Sickle Cell Pain Crisis Research Articles

8194 Extramedullary Hematopoiesis Involving Bilateral Adrenal Glands In A Patient With Sickle Cell Anemia

Abstract Disclosure: V.T. Pham: None. L.N. Sendos: None. Title: Extramedullary hematopoiesis involving bilateral adrenal glands in a patient with sickle cell anemia Background: Extramedullary hematopoiesis refers to blood cell production occurring outside the bone marrow. It is a reactive process caused by inadequate production or excessive destruction of blood cells typically seen in patients with hereditary anemias or infiltrative bone marrow disorders. Extramedullary hematopoiesis usually occurs in the spleen, liver and lymph nodes, but it can also very rarely arise from the adrenal glands. Case Presentation:We present a case of a 42-year-old male with a history of sickle cell anemia who presented with chest pain and shortness of breath and had a chest CT angiography which incidentally showed a 5.6 x 3.8 cm left adrenal mass and a 2.9 x 2.1 cm right adrenal mass. Further evaluation with an MRI abdomen with and without contrast revealed a 5.5 cm lobulated left adrenal mass with patchy areas of microscopic fat and faint delayed heterogeneous enhancement as well as a 2.2 cm right adrenal nodule. The nodules were described as markedly T2 hypointense with heterogeneous T1 hyperintense/isointense signal on MRI with a broad differential diagnosis including extramedullary hematopoiesis in bilateral adrenal glands, lipid poor adenoma or neoplasm. Regarding his sickle cell disease history, the patient was diagnosed as an infant and had very rare episodes of sickle cell pain crisis as a child. However, once he entered adulthood, he began to have multiple episodes of sickle cell pain crisis requiring hospitalizations and transfusions. On further review of patient’s prior imaging scans during these previous hospitalizations, he was first noted to have bilateral sub centimeter adrenal nodules on a CT Abdomen without contrast done almost a decade prior to his current presentation. We ordered biochemical evaluation which did not show any evidence of adrenal hormonal hypersecretion. His case was discussed at our multidisciplinary conference with the radiology and surgery team and it was concluded that the imaging characteristics were most consistent with extramedullary hematopoiesis in the setting of bilateral adrenal gland involvement and patient’s history of sickle cell anemia. Therefore, no immediate surgical resection was recommended. Given the size of the left adrenal mass being greater than 4 cm in size, we advised follow-up imaging for surveillance. Discussion:There has been a rise in detection of adrenal incidentalomas due to the increased use of advanced diagnostic imaging in healthcare settings. When patients with hematologic diseases are found to have adrenal incidentalomas, it is important to consider extramedullary hematopoiesis in the differential diagnosis to avoid unnecessary invasive procedures and surgeries. Presentation: 6/2/2024

Abstract 4031: P-selectin as an emerging target for the treatment of primary and secondary brain tumors

Abstract Glioblastoma (GB) is an aggressive type of brain cancer with a high mortality rate. It is a highly angiogenic tumor exhibiting an extremely invasive nature. As such, its brain microenvironment plays a crucial role in its progression. Microglia are the brain resident immune cells that have been shown to facilitate GB cell invasion and immune suppression. The mechanism by which GB cells alter microglia behavior is yet to be fully understood. One proposed mechanism involves adhesion molecules such as the Selectins family of proteins which are expressed on the surface of endothelial and immune cells and are involved in immune modulation and cancer immunity. We have previously shown that one member of the Selectin family, P-Selectin (SELP), is expressed by GB cells. Here, we investigated the functional role of SELP in GB-microglia interactions. First, we found that microglia cells facilitate the expression and secretion of SELP by GB cells, and that GB cells facilitate the expression of P-Selectin ligand-1 (PSGL-1) by Glioma-associated microglia/macrophages (GAMs). We then showed that SELP mediates GAMs-enhanced GB invasion and proliferation in our unique 3D-bioprinted ex vitro models and has a role in GAMs activation state. These findings were validated in vivo, showing that inhibition or downregulation of SELP leads to reduced tumor growth, increased overall survival, and improved immune response. Single-cell RNA-seq analysis of the tumors revealed an increase in pro-inflammatory GAMs signature, reduction in cancer cell tumorigenesis potential, and improved T cell activation. Thus, combining SELP inhibition with other immune checkpoint inhibitors, such as anti-PD-1, may have a synergistic effect by harnessing both the innate and the adaptive immune systems against the tumor. Furthermore, we found SELP/PSGL-1 axis to be involved in the progression of brain metastasis originating from melanoma, and breast, and lung cancer. Thus, we have begun an investigator-initiated clinical trial, testing the efficacy of the anti-SELP antibody, Crizanlizumab, alone or in combination with anti-PD-1 antibody, Nivolumab, for GB and melanoma brain metastasis patients (NCT05909618). Crizanlizumab, approved by the FDA and EMA for sickle cell pain crisis (VOC, Vaso-Occlusive Crisis) of sickle-cell anemia patients, was proven to be safe for human use, and efficient in inhibiting SELP function. As such, it has the potential to reduce tumor burden and improve patient outcomes. This work can improve our understanding of GAMs function, which may pave the way for new and effective treatments for primary and secondary brain tumors. Citation Format: Eilam Yeini, Ronnie Frommer-Shapira, Alisa Talianski, Paula Ofek, Sabina Pozzi, Nitzan Albeck, Dikla Ben-Shushan, Galia Tiram, Sapir Golan, Ron Kleiner, Ron Sheinin, Shlomit Reich-Zeliger, Rachel Grossman, Zvi Ram, Henry Brem, Thomas M. Hyde, Prerna Magod, Dinorah Friedmann-Morvinski, Asaf Madi, Ronit Satchi-Fainaro. P-selectin as an emerging target for the treatment of primary and secondary brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4031.

