-occlusive crisis or acute chest syndrome requiring hospitalization; and (2) hemoglobin level after intervention. We used Review manager software to perform statistical analyses. The random effect model was applied to all analyses due to anticipated heterogeneity. Pooled mean differences and 95% confidence intervals (CI) were used to assess outcomes. Results We screened 188 studies and included four RCTs and one self-controlled cohort in the meta-analysis. Our population included 349 patients aged between 2 years to adults; 54.7% received O3FA supplements. The docosahexaenoic acid (DHA) dose ranged from 10 to 60 mg per kilogram daily. Follow-up varied from 3 to 12 months. More than two-thirds were hemoglobin SS disease, as presented in Table 1. Other SCD syndromes included hemoglobin S-beta 0 thalassemia and hemoglobin SC disease. Severe baseline disease (³ 3 episodes of painful vaso-occlusive crisis per year requiring hospital admission) ranged between 23.5% and all patients among studies. The vaso-occlusive crisis episodes were significantly reduced in the O3FA group compared with standard treatment: mean difference (MD)-1.63 times (95% CI: -2.35 to -0.91; p = 0.00001; I 2 = 54%), as seen in Figure 1a. There was no difference in hemoglobin levels after intervention with O3FA versus standard treatment (MD: 0.03; 95% CI: -0.25 to 0.32; p = 0.82). In the subgroup of patients without hydroxyurea treatment, the mean frequency of vaso-occlusive crisis was significantly lower with O3FA supplements compared with standard treatment (MD: -1.60; 95% CI: -2.47 to -0.72; p = 0.0004; I 2 = 67%), as shown in Figure 1b. There were no significant adverse events (AE) in the O3FA group. The most common AE were increased appetite, dyspepsia, and occasional “fishy” smell. One patient discontinued O3FA supplements because of drug-related abdominal pain. Conclusion Our systematic review and meta-analysis support O3FA supplementation as a safe and effective complementary strategy to reduce painful vaso-occlusive crises in patients with SCD.

Apohemoglobin-Hpatoglobin Promotes Blood Flow in Sickle Cell Disease Mice

In sickle cell disease (SCD), a single change in the β-globin gene coding sequence results in the production of hemoglobin S (HbS). This HbS polymerizes when deoxygenated, causing red blood cell (RBC) sickling, hemolysis, anemia, reduced blood flow in small vessels, activation of vascular endothelial cells, vaso-occlusion, and ischemia. These abnormalities lead to various clinical complications, including fatigue, painful vaso-occlusive crises (VOC), reduced quality of life, organ damage, and early death. The management of SCD involves supportive care, pain management, blood transfusions, and disease-modifying therapies, all aimed at alleviating symptoms and improving the overall quality of life for affected individuals. We propose a new therapy that uses a biologic called apohemoglobin-haptoglobin (apoHb-Hp), which scavenges free circulating Hb and heme. This study examined the efficacy of apoHb-Hp in reducing vaso-occlusion in a mouse model of sickle cell disease (SCD) using transgenic mice expressing HbSS-Towne (sickle cell mice) and compared them to mice expressing normal Hb, HbAA-Towne. A single dose (10 mg/kg) of normal saline (control), Haptoglobin (Hp), or apoHb-Hp was administered before the experiment, and twenty-four subcutaneous venules were selected and mapped after baseline selection. The same vessels were re-examined for stasis at 2, 8, 24, and 48 hours, and the percentage of stasis was calculated. The results demonstrated that microvascular stasis occurs spontaneously in the Towns transgenic mice model but can be reduced by a single dose of the apoHb-Hp complex. In another set of experiments, mice were pretreated with the apoHb-Hp complex or Hp and then challenged with hypoxia-reoxygenation (hypoxia of 10% oxygen for one hour) and followed for 48 hours. Hypoxia induced microvascular stasis, also known as vaso-occlusion, which increased post-hypoxia and slowly disappeared over time in Towns mice. The study showed that pre-treatment with the apoHb-Hp complex or Hp improved the rates of recovery from vaso-occlusive crises. A single dose of the apoHb-Hp complex also reduced vascular stasis. In the last study, we administered Hb mixed with either Ringer's lactate, apoHb-Hp complex, or Hp to Towns mice fitted with the dorsal window. We knew that exogenous Hb could cause vascular stasis in Towns mice, so we aimed to investigate the effectiveness of the apoHb-Hp complex compared to Hp in preventing Hb-induced vascular stasis. The Hb infusion led to maximal stasis within an hour in the control group. Therefore, microvascular stasis occurred one hour after infusing Hb alone or with equimolar apoHb-Hp complex and Hp. Our results showed that mice co-infused with Hb + apoHb-Hp complex or Hb + Hp had significantly lower stasis levels compared to mice infused with Hb alone. Surprisingly, the apoHb-Hp complex was more effective than Hp alone in reducing Hb-induced stasis. These findings provide insight into the underlying mechanisms of the apoHb-Hp complex and demonstrate its efficacy in reducing vaso-occlusion. Further studies are necessary to optimize the therapeutic use of the apoHb-Hp complex.

