Vaso-occlusive Pain Research Articles

Mechanism(s)-of-Action for Arginine Therapy in Children with Sickle Cell Disease and Vaso-Occlusive Pain: Results of a Pharmacokinetics/Pharmacodynamics Study

Introduction: Low L-Arginine (Arg) bioavailability is associated with sickle cell disease (SCD) mortality and morbidity, including acute pain severity. Multiple phase 2 trials support the safety and efficacy of Arg therapy in children with SCD experiencing vaso-occlusive pain. Nitric oxide (NO) is a potent vasodilator depleted in SCD due to hemolysis. As the obligate substrate for NO production, Arg's mechanism-of-action is unknown but thought to be related in part to NO production. Kyotorphin (KTP) is an endogenous opioid analgesic composed of the amino acids tyrosine and Arg. Its nociceptive effects are through induction of Met-enkephalins release in the brain. Oral administration of Arg in wild-type mice increases the levels of KTP centrally. We have previously shown that Arg supplementation increases NO metabolites (NOx), improves mitochondrial function, decreases oxidative stress, and has opioid sparing effects in children with SCD. The association between IV Arg supplementation as a precursor to KTP in SCD is unknown and may represent a novel mechanism by which Arg decreases pain in patients with SCD. Objective: To analyze the results of a pharmacokinetics/pharmacodynamics study, evaluating the association between Arg supplementation and plasma levels of KTP and other potential mechanisms-of-action related to Arg in children with SCD and vaso-occlusive pain episodes (VOE). Methods: We conducted a pharmacokinetics/pharmacodynamics study of children aged 7-21 years with SCD hospitalized for VOE and randomized to treatment utilizing one of 3 dosing arms of Arg: 1) 100mg/kg IV three times/day, standard dose (n=4); 2) loading dose (200mg/kg) followed by standard dose (n=5); or 3) loading dose (200mg/kg) followed by continuous infusion (300mg/kg/day) until discharge (n=4). Plasma amino acids (arginine, ornithine, citrulline), global arginine bioavailability ratio (GABR; Arginine/[Citrulline+Ornithine]), KTP, NOx, exhaled NO, plasma arginase activity, and arginase-1 and -2 were measured. Mean±SD, paired t-tests, and Pearson correlation analyses between groups were performed where appropriate. Results: A total of 13 patients (age 13±3 years, 56% male, 88% Hb-SS, 85% on hydroxyurea) were enrolled. Statistically significant increases in plasma arginine levels (Fig1A), plasma KTP levels (Fig1B), and GABR from pre-dose (0 hour) to 1, 1.5, and 2 hours after arginine infusion were observed, with a return to baseline 8 hours after Arg administration. Arg and KTP levels peaked between 60-90 minutes after arginine infusion in all study arms (p<0.001, p=0.004 respectively). There were no significant differences in peak concentration across all study arm doses. Rise in KTP levels strongly correlated with changes in plasma Arg concentration ( r=0.72, p<0.0001). Plasma NOx levels significantly increased from pre-dose to Tmax (Tmax= 1-2 hours; mean percent change 156±313%, p=0.02), as did exhaled NO (mean percent change 31±27%, p=0.02). Arginase activity also increased significantly after IV Arg infusion peaking at approximately 90 minutes (mean percent change 137±183%, p= 0.03) with return to baseline at 8 hours, while there was no significant change in arginase-1 or -2 concentrations over time. Conclusion: IV Arg therapy increased plasma arginine concentration 2-5 times above baseline at presentation for VOE, and GABR also increased as expected in this pharmacokinetics study with both reaching a maximum concentration within 1 hour of infusion initiation in all dosing schemes. IV Arg supplementation increases plasma NOx levels suggesting a role for vasodilation as a potential mechanism-of-action during SCD-VOE. Exhaled NO also increased significantly, consistent with previous reports. Interestingly, IV Arg supplementation acutely increased arginase activity without a significant change in arginase concentration. Most notably, we report for the first time the impact of IV Arg therapy on plasma levels of KTP in SCD. As KTP is an endogenous opioid analgesic, this may represent a novel mechanism-of-action of Arg therapy that warrants further investigation. This observation may also have implications for the potential use of arginine supplementation in pain syndromes beyond sickle cell disease.

Standardized Clinical Pathways Improve Management of Vaso-Occlusive Episodes in the Pediatric Emergency Department

Introduction: Pain secondary to vaso-occlusive episodes (VOE) is one of the most common and debilitating complications of sickle cell disease (SCD). Although there are guidelines for pain management, these are often not well-followed. Pain management is entrenched in subjectivity and susceptible to implicit bias. Research has shown that clinical pathways improve care for patients which is especially important in vulnerable populations such as pediatric patients with SCD. Following a quality improvement project at our institution that resulted in significantly improved inpatient care for pediatric patients with SCD, the goal of this project was to create an accessible clinical pathway with multidisciplinary input to streamline management of VOE in the emergency department (ED) and assure equitable care for all. We aimed to improve time to analgesics, increase the percent of patients receiving pain medications within 30 minutes, and increase intranasal fentanyl and patient-controlled anesthesia (PCA) utilization in the pediatric ED. Methods: The care signature clinical pathway was created using a multidisciplinary approach with individuals representing the department of pediatric hematology-oncology, pediatric emergency, anesthesiology, pharmacy, and nurse management. The pathway was developed based on updated American Society of Hematology guidelines for pain management in pediatric VOE. The pathway became available for use via electronic medical record on July 12 th, 2022. Outcome measures regarding pain management were evaluated for one year prior to pathway publication and compared to outcomes one year after publication. Patients with a primary or secondary diagnosis of SCD presenting to the Yale pediatric ED with vaso-occlusive pain were included. Results: A total of 214 ED visits were evaluated. The pre-pathway cohort included 108 encounters from July 1 st, 2021 to June 30 th, 2022 and the post-pathway cohort included 106 ED encounters from August 1 st, 2022 to July 21 st, 2023. During the first year post implementation, a provider utilized the clinical pathway a total of 534 times (121 individuals) with an average of 1 time per day. An analgesic was ordered for 63 (58.3%) patients and administered for 31 (28.7%) patients within 30 minutes of arrival in the pre-pathway cohort. An analgesic was ordered for 73 (68.9%) and administered for 32 (30.2%) patients within 30 minutes of arrival in the post-pathway cohort. Comparing pre- and post-pathway cohorts, the median time to pain medication order was 22 vs 17 minutes and pain medication administration was 42 vs 40 minutes respectively. Intranasal fentanyl was used for 2 (1.9%) patients in the pre-pathway cohort and 12 (11.3%) patients in the post-pathway cohort. A total of 0 (0%) hydromorphone PCAs were administered in the ED in the pre-pathway cohort compared to 4 (3.8%) hydromorphone PCA administered in the ED in the post-pathway cohort. Conclusion: Standardizing pain management using a clinical pathway has shown improvement in ED management of VOE in the first year post implementation with increased utilization