Knowledge, Awareness and Opinion Related to Sickle Cell Disease Among the Professional College Students of Amravati, Maharashtra

The aim of this study is to investigate the awareness, clinical manifestations, treatment and populations at risk of Sickle Cell Disease (SCD) amongst the professional college students of Amravati district. This study was also focus on knowledge about carriers (HbAA) and sufferers (HbSS). The total 842 students from technical streams such as engineering, pharmacy and biotech were enrolled. All participants were assessed on their general knowledge of the disease. The structured questionnaire containing the questions on origin, prevalence, incidences, life expectancy, painful crisis, counseling methods, treatments, management, attitude and behavior towards SCD were provided to all participants. The results had shown that, only 144(17.1%) subjects were found to be known about SCD. Out of them, 56(38.8%) individuals had appreciable knowledge, 80(55.5%) had limited knowledge and 8(5.5%) had marginal knowledge of SCD. The 30.5%(n=44) respondents were known about need of blood transfusion and 18.75%(n=27) participants had knowledge of interrelation between sickle cell anemia and the disease jaundice be an important clinical complaint in SCD. 25.69% (n=37) respondents known to have about intimate relationship between sickle cell disease and pain crisis. Majority of respondents (512/842) was believed that, people should have knowledge and awareness about the genetic diseases that helps to restrict its further spread. Keywords: Sickle cell disease, Professional college, Amravati, Maharashtra

Manual red cell exchange (RBCXm) in acute sickle cell crisis: A feasible modality in resource limited settings

This short communication highlights the significance of manual red blood cell exchange (RBCXm) procedure which is an emergency procedure for patients of sickle cell disease (SCD) in sickle cell crisis . To the best of our knowledge there is no standardised technique for performing RBCXm meanwhile, an automated method using an apheresis machine is either unavailable or is unaffordable. As a result, patients end up receiving top up red cell transfusions further associated with risk of iron overload, hyper viscosity and sometimes volume overload overshadowing the benefits of red cell exchange. Therefore, we developed a protocol for manual red cell exchange (RBCXm) and performed it in a patient with painful sickle cell crisis who had cost constraints for automated red cell exchange (RBCXa) procedure. RBCXm provided symptomatic relief to our patient with adequate sickle cell reduction. This RBCXm protocol may be useful in low income (LIC) and low middle income countries (LMIC) where patients have recurrent episodes of sickle cell crisis and there is unavailability or unaffordability for RBCXa using an apheresis equipment.

Improved Management of sickle cell pain crisis in a Pediatric Emergency Department through Use of Intranasal Fentanyl.

Introduction: National Heart, Lung, and Blood Institute recommends giving the first dose of opioids within 30 minutes of presentation to the emergency department for sickle cell disease patients with moderate to severe vaso-occlusive crisis. Intranasal fentanyl has been used extensively and shown to reduce time to the first dose of analgesic, improve pain scores at 20 minutes, and increase the odds of getting discharged from the emergency department. Material and methods: For phase one of the project, baseline data was collected. The new pain algorithm was introduced at the start of the second phase, which involved giving intranasal fentanyl as the first analgesic for vaso-occlusive crisis in the emergency department. After the intervention, the second analysis compared outcomes with phase one. Wilcoxon-Mann-Whitney tests were used for comparing data between phase one and phase two and Wilcoxon signed-rank tests (paired version) were used for comparing pain scores before and after analgesic. Results: Visits at phase two had significantly lower hospitalization rate [phase one 53.5% vs. phase two 34.2%(p value 0.005)], more fentanyl use [phase one 1.5% vs. phase two 50.6% (p< 0.001)], less patient-controlled-analgesia (PCA) opioid use after admission [phase one 13.0% vs. phase two 2.53% (p= 0.016)], higher compliance with outpatient visits [phase one 61.3% vs. phase two 98.7% (p < 0.001)], shorter length of hospital stay [phase one 117.6 ± 112.7 hours vs. phase two 68.3 ± 47.2 hours (p-value 0.01)], decrease in the time to first analgesic after coming to the emergency department (phase one 78.2 ± 131.2 minutes vs. phase two 38.3 ± 31.2 minutes (p 0.85)], and decrease in the mean pain score after first medication in the emergency department [phase one 5.48 ± 3.12 vs. phase two 4.46 ± 2.88 (p value 0.021)] Conclusion: Intranasal fentanyl led to more effective and timely management of vaso-occlusive crisis with improvement in clinical outcomes compared to standard management.