A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study of Mitapivat in Patients with Sickle Cell Disease: RISE UP Phase 2 Results

Background: Sickle cell disease (SCD) is characterized by the presence of hemoglobin S (HbS), a structural variant caused by a mutation in the HBB gene. Deoxygenated HbS molecules polymerize into “fibers”, causing red blood cells (RBCs) to sickle and hemolyze. Sickled RBCs have a shortened lifespan and impede blood flow to tissues, causing painful vaso-occlusive crises. Recurrent microvascular damage and chronic hemolytic anemia result in progressive multi-organ damage. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase, a key enzyme in RBC metabolism, with a dual mechanism of action under investigation in SCD: it increases adenosine triphosphate (ATP) in RBCs, improving survival, and decreases 2,3−diphosphoglycerate, increasing Hb oxygen affinity and thus diminishing HbS polymerization and RBC sickling. RISE UP is a global Phase (Ph) 2/3 double-blind, randomized, placebo (PBO)-controlled trial evaluating the efficacy and safety of mitapivat in patients (pts) with SCD (NCT05031780). Methods: In the Ph 2 double-blind period (DBP), 2 dose levels of mitapivat were evaluated against PBO for 12 weeks (wks). Eligible pts were ≥16 years with ≥5.5 to ≤10.5 g/dL Hb and ≥2 to ≤10 sickle cell pain crises (SCPCs, including pain, priapism, acute chest syndrome, hepatic sequestration, and splenic sequestration) in year prior to entry. Pts were randomized 1:1:1 to mitapivat 50 mg twice daily (BID), mitapivat 100 mg BID, or matched PBO. Pts completing the DBP were eligible to receive mitapivat in a 216-wk open-label extension. Primary endpoints were Hb response (≥1.0 g/dL increase in average Hb concentrations from Wks 10 through 12 compared with baseline [BL], tested with Fisher's exact test at 2-sided 0.05 significance level) and adverse events (AEs), including the type, severity, and relationship to study drug. Prespecified secondary endpoints included average change from BL from Wks 10 through 12 in Hb, markers of hemolysis, markers of erythropoiesis, and pt-reported fatigue score, as well as annualized rate of SCPCs. Results: In the Ph 2 DBP, 79 pts were randomized and treated with mitapivat 50 mg BID (n=26), mitapivat 100 mg BID (n=26), or PBO (n=27). In the 50 mg BID, 100 mg BID, and PBO arms, mean (SD) age was: 29.9 (7.79), 30.2 (10.52), and 28.5 (10.30) years; female: 57.7%, 61.5%, and 74.1%; mean (SD) BL Hb: 8.76 (1.295), 8.82 (0.898), and 8.49 (1.141) g/dL; mean (SD) number of SCPCs during previous year: 3.1 (1.83), 3.2 (1.65), and 3.4 (1.91), respectively. The primary endpoint was achieved; 46.2% (12/26) of pts in the 50 mg BID arm and 50.0% (13/26) in the 100 mg BID arm demonstrated a significant increase in Hb response compared with 3.7% (1/27) of pts in the PBO arm (2-sided p=0.0003 and p=0.0001, respectively). Mitapivat was generally well tolerated; observed safety profile was consistent with previously reported data of mitapivat in SCD and other hemolytic anemias. No serious treatment-emergent AEs were related to study drug; no AEs led to study drug discontinuation or death. Least-squares mean (LSM [95% CI]) for average change from BL in Hb levels from Wks 10 through 12 was 1.11 (0.77, 1.45) g/dL, 1.13 (0.79, 1.47) g/dL, and 0.05 (−0.28, 0.39) g/dL for 50 mg BID, 100 mg BID, and PBO arms, respectively ( Figure). Improvements were observed in markers of hemolysis and erythropoiesis. SCPCs annualized rates (95% CI) were 0.83 (0.34, 1.99) and 0.51 (0.16, 1.59) for 50 mg BID and 100 mg BID arms, respectively, compared to 1.71 (0.95, 3.08) for PBO. LSM (95% CI) for average changes from BL in pt-reported fatigue score from Wks 10 through 12 was −3.80 (−7.16, −0.45), −0.10 (−3.27, 3.08), and −0.17 (−3.40, 3.07) for 50 mg BID, 100 mg BID, and PBO arms, respectively ( Table). Conclusion: During the Ph 2 DBP of RISE UP, treatment with mitapivat demonstrated statistically significant and clinically meaningful improvement in Hb response at both dose levels (50 mg BID and 100 mg BID) compared to PBO. Improvements in markers of hemolysis/erythropoiesis and annualized rate of SCPCs were observed for both doses as compared with PBO; the magnitude of improvement in markers of hemolysis and annualized rate of SCPCs was larger in the mitapivat 100 mg BID arm. Mitapivat was well tolerated with a safety profile consistent with previous studies. These data suggest that mitapivat, through its dual mechanism of action, may provide clinical benefit to pts with SCD and support continued development in the Ph 3 portion of the RISE UP trial.