Characteristics and Trends of Hospitalizations for Sickle-Cell Related Complications

Introduction There are approximately 100,000 people living with sickle cell disease (SCD) in the United States. As per the Center for Disease Control estimates, almost all patients with SCD will require hospitalization more than once a year and visit the emergency department at least 2-3 times a year on average. Previous studies have shown that SCD hospitalization trends are steadily increasing in the country. In November of 2019, two new drugs, crizanlizumab (to decrease the frequency of vaso-occlusive crises) and voxelotor (to increase hemoglobin response), were approved by the Food and Drug Administration (FDA) for the treatment of sickle cell disease. Around the same time, the entire health care system experienced disruption in the form of the COVID-19 pandemic. Hence, we conducted this retrospective study to assess SCD hospitalization trends from 2016-2020 and stratified them across various demographic factors to analyze the underlying causes. Methods We conducted a retrospective study from the National Inpatient Sample (NIS), which is a large all-payer database created by the Health Care Cost and Utilization Project (HCUP). We included all adult patients with a diagnosis of SCD (HbSS, HbSC, Sickle/b thal, and other variants) and identified their trends of hospitalizations for various SCD-related complications like vaso-occlusive crises, heart failure exacerbation, acute kidney injury, stroke, sepsis with and without septic shock, bacteremia, pneumonia, osteomyelitis, acute chest syndrome, splenic sequestration, and priapism. We then did a linear-to-linear analysis and ANOVA test to stratify these trends across various age, gender, income, and location groups. SPSS was used for the statistical analysis. Results Our study included a total of 19,250 patients who had at least one admission for sickle cell-related complications during 2016-2020. The average number of admissions for sickle cell pain crisis steadily increased from 10.2 per 100,000 in 2016 to 14.7 in 2019 and then decreased to 13.9 in 2020. Priapism steadily declined from 2.3% in 2016 to 1.4% in 2020 (p<0.001). Acute kidney injury complicated 4.9% of admissions in 2016 and steadily rose to 5.2% of admissions in 2020 (p = 0.88). Admissions complicated by bacteremia peaked in 2017 (0.9%) but have since been on a decline (0.5% in 2020) (p-0.02). Admissions complicated by pneumonia showed a steady decline from 6% in 2016 to 4.3% in 2020 (p<0.001). Admissions with osteomyelitis, splenic sequestration, acute chest syndrome, heart failure exacerbation, stroke, and sepsis complicated <1% of all admissions and were not statistically relevant. When stratified by age, it was noted that the age group of 18-39 had the most admissions. Females consistently had more admissions than males. Medicaid was the predominant insurance among all the admissions, followed by Medicare. Around 50% of the patients admitted for SCD-related complications were in the 0-25th percentile of median household income quartiles. The majority of admissions were seen in urban teaching hospitals. The majority of these admissions were also seen in the Southern regions. Conclusion Our results show that female patients in the age group 18-39 years, those covered by Medicaid and Medicare, and those in lower income quartiles comprised the majority of admissions for SCD-related complications. This demonstrates disparities in SCD care, wherein patients in lower socio-economic strata may not have access to newer advances in SCD treatment. Although it is optimistic to note that admissions for pain crises had a significant decline from 2019-2020, it remains to be seen whether these numbers are due to new therapies or due to the disruption of healthcare services caused by the pandemic. Analyzing more long-term trends after the year 2020 will help us understand this impact. The overall trend of infections and sepsis has been low, likely due to widespread vaccinations and early antibiotic treatments. It is interesting to note that although there was a downtrend for the majority of SCD complications, the incidence of AKI during admissions is steadily rising, validating the need to focus more on renal care in sickle cell patients.

Implementation of a Best Practice Alert and Dedicated Hematology Consultation on Hospitalization Outcomes of Patients with Sickle Cell Disease

Introduction The American Society of Hematology (ASH) guidelines recommend rapid (within 1 hour) administration of tailored pain medication and frequent reassessments to optimize pain control in persons with sickle cell disease (SCD) presenting with acute pain related to SCD (Brandow et al., 2020). Implementation of an individualized pain plan (IPP) has been associated with decreased length of stay and lower rate of 7-day readmissions (Welch-Coltrane et al., 2021).Early initiation of sustained analgesia results in more rapid resolution of vaso-occlusive crises (VOC) in 80% patients. While all of our patients have an IPP, provider knowledge of the existence of IPPs and where to find them has been challenging to properly implement this practice. All inpatient SCD patients receive hematology consults but lack of continuity and experience with patients can be challenging for them. The study aimed to investigate the impact of implementing a Best Practice Alert (BPA) and introduction of dedicated SCD nurse practitioner (NP) on consults on various clinical metrics related to patients with sickle cell disease during hospitalization. Methods We created a best practice alert (BPA) that is triggered when a patient with SCD is admitted to the inpatient service. It directs the admitting team and nursing staff to the IPP and an order set for sickle cell pain crisis. The nursing interface of the BPA also includes a link to an educational module. Data was collected pertaining to length of stay, readmission, and percentage of admissions with a hematology consult placed from before and after implementation of the BPA. Around the same time, a dedicated nurse practitioner managed consults for patients hospitalized with sickle cell VOC and provided education to the primary team. We then conducted a retrospective chart review of all sickle cell patients at the University of Wisconsin from January 1, 2021, to December 31, 2023. We included all patients 18 years and greater with a sickle cell disease diagnosis as identified by the ICD-10 code (D57.00) and excluded patients with restricted research participation. We used descriptive statistics to obtain summaries of patient demographics as percentages for categorical variables and mean values for continuous data. Results Preliminary data demonstrated that the number of distinct patients with admissions decreased from 47 pre-BPA to 30 post-BPA (Table 1, Figure 1). The average length of stay in days decreased with 7.87 days pre-BPA to 6.35 days post-BPA. The average number of days between previous discharge and readmission increased from 45.65 to 85.65 after implementation. Readmissions at 7 and 30 days decreased by 17% and 4%, respectively. Conclusion The goal of this QI initiative was to improve IPP implementation by introducing a BPA in the chart directing admitting providers to the plan for efficient use. Dedicated SCD NP provided continuity and ensured IPPs were followed. While we could not directly measure the implementation of IPP with each BPA trigger, relevant patient-related outcomes such as readmissions and length of stay were reduced with meaningful reduction in LOS by 1.52 days during the first 9 months of these changes. In the future, we plan to further refine this process and expand our outcomes data by obtaining patient and provider feedback via surveys to fully understand the impact of this process and continue improvements. The role of SCD NP will be expanded due to encouraging results. In summary, BPA alerts in the chart for rapid implementation of IPPs, along with a knowledgeable SCD consult provider to ensure proper follow up of plans is a feasible strategy to improve patient outcomes when admitted with VOC.

Use of IV Hydration Instead of Exchange Transfusion for Prophylactic Management of Pain Crisis in Homozygous (SS) Sickle Cell Disease Helps Maintain Hgb Levels and Prevents Further Escalation of Iron Overload

Introduction: Indications for exchange transfusion in the management of sickle cell disease and its complications are over time becoming limited. Currently accepted indications include acute chest syndrome and cerebrovascular accidents only. However, there is often consideration of using exchange transfusions for management of sickle cell pain crisis episodes resistant to opioid-based pain management. This is, however, of questionable efficacy due to concerns of iron overload as well as alloimmunization. The excessive utilization of blood products also presents a significant challenge. Therefore, it is important to explore alternatives to exchange transfusion in the management of pain crisis in sickle cell disease. Method: This study aimed at investigating the effects of transitioning patients with homozygous SS disease from routine exchange transfusions to IV hydration protocols. The main objective was to examine the changes in Hgb levels and the status of iron overload in these patients. A cohort of 16 patients with a Ferritin level above 1000 ng/ml, who were already receiving regular exchange transfusions, were included in the study. Their Hgb levels and Ferritin levels were measured periodically. This group was then given IV hydration twice a week, regardless of whether they were experiencing pain issues. We then compared the Hgb and Ferritin levels during a 6-month period of active exchange transfusions and 6-month period of being on IV hydration protocols. Both periods were a year apart, allowing for adequate homeostatic changes to take place. Additionally, we compared the number of simple transfusions during both these periods. Result: The mean ferritin level in patients getting exchange transfusions was 6097 ng/mL with the mean Hgb level maintained at 7.48 g/dL. During the initial study period, there were 14 exchange transfusion sessions involving 96 units of packed red blood cells (PRBCs). Additionally, 8 units of simple transfusion units were administered during the same period. Interestingly, as this cohort transitioned away from exchange transfusions, the number of simple transfusions increased to 30. Only one exchange transfusion occurred during the second 6-month observation period. During this time, ferritin level stopped increasing, and the mean was measured at 6076 ng/ml. The Hgb levels did show a slight decrease, with the mean being 6.90 g/dL, but the difference was not statistically significant. Conclusion: The findings of this study suggest that the use of IV hydration protocol is effective in managing iron overload issues and maintaining an adequate Hgb level in patients who were previously undergoing routine exchange transfusions to prevent or manage pain crisis episodes. The results indicate that IV hydration should be initiated when ferritin levels increase beyond 1000 ng/ml, rather than waiting for more advanced stages. Moreover, the study shows that even when IV hydration is started at a later stage of iron overload, it still appears to limit further iron accumulation, as evidenced by the stabilization of ferritin levels. Overall, the use of IV hydration as an alternative to routine exchange transfusions holds promise in managing pain crisis and iron overload in sickle cell disease.

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.

PB2513: A RE-AUDIT OF PAIN MANAGEMENT IN SICKLE CELL PAIN CRISES

PB2513: A RE-AUDIT OF PAIN MANAGEMENT IN SICKLE CELL PAIN CRISES

Major Advances for Sickle Cell Pain Crisis

Major Advances for Sickle Cell Pain Crisis

Design of an adaptive randomized clinical trial of intravenous citrulline for sickle cell pain crisis in the emergency department

BackgroundVaso-occlusive pain crisis (VOC) is the most frequent cause for Emergency Department (ED) visits and hospital admissions for patients with sickle cell disease (SCD). Nitric oxide plays a critical role in the pathogenesis of vaso-occlusion. The amino acid, citrulline, is the main endothelial nitric oxide booster that offers the potential to ameliorate vaso-occlusion and decrease the risk of hospitalization. ObjectiveIn this two-part study, the goal of the first part is to determine the pharmacokinetic profile of intravenous (IV) l-citrulline and optimal dose for the second part of the study, which is to determine the efficacy and tolerability of the intervention in patients with SCD. DesignA phase I/IIA open-label dose-finding study with subsequent double-blind, placebo-controlled, randomized Study of l-citrulline in children and adolescents with SCD presenting to the ED in VOC. MethodsPart 1: Subjects experiencing VOC are enrolled in an open-label, ascending dose of IV l-citrulline to identify the optimum dose with endpoints of pharmacokinetic parameters, pain scores, reduction of opioid use, quality of life, proportion admitted to the hospital for treatment of pain, readmission rates, and assessment of adverse events. Part 2 of the trial is a double-blind, placebo-controlled adaptive “pick-the-winner” design to evaluate the efficacy and tolerability of IV l-citrulline in patients with SCD while receiving standard of care therapy for VOC. SummaryThis ED based sickle cell adaptive trial will determine the optimal dose for IV citrulline and whether the intervention improves outcome as a potential novel therapy for VOC in SCD.