Characterizing the Immature Immunophenotype of Sickle Cell Disease Monocytes during Vaso-Occlusive Crisis

Sickle cell disease (SCD) is marked by episodic vaso-occlusive crisis (VOC). Painful VOC is the leading cause of emergency room visits and hospitalization in SCD, contributing heavily to the morbidity and mortality of this disease. Recurrent VOC creates a pro-inflammatory state that induces phenotypic alterations in the innate immune system. This inflammation-induced immune profile remodeling results in chronically active monocytes and neutrophils that antagonizethe vascular endothelium and further predispose SCD patients to VOC. While the mechanism of neutrophil involvement in VOC has been elucidated, less is known about the pathologic role of monocytes. Monocytes are of particular interest to VOC pathophysiology because they are especially malleable to inflammatory signaling. Indeed, inflammatory disease states such as COPD, obesity and atherosclerosis are known to influence monocyte development and alter monocyte subpopulations. Recently, nonclassical monocytes (CD14 dimCD16 +) with high heme oxygenase-1 expression have been shown to have a critical role in preventing VOC, generating renewed interest in monocytes as a therapeutic focus in SCD. In this study, we describe the monocyte subsets found in SCD patients during VOC by performing immunophenotypic flow cytometric, enzymatic, and morphologic analysis on peripheral blood obtained during hospitalization for VOC. Herein, we add to the growing body of evidence suggesting aberrant monocyte populations underpin VOC pathophysiology. We found that SCD monocytes during VOC possess an immature phenotype as demonstrated by 1) decreased CD4 positivity (p &amp;lt; .01), 2) low α-naphthyl butyrate esterase (ANBE) expression, and 3) naïve morphologic features (high nuclear/cytoplasmic ratio, indented or less lobular nuclei, and decreased cytoplasmic vacuolization). We additionally found an increase in CD14 +CD16 -CD4 - monocytes (p &amp;lt; .01), a subset associated with the impaired immune response of post-trauma patients. Interestingly, we also found a large proportion of CD14 +CD4 -HLA-DR - monocytes which, under normal circumstances, are exclusively found in neonates (p &amp;lt; .01). Finally, we report an increase in nonclassical monocytes (CD14 dimCD16 +), providing further evidence for the connection between this subset and the molecular mechanisms driving VOC. Taken together, these findings suggest that SCD patients in VOC deploy relatively immature monocytes that possess a lower capacity for antigen presentation, likely contributing to the immune dysfunction observed in SCD.