Pethidine-related neurotoxicity in pediatric sickle cell disease: a systematic review

Sickle cell disease describes a set of related blood disorders that result from defective production of hemoglobin that causes rigid fibers to form in the red blood cells, bending them into a characteristic sickle shape. These misshapen blood cells are then prone to becoming lodged in smaller blood vessels, resulting in a vaso-occlusive crisis, which can be very painful. Rapid and potent analgesia is crucial in the care of patients presenting with sickle cell crisis, and opioid analgesics, such as pethidine and morphine, have been the mainstay of treatment for decades. However, there are reports in the literature of seizures associated with pethidine use, particularly if used for more than a few days or in patients with kidney disease. A systematic review of the literature was conducted to identify any case reports or studies of the use of pethidine in children presenting with painful sickle cell crisis with a specific focus on the prevalence of seizures in this patient group. The pharmacology and pharmacokinetics of pethidine and its active metabolite norpethidine are briefly explored, along with alternative analgesic approaches, both pharmacological and nonpharmacological.

Effect of Intravenous Fluid Therapy in Managing Acute Painful Crises in Sickle Cell Disease Patients

Background: Sickle cell disease (SCD), an autosomal recessive mutation leading to alterations in the shape of red blood cells, compromises their oxygen-carrying capacity, and is prevalent in Saudi Arabia. Individuals with SCD experience vaso-occlusive crises, leading to severe pain episodes. Although fluid administration is a common practice to deter the sickling process, limited data exist on its efficacy. Method: This substudy was preplanned within the published randomized control trial titled \"Ketamine Administration for Acute Painful Sickle Cell Crisis: A Randomized Controlled Trial,\" conducted at King Fahad University Hospital in Saudi Arabia in 2019. Results: The analysis included 139 patients. Both arms received equal amounts and types of analgesics, with 51.7% receiving up to 500 ml intravenous fluid and 48.3% receiving more than 500 ml. Of the participants, 23.7% were admitted to the hospital, while 76.3% were discharged. The average length of stay in the emergency department (ED) was 4.6 ± 2.1 hours. There was no significant difference in the average pain score between the arms at 30-120 minutes. However, patients who received more fluid (> 500 ml) exhibited a higher admission rate and a longer ED stay. Conclusions: The amount of fluid administered to SCD patients in the emergency department during a vaso-occlusive crisis did not show a significant difference in pain score improvement. Notably, patients receiving more fluid demonstrated longer ED stays and higher admission rates.

Assessing the Recovery Process after a Vaso Occlusive Crisis

Introduction: Adults with sickle cell disease (SCD) suffer from vaso-occlusive pain episodes (VOEs) for which they often receive care in infusion clinics (ICs). Typically, 80% of patients treated for VOE are discharged home but it is not clear how long it takes to recover to baseline functioning after an acute visit.1 Recent clinical trials have struggled to identify practical and useful outcomes for novel therapies that decrease the length of VOE or pain during hospitalization. As many patients with VOE are seen and treated in an IC and discharged home, identifying potential endpoints for novel therapies in this site of care are needed. The purpose of this study was to measure time to recovery for two weeks post an IC visit for management of VOE and to identify patient characteristics that predict a return visit for pain management within that time period. Methods: A convenience sample of adults with SCD (≥18YO) were consented to and enrolled into this IRB-approved study during a visit to the IC for VOE. Medical records of all subjects were reviewed to collect data on the number of acute visits, hospitalizations, use of disease-modifying therapies, use of pain medications, baseline laboratory data, and comorbidities. Data was collected on the date VOE pain started, pain scores before and after treatment, and analgesic management. Baseline surveys were collected on the day of the visit and patients were sent follow-up surveys after discharge electronically through REDCap on post-discharge days 2,4,6,8,10,12,14. Participants were asked to rate their pain on a 0-10 Visual Analog Scale. The PROMIS pain interference and Fatigue scales were used to assess pain impact and the Subjective Opioid Withdrawal Scale (SOWS) was used to assess for signs of opioid withdrawal. Return to baseline functioning was estimated by asking participants at each contact post-visit to rate their current level of functioning in activities of daily living on a scale of 0-100, with 100 being their baseline level of function. A similar scale was used to measure the resolution of pain, with the anchor being "back to your usual, non-crisis, level of daily pain." Subjects were encouraged to complete surveys through text message reminders and were compensated with a fifty-dollar gift card if all surveys were completed. Cox proportional hazards modeling was used to examine predictors of time to a return acute care visit within 14 days of the index visit. Results: Table 1 shows the characteristics of the 48 patients enrolled in the study. Despite multiple text/email reminders, few patients completed all the surveys (8/48). Thirty-two out of 48 people completed initial surveys. Of the 17 patients who completed a day 2 or later SOWS score 7 had moderate or severe withdrawal symptoms and of those 3 had a return visit within 14 days while 5/10 of those with mild scores had a return visit. Nineteen out of 48 patients returned for treatment within 14 days. Controlling for pain at discharge, sex, and genotype only the number of acute visits in the six months prior to the index visit was associated with a return visit in 14 days (HR 1.31, 95% CI: 1.13 1.53). The figure shows the probability of a return visit over time by genotype. The median number of visits the entire cohort had in the six months prior to the index visit was 4.5 (IQR: 2,10) however, in those patients that returned for treatment within 14 days the median number of visits in the last six months was 8 (IQR: 5,11). Conclusions: In this study of patients' experience post an acute visit for pain management at an IC, we identified that the number of acute visits in the six months prior to the index visit predicted a return visit within 14 days. It was challenging for patients to complete surveys after their acute visits suggesting that this was not a feasible way to collect these important patient-reported outcomes. With almost 40% of patients returning for an acute care visit within 14 days, decreasing the percentage of patients with return visits may be a potential outcome for trials of novel therapies to treat VOE in the IC setting. 1. Lanzkron S, Carroll CP, Hill P, David M, Paul N, Haywood C, Jr. Impact of a dedicated infusion clinic for acute management of adults with sickle cell pain crisis. Am J Hematol. 2015;90(5):376-380. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prospective Study of Complement Activation with Functional and Genetic Assays in Sickle Cell Disease