Nocturnal Autonomic and Vasoconstriction Parameters By Wearable Wrist Photoplethysmography Predict Intensity of Imminent Pain in Subjects with Sickle Cell Disease

Introduction: Sudden and unpredictable onset of pain is one of the biggest contributors to the morbidity of sickle cell disease (SCD), thought to occur due to obstruction of microvascular blood flow by rigid sickle-shaped red blood cells. Autonomic mediated vasoconstriction in the peripheral vasculature, with resulting decrease in tissue perfusion, is likely a triggering mechanism for the onset of vaso-occlusive pain, while the autonomic nervous system is also implicated in the pathogenesis of chronic neuropathic pain. Our analysis of 212 polysomnograms in SCD subjects showed that greater magnitude of nocturnal vasoconstriction (Mvasoc) is predictive of increased frequency of hospitalizations for vaso-occlusive pain crises (VOC) in the subsequent years (Chalacheva et al., Am J Hematol, 2020). In order to further develop this finding into a biomarker of more imminent pain, we monitored nocturnal photoplethysmography (PPG) at home with a wearable wristband device to measure vasoconstriction activity and heart rate variability, along with a daily electronic pain survey. Methods: 10 subjects with SCD were consented and underwent autonomic monitoring with a wristband device (Biostrap Inc) that uses an optical sensor to measure continuous PPG during sleep, with the raw PPG waveforms available from a cloud-based server. A unique biomarker (Mvasoc) was used to quantify the magnitude of vasoconstriction from the raw PPG signal, considering the frequency, magnitude, and duration of autonomic mediated spontaneous vasoconstrictions each night. Heart rate variability was derived from the pulse-to-pulse interval (PPI) of the PPG signal. Spectral indices of the PPI represent parasympathetic activity (high frequency power; HFP) and sympatho-vagal balance (Low to high Ratio; LHR = low frequency power(LFP)/HFP). Subjects concurrently documented daily pain incidence using an electronic text-based REDCap survey, with pain intensity measured on a scale of 1-10 if experiencing pain. Daily stress levels were also recorded on a scale of 1-10. Multivariate regression analysis was performed. Results: The subjects had a mean age of 25 years (range 14- 40 years) with an average hemoglobin of 8.8 g/dl . A total of 68 usable nocturnal PPG recordings were made (3-16 nights per subject). Therewere 25 incidents of pain on the day following autonomic monitoring with Biostrap, with the pain intensity ranging from 3-8. Multivariate analysis of nocturnal autonomic and vasoconstriction parameters revealed that a lower HFP ( p =0.0002) and a higher Mvasoc ( p=0.02) both preceded a higher intensity of pain the following day (Table 1). These results are consistent with a greater parasympathetic withdrawal and a higher magnitude of peripheral vasoconstriction predicting higher intensity of imminent pain. Age, gender, hemoglobin, stress levels and LHR were not predictive of pain the following day. Conclusion: Augmented nocturnal vasoconstriction and parasympathetic withdrawal noted prior to high intensity of pain imply that dysautonomia, with attendant changes in peripheral perfusion, has a significant role in pathogenesis of pain in SCD. Furthermore, autonomic vasoreactivity parameters were not significantly altered on the night after pain onset suggesting that the dysautonomia precedes pain. These results support the possibility of employing indices of nocturnal autonomic vasoreactivity as a predictive biomarker for imminent pain in SCD and provides a potential window for therapeutic intervention. This pilot study demonstrates the successful use of a wearable device PPG to remotely monitor nocturnal autonomic vasoreactivity and the ability to objectively quantify peripheral vasoconstriction responses. These findings will need to be applied in a larger cohort of SCD subjects with longer term monitoring for further validation and development of autonomic vasoreactivity as a predictive tool for pain in SCD.

Effects of Air Pollution on Respiratory Events and Pain Crises Among Children with Sickle Cell Disease in New York City

Introduction: Sickle cell disease (SCD) has the highest U.S. disease burden among Black and Hispanic populations, who more commonly live in urban areas with poor ambient air quality. The effect of air pollution exposure and social environmental factors on health outcomes in SCD have not been extensively studied, especially among children, and may further contribute to health disparities. Objectives: This study aims to examine the associations between air pollution exposure and acute respiratory and pain events and to determine whether neighborhood-level social disadvantage would modify their associations. Methods: We collected retrospective data on unscheduled outpatient visits, emergency department (ED) visits, and hospital admissions for respiratory events (i.e., respiratory tract infections, asthma exacerbation, acute chest syndrome) and vaso-occlusive pain crises requiring hospitalization (VOCs) for children with SCD in a tertiary care center in New York City (NYC) from 2015-2018. A total of 114 children with SCD (Table 1) were included in this study and had between 1-4 annual repeated measures of annual average air pollutants (i.e., black carbon (BC), fine particulate matter (PM 2.5), and nitrogen dioxide (NO 2)) with a total of 425 visits. Using home addresses, modeled data from the NYC Community Air Survey data were used to estimate street-level, annual average exposure to air pollution. The area deprivation index (ADI), a composite index of neighborhood-level social disadvantage, was dichotomized at the upper tertile (higher vs lower). Multivariable Poisson regression in generalized estimating equation (GEE) models were used to estimate relative risks (RR), after adjusting for potential covariates. Results: Overall, there were no significant associations between air pollution levels and acute respiratory and pain events among children with SCD. When stratified by ADI, increased exposure to PM 2.5 and NO 2, but not BC, was significantly associated with more frequent respiratory outpatient and ED visits among children residing in higher ADI neighborhoods (RR (95%CI)= 1.13 (1.00, 1.28) and 1.43 (1.01, 2.02) for PM 2.5 and NO 2, respectively, p&amp;lt;0.05 for all), but not among those in lower ADI neighborhoods (P-value for interaction=0.2 and 0.02 for PM 2.5 and NO 2, respectively) (Figure 1). Associations of air pollution with hospital admissions and VOCs were not observed for neither high ADI nor low ADI neighborhoods (p-value&amp;gt;0.05). Conclusions: Exposure to air pollutants increased respiratory complications among children living in deprived neighborhoods.

Emergency Admissions and the Prescribing of Buprenorphine, Methadone, and Psychotropic Medications in People with Sickle Cell Disease: An Analysis of National Insurance Claims