Background: Despite advances in the therapeutics of Sickle Cell Disease (SCD), vaso-occlusion, painful crisis, and other complications (such as delayed hemolytic transfusion reaction/DHTR) remain a major cause of morbidity and mortality. Recent research data suggest complement activation, especially during SCD complications. These advances led to recommendation of complement inhibition in patients with DHTR and ongoing hyperhemolysis. However, limited data exist about other SCD complications. Hypothesis: We hypothesized that novel functional assays will be useful in detecting complement activation in SCD, especially during complications, and that these patients present distinct clinical or genetic features that have not been investigated yet. Methods: We enrolled consecutive SCD patients from four Thalassemia Units, meeting the eligibility criteria: (i) age > 16 years, (ii) established SCD diagnosis and (iii) willingness to participate in the study and sign a written informed consent. We collected samples at enrolment and at any updates of disease status during 1-year follow-up (initiation of hydroxyurea, vaso-occlusive crisis, hemolytic reactions, nephropathy, or TMA) or at last follow-up if no update was observed. Complement activation was detected using soluble C5b-9 (Quidel kit), and the modified Ham test. Values above 245 ng/ml have been established in our laboratory as above normal limits for C5b-9, and 20% for modified Ham test, respectively. The latter is a cell proliferation assay based on the susceptibility of a PNH (paroxysmal nocturnal hemoglobinuria)-like cell line to complement-activated serum. We also utilized next generation sequencing (NGS) analysis with a customized panel (complement factor H/CFH, CFH-related, CFI, CFB, CFD, C3, CD55, C5, CD46, thombomodulin/THBD, ADAMTS13, MiniSeq, Illumina). Identified variants were evaluated by using 4 bioinformatic tools. Variants predicted to be deleterious from at least 2 tools (50%), were assumed as pathogenic and were compared with the 2018 database of complement gene variants. Results: We studied 81 adult SCD patients (Table 1). Among them, 23 presented a disease update during follow-up (17 vaso-occlusive crises and 6 proteinuria). Patients with SCD complications during follow-up had excessive complement activation detected even from steady state with increased C5b-9 (7/23, 30%, p=0.028) and positive modified Ham test (5/23, 21%, p=0.001). During follow-up, C5b-9 significantly increased (p<0.001), particularly in patients with complications (p=0.046). Modified Ham test positivity remained the same. Regarding genetics, we detected 25 rare variants (Minor Allele Frequency < 1%). Only 3 of them found in 3 patients were also characterized as pathogenic: rs117793540 in C3, rs1800579 in THBD, and rs143568784 in ADAMTS13. We also documented 5 additional deleterious variants in 12 patients: rs144082872 in CFI, rs12614 in CFB, rs28503257, rs145825553 and rs28647808 in ADAMTS13. Patients were heterozygous, except for 1 homozygous for rs28647808. Patients with deleterious variants had increased complement activation by functional assays, except for 2 patients with CFB and 2 with ADAMTS13 variants. Interestingly, patients with a combination of a deleterious variant had a significantly higher transfusion dependency rate (65% versus 35%, p=0.031). Conclusion We have shown for the first time prospectively that complement is activated even from steady state in patients that develop SCD complication, with significant increase during complications. Complement-related genetic variants undeline this predisposition to complement activation in certain patients. Considering safety and efficacy of complement inhibitors in other complementopathies and preliminary data from SCD, our study highlights useful tools to early detect patients that might benefit from complement inhibition. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prevention and Management of Sickle Cell Pain Crises: Lessons Learned from Older Adults with Sickle Cell Disease