Background Although there have been efforts to address overdose risks and treatment gaps in general populations receiving opioids, there is has been little research examining potential drug-related poisoning risks in some of the highest-need and complex populations, including those with sickle cell disease (SCD). Chronic opioid medications are necessary and well-tolerated for the treatment of chronic pain, diffuse inflammation, chronic organ damage, and vaso-occlusive pain crises for people with SCD. Previous studies have found that patients with SCD are not more likely to develop addiction to opioids than the general population. However, amid the ongoing endemic of drug-related poisonings in the U.S., epidemiological data is scarce regarding the clinical characteristics of people who have SCD and physiologic opioid tolerance and dependence. There has been particularly limited work on the intersection of sociodemographic characteristics, substance use, and other mental health conditions in the SCD population. Concern has also been raised about the ongoing opioid epidemic contributing to increased stigma, and greater barriers to the management of acute and chronic pain in SCD. Studies have shown that preoccupation with opioid prescription monitoring hindered the ability of physicians to provide comprehensive SCD care. People with SCD often face more restrictive utilization management policies for opioids than peers with other forms of chronic pain (i.e., cancer-related pain). In order for us to develop better interventions for people with SCD, real-world data is urgently needed to describe the current treatment landscape and identify gaps in care for people with SCD and physiologic opioid dependence or tolerance. Using administrative claims data in the US, we aim to: 1) quantify the burden of hospitalization and emergency room admission for medication-related poisoning events, 2) describe the prevalence of opioid prescriptions, such as buprenorphine and methadone, in people with SCD and physiologic opioid dependence or misuse. Methods In this retrospective cohort study of people with physiologic opioid dependence or opioid use disorder (OUD), we analyzed ten years (1/2006-12/2016) of data from the Merative™ MarketScan® Commercial and Multi-State Medicaid Databases. The predictor variable was SCD (versus a comparator group of people with chronic pain) with diagnoses identified using ICD-9/10 codes. The outcome variables were 1) emergency admissions or hospitalization for non-fatal drug/medication-related poisoning events during enrollment, and 2) prescriptions for buprenorphine, methadone, and other opioids, identified via procedure codes and linked pharmacy records respectively. We used multivariable cox regression to estimate the relationship between SCD diagnosis and time until poisoning events. Multivariable poisson regression models were used to assess the relationship between SCD and buprenorphine, methadone, and other opioid prescriptions. Results Our overall cohort consisted of 25,448 people with ICD9-10 opioid dependence or misuse, including 313 with SCD and 25,135 with non-SCD chronic pain. In the SCD cohort, the median age was 30.8 years, and 82% were enrolled in Medicaid. Compared to the non-SCD chronic pain cohort, the SCD cohort had more hospitalizations or emergency admission for iatrogenic events (37.4% vs 9.8%, aHR=2.21[2.12-2.31]). With regards to medication receipt compared to peers with non-SCD chronic pain, the SCD cohort had a lower prevalence of buprenorphine prescriptions (8% vs 30.1%, aRR=0.20[0.18-0.21]) and a higher prevalence of methadone prescriptions for chronic pain (63.6% vs 6.8%, aRR=5.36[5.21-5.51]) and non-methadone/non-buprenorphine opioid prescriptions (80.5% vs 33.7%, aRR=2.20[2.15-2.25]). Conclusions We observed an elevated rate of emergency admission and/or hospitalization for drug/medication-related poisoning, as well as a significant burden of psychiatric comorbidity in a cohort of people with SCD and physiologic opioid dependence or OUD. The prescribing of potentially safer opioids, such as buprenorphine, was uncommon in the cohort. Further research is urgently needed to optimize opioid treatment strategies, combat stigma, and improve the comprehensive management of pain and co-occurring disorders in the SCD population.

Donor Hemoglobin Genotype Does Not Impact Outcomes Following Matched Related Donor Hematopoietic Cell Transplantation for Sickle Cell Disease: A STAR Study