Background Innovations in medicine over the last fifty years have extended the median lifespan of people living with sickle cell disease (SCD) from 14 years to as long as 61 years in cohorts from academic centers. There is a paucity of information on the experiences preventing and managing vaso-occlusive pain crises by older adults with SCD. Older adults with SCD have decades of experience navigating pain and other complications of SCD. They have a wealth of knowledge about how to care for themselves, which can be shared with a younger generation of those with SCD. The purpose of this study was to describe strategies used by older adults (≥50 years) to prevent and manage pain crises. Methods We enrolled 19 men and women at least 50 years old from a single comprehensive sickle cell center in the Southeastern United States. We conducted semi-structured qualitative interviews by phone or in person. A single interviewer asked open-ended questions about the participant's experiences living with SCD and strategies they feel helped them live a long life. Participants described strategies they have adopted to cope with and prevent pain crises. A commercial service transcribed audio-recordings of the interviews verbatim. We used conventional content analysis to code the transcripts. Results The mean age of participants was 58 years (range 50-71). Over half (53%) had HbSS genotype, 37% had HbSC, and 11% had HbSβ+-thalassemia. Almost half (45%) were hospitalized and 63% had an emergency room visit in the last year. Most participants (84%) were on short-acting and 37% were on long-acting opiates. The majority (58%) reported current use of hydroxyurea. During the interview participants discussed strategies used to prevent and manage their pain crises. There were two major themes. (Figure 1) Theme 1 was "Strategies for Pain Prevention", which centered on methods they adopted throughout their lives to help prevent pain crises. Participants described that when they were younger pain medicine was not readily available, causing them to focus on strategies to prevent pain crises. They often relied on their parents to set limits on their activity levels to avoid having a crisis. When they reached adulthood, they learned to advocate for themselves by communicating their limitations. Having a good support system to encourage them to rest also helped. Most participants emphasized the importance of moving at their own pace and slowing down when they needed to. They discussed how knowing their triggers helped avoid a pain crisis or manage it better on their own. Sometimes simply sleeping once they felt a pain crisis coming on could help avert a crisis. Avoiding stressful situations, emotional triggers, temperature extremes, being underdressed, sitting long periods, and dehydration helped to prevent pain crises. Most participants described how a healthy diet and exercise were key in the prevention of pain crises. Eating fruits and vegetables, avoiding sugary drinks, excessive alcohol, and processed foods helped reduce pain episodes. They described low impact exercises they engaged in such as walking, yard work, and cycling. Theme 2 was "Strategies for Managing Pain” which included using pharmacological and non-pharmacological methods. One of the most important strategies participants mentioned was to rest as soon as a pain crisis started. For some, physical activity helped relieve pain, while for others, it was a trigger for a crisis. The strategies adopted also included hydration, heating pads, resting, distraction techniques, and avoiding stress as much as possible. Alternative pain management strategies that were reported included acupuncture, massage, and aquatic therapy. While pain medication was useful, many participants stated that they did not like being prescribed pain medicine without other therapies. Conclusion The growing population of older adults with SCD have a wealth of knowledge that can benefit younger adults with SCD to prevent and manage pain crises. Strategies they have learned through a lifetime of experience living with SCD have given them a unique insight into how to best cope with pain crises. In future research we will evaluate how best to share approaches developed by people with SCD for preventing and managing SCD complications. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PSAT066 Adrenal Insufficiency Associated with Amyloidosis and Sickle Cell Disease

Abstract Background Amyloidosis causes chronic inflammation by the deposition of amyloid protein fragments in multiple organs, such as kidneys, adrenal, and pituitary glands. It is a challenge to access adrenocortical function in renal amyloidosis patients due to heavy proteinuria induced hypoproteinemia and low corticosteroid-binding globulin (CBG) which may cause false positive adrenocorticotropin (ACTH) test and the reduced cortisol level uncorrelated with free cortisol. On the other hand, adrenal insufficiency also frequently occurs in Sickle Cell Disease (SCD) patients. The hypothalamic-pituitary-adrenal (HPA) axis can be affected by tissue hypoxia during recurrent small vessel occlusion, chronic anemia, and iron-overload related oxidative stress. We report a SCD patient with nephrotic syndrome due to amyloidosis, who has adrenal insufficiency. Case Presentation A 41 years old female with Nephrotic syndrome secondary to Amyloid A (AA) amyloidosis, Adrenal insufficiency, Sickle cell disease (HbSC), Graves’ Hyperthyroidism, CVA, and bilateral femoral head avascular necrosis, presented with sickle cell pain crisis and anasarca with hypotension. She was on Hydrocortisone for 12 years but was not compliant for 2 months. She was on Methimazole for several years before it was discontinued one year ago. She has amenorrhea, severe edema with anasarca from the lower extremities to the abdomen. Labs showed morning cortisol 5.46 ug/dL, low albumin 2.4 g/dL, high TSH 5.43 uIU/mL, normal FT4 1.60 ng/dL, high urine protein 996.2 mg/dL, and eGFR 21.2. CT revealed pericardial effusion, free pelvic fluid, splenomegaly, edema, and thyroid goiter. Previous labs showed persistent low cortisol 0.9 to 3.5 ug/dL, high ferritin 1007 ng/mL, and pituitary workup was normal for Prolactin 4.6 ug/L, LH 5.02 mIU/mL, FSH 9.9 mIU/mL, IGF1 216 ng/mL, and ACTH 13.1 pg/mL. NM thyroid uptake elevated 51.7% and positive TPO 79.7 IU/mL. CT head was unremarkable. The patient was managed with Lasix and Albumin infusion for anasarca, Cyclosporine for amyloidosis, and Midodrine 10 mg TID for hypotension. Hydrocortisone stress dose was given followed by Prednisone 30 mg BID. Her symptoms improved. Discussion In Amyloidosis patients with heavy proteinuria, the low serum CBG levels affect total cortisol level. Therefore, the proper assessment for the adrenal function should be used with albumin-calculated free cortisol or cortisol/CBG ratio in addition to the ACTH stimulation tests. It is essential to differentiate between adrenal insufficiency and amyloidosis-related symptoms to prevent adrenal crisis and refrain from glucocorticoid side effects by unnecessary steroid use. On the other hand, endocrine manifestations of SCD may include hypogonadism, thyroid, adrenal, and pituitary dysfunction due to vaso-occlusive episodes induced multi-organ ischemic damage. This patient has amenorrhea, adrenal insufficiency, and normalized thyroid function test in Graves’ disease. It is crucial to avoid iron-overload induced oxidative stress which would worsen endocrine dysfunctions as well. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