Sickle cell disease (SCD) is an inherited hemoglobin (Hb) disorder which leads to significant morbidity and early mortality. Hematopoietic cell transplantation (HCT) is the only curative treatment with long-term outcome data, demonstrating excellent symptom-free survival particularly when a matched related donor (MRD) is available. Most MRD have sickle cell trait (Hb AS), but trait donor HCT is considered acceptable by the FDA and without negative impact. Further, initial gene addition and editing approaches for SCD have resulted in a trait-like status with benefit. Sickle trait, however, is associated with complications such as papillary necrosis, bacteriuria, splenic infarction, and exercise-induced death. The primary aim of this study was to compare long-term outcomes following MRD HCT for SCD based on donor Hb genotype, to objectively describe any impact on outcomes. Retrospective data was available for this analysis on 182 SCD patients ≥1 year post MRD HCT at 10 participating Sickle Transplant Advocacy and Research (STAR) Alliance centers. Summary statistics were presented as mean (standard deviation) for continuous variables and count (%) for categorical variables. Comparisons were made between Hb AA and Hb AS donor groups using both parametric and non-parametric tests for continuous variables and Chi-square test/exact test for categorical variables, with p-value &amp;lt;0.05 set as significant. Amongst 182 patients undergoing MRD HCT, 67% (n=122) had a Hb AS donor ( Table). In the overall cohort, median age at HCT was 8.7 (4.8) years and most patients had HbSS (n=174; 96%) with a severe clinical phenotype (n=97; 54%). HCT was performed using bone marrow (n=166; 92%) with myeloablative conditioning (n=156; 86%) in the majority. Patients with a severe disease phenotype and Hb AS donor were significantly more likely to have recurrent vaso-occlusive pain crises as an indication for HCT (p=0.033), otherwise there were no differences in baseline patient or HCT characteristics between cohorts. With mean post-HCT follow up of 4.5 (3.9) and 5.1 (4.1) years in Hb AA and Hb AS donor cohorts (p=0.145), no significant differences were seen in recipient outcomes including time to neutrophil and platelet engraftment, number of or time to last platelet transfusion, myeloid or unsorted % donor chimerism, number with acute (day 100) or chronic GVHD (1 year), or time to discontinue immunosuppression (data not shown). Disease recurrence and need for 2 nd HCT were rare in both cohorts (AA: 2 [3%] and 2 [3%]; AS: 3 [3%] and 4 [3%]; p=0.665 and 1.0, respectively). Two (3%) and 5 (4%) patients died in the AA and AS cohorts, respectively (p=1.0). Aside from a statistically (but not clinically) significant difference in Hb at day 30 (p=0.044), no difference was seen in longitudinal Hb or markers of hemolysis (LDH and ARC; Figure). No significant difference was seen in median number of RBC units transfused (AA: 4.0 [2.0-6.0]; AS: 3.0 [2.0-6.0]; p=0.454) or days to last transfusion (AA: 23.0 [14.0-77.0]; AS: 22.0 [13.0-75.0]; p=0.86). SCD complications were rare post-HCT, with no difference seen between cohorts in number (%) with VOC (AA: 1 [2%; had 2 separate VOC events]; AS: 3 [3%]; p=1.0), ACS (none reported), chronic pain (AA: 0 [0%]; AS: 1 [&amp;lt;1%]; p=1.0), or other SCD-related complications (AA: 2 [3%]; AS: 9 [7%; had 11 separate other events]; p=0.456). Stroke occurred in a significantly higher proportion with an AA versus AS donor (5 [8%] and 2 [2%], respectively; p=0.04). No significant differences were seen in longitudinal (1 and 2 years and at last follow up) post-HCT cardiac (EF, SF, TRJ velocity), pulmonary (FEV1, FVC, DLCO), or renal (GFR) function between cohorts (data not shown). Our results indicate that in MRD HCT for SCD, AS and AA donors yield comparable long-term outcomes. In this retrospective and registry-based study design, detailed analyses did not show differences between the two cohorts at baseline or at any timepoint post-HCT. While there were some outcome differences between the cohorts, they were either not clinically significant or did not have a scientific rationale, and thus were likely due to chance alone (denoted by bolding in Table). Given the young age of our cohort at HCT and thus a smaller proportion with SCD-related organ dysfunction, our results may not be applicable to an older cohort with significant organ dysfunction which will require a separate analysis.

Iatrogenic Hyperhydration in Sickle Cell Disease Patients Admitted for Acute Pain Crisis Management: A Retrospective Analysis from a Single Institution

Background: Parenteral fluids are an important component of acute pain crisis management in sickle cell disease patients. However, lack of uniform guidelines for fluid replacement coupled with underlying host comorbidities result in risk to patients from complications associated with hyperhydration. Contributing factors include inappropriate choice of fluid, rapid fluid infusion rates with prolonged time periods and inadequate monitoring of signs of hyperhydration. Complications of fluid replacement include excessive weight gain, extremity swelling, pulmonary edema and heart failure. In our study we examined the prevalence of hyperhydration in sickle cell anemia patients admitted for acute pain crisis management at our hospital. Methods: We conducted a retrospective chart review on EPIC of sickle cell anemia patients treated for acute pain crisis in the inpatient unit of John Dempsey Hospital, University of Connecticut between January 2022-December 2022, following IRB approval. To capture patients with signs and symptoms of hyperhydration and its clinical consequences, we looked at surrogate markers such as excessive weight gain during admission, signs of fluid retention, charting of patient fluid intake and output, increased oxygen use, diuretic (Lasix) administration, bronchodilator use, abnormal chest x ray findings indicative of fluid overload pattern, activation of rapid response team for patients developing acute symptoms of fluid overload, and urgent patient transfer to a higher level of care including intensive care unit. Results: 256 admitted patient charts were analyzed representing a total of 95 unique sickle cell disease patients. The median length of hospital stay (LOS) was 3 days. 168 patients had LOS from 3 to 10 days. We observed that 10.7% of the patients experienced an increase in oxygen requirements during their hospital stay. Daily weight was collected in only 27 patients (10.5%) for 3 or more days limiting its usefulness to detect subclinical hyperhydration( figure 1). 69 patients (27%) received parenteral Lasix injection for acute symptoms whose chest x rays also showed pulmonary edema or pleural effusions. 13 patients (18%) were transferred to a higher level of care that included 9 patients to step-down unit and 4 to intensive care for endotracheal intubations and ventilatory support. The median hospital stay was 4 days in patients requiring Lasix compared to 3 days in those who did not. Conclusion : Hyperhydration is undesirable complication associated with fluid administration of sickle cell anemia patients admitted with acute vaso-occlusive pain crisis. It occurs in a significant proportion of affected patients that can result in life threatening complications and prolonged hospitalization. Hyperhydration were missed in this retrospective analysis since daily weight measurements were not available in the majority of patients. Strict charting of fluid intake and output, choice of half normal saline for hydration, as well as clinical monitoring of signs and symptoms of subclinical hyperhydration will help reduce this complication and improve patient outcomes. Improving awareness of this complication among health care providers is important towards achieving this goals. Findings from this study are used to design a prospective quality improvement project in our hospital to improve outcomes and reduce hospitalization in sickle cell anemia patients admitted for acute vaso-occlusive pain crisis.