ODP124 Sickle Cell Bone Disease and Response to Intravenous Bisphosphonates in Children

Abstract Purpose To evaluate bone morbidity and the response to intravenous (IV) bisphosphonate therapy in children with Sickle Cell Disease (SCD). Methods We conducted a retrospective review of patient records from 2003 to 2019 at three Canadian pediatric tertiary care centers. Radiographs, magnetic resonance images, and computed tomography scans were reviewed for the presence of avascular necrosis (AVN), bone infarcts, and myositis. IV bisphosphonates were offered for bone pain management. Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA). Results Forty-six children (20 girls, 43%) had bone morbidity at a mean age of 11.8 years (SD 3.9) including AVN of the femoral (17/46, 37%) and humeral (8/46, 17%) heads, H-shaped vertebral body deformities due to endplate infarcts (35/46, 76%), and non-vertebral body skeletal infarcts (15/46, 32%). Five children (5/26, 19%) had myositis overlying areas of AVN or bone infarcts visualized on magnetic resonance imaging. Twenty-three children (8/23 girls) received IV bisphosphonate therapy. They all reported significant or complete resolution of bone pain. There were no reports of sickle cell hemolytic crises, pain crises or stroke attributed to IV bisphosphonate therapy. Bone mineral apparent density Z-score increased at the lumbar spine (N=14, mean change +0.6, SD 0.4) and total body less head (N=14, mean change +0.5, SD 0.4) after IV bisphosphonate therapy (mean 1.5 years, SD 0.8). Conclusion Children with SCD have the potential for extensive and early-onset bone morbidity. In this series, IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications. Presentation: No date and time listed

S3167 Sickle Cell Hepatopathy in a Young Patient With Markedly Elevated Bilirubin

Introduction: The vaso-occlusive events that characterize a sickle cell pain crisis are known to affect multiple organ systems. Sickling in the hepatic sinusoids leads to ischemia, cholestasis, and sequestration, which collectively contribute to acute liver dysfunction often referred to as sickle cell hepatopathy (SCH). As one of the rarer complications of sickle cell disease (SCD) SCH may go under-recognized. Here we present a case of acute sickle cell hepatic crisis, a subset of SCH, with the aim of increasing the available literature on this important topic. Case Description/Methods: A 20-year-old male with a history of sickle cell disease (SCD) presented for evaluation of right upper quadrant abdominal pain. Vitals signs were normal and physical examination was notable for jaundice and right upper quadrant abdominal tenderness. Labs revealed mildly elevated liver enzymes and elevated direct bilirubin of 34 mg/dL. Abdominal sonography revealed findings suggestive of hepatitis and common bile duct dilation, with suggestion of gallbladder wall thickening. MRCP showed mild intrahepatic and extrahepatic bile duct dilation, as well as splenic hemosiderosis. The common bile duct was 0.9 cm in diameter. Hepatitis A, B, C, as well as HIV, CMV, and herpes screening tests were nonreactive. An ultrasound-guided liver biopsy then revealed features of an acute sickle cell hepatic crisis, including distended sinusoids with erythrocyte sludging. With two days of symptomatic treatment alone, the patient had improvement in his direct bilirubin to 7 mg/dL and was discharged after complete resolution of his symptoms. (Figure) Discussion: Acute sickle cell hepatic crisis (ASCHC), a subset of sickle cell hepatopathy (SCH), is often difficult to diagnose for a multitude of reasons including vague presenting symptoms and clinician unfamiliarity with the disease. While treatment guidelines are lacking with regards to the specific treatment for ASCHC, it is worth noting that in our case clinical and assay improvement was seen after several days of symptomatic treatment alone. Although not present in our case, ASCHC has the potential to be concurrent with a more severe form of the disease known as sickle cell intrahepatic cholestasis (SCIC), which if untreated can be fatal. Both ASCHC and SCIC can present with jaundice, as in our patient, but only SCIC progresses to organ failure. As more cases are described, the optimal treatment modalities for these rarer complications of sickle cell disease will only increase.Figure 1.: Liver parenchyma with dilated sinusoids, readily visualized sickled red blood cells (right side of the image) and canalicular cholestasis (brown pigment on the left side of the image).