A Retrospective Study Evaluating the Association of Qualitative and Quantitative Aspects of Vaso-Occlusive Crises (VOC) with Length of Hospital Stay in Children with Sickle Cell Disease Hospitalized for a VOC

Background: Children with sickle cell disease (SCD) are at risk for developing a vaso-occlusive pain crisis (VOC) due to sickled red blood cells causing turbulent blood flow and obstruction within the vasculature, leading to local tissue infarcts and subsequently pain. A VOC can often be managed with analgesics and supportive care either at home or in the emergency room. However, sometimes the pain is not adequately controlled in those settings, so children require hospitalization for further management of their VOC. There exists a high degree of variability in length of hospital stay (LOS) among children who are admitted for VOCs. The purpose of this study is to determine which factors are associated with decreased or increased length of hospital stay (LOS). By identifying these factors, it will allow for a more targeted approach to VOC management with the goal of improving overall pain and reducing LOS. Methods: This 3 year (2019 - 2022) retrospective cohort study includes 88 patients (5 years to 27 years of age) with sickle cell disease (HbSS, HbSB0, HbSB+, HbSC) who were hospitalized for VOC management. Several variables were analyzed to determine if they correlated with LOS. These variables included SCD genotype, age, sex, pain scores, average hemoglobin and reticulocyte levels during hospitalization, pain medication dosage and frequency, blood transfusions and complications during hospitalization. The statistical analysis of these variables was conducted across all VOCs of all patients. Results: There were 289 hospital admissions for VOCs with a mean of 3.55 hospital admissions per patient among the 88 patients with SCD during study duration. LOS for these VOC hospital admissions ranged from 1 day to 10 days with an overall mean of 3.81 days per hospital admission. LOS was independently highest in females (mean LOS = 4.123 days, F (1, 287) = 6.415, p = .012) and patients who developed acute chest syndrome (mean LOS = 6.333 days, F (9, 277) = 4.771, p &amp;lt; .001). LOS positively correlated with pain scores (r 2 = .272, p = .002), number of blood transfusions (r 2 = .229, p &amp;lt; .001) and total units of blood transfused during admission (r 2 = .230, p &amp;lt; .001) and negatively correlated with morphine frequency (r 2 = -.125, p = .042) and average hemoglobin during admission (r 2 = -.142, p = .016). SCD genotype, age, reticulocyte levels and medication dosage were not found to have a statistically significant association with LOS. Conclusion: Our study showed that factors such as higher average pain scores, number of blood transfusions, total units of blood transfused, females and acute chest syndrome were associated with longer LOS. Other factors such as more frequent morphine administration and higher average hemoglobin levels were associated with shorter LOS. While this study provides initial insight into some of the factors that are associated with LOS in children with SCD admitted for a VOC, further studies are warranted to determine if these factors can be used to risk stratify patients in terms of severity of VOC and thereby better optimize and individualize their pain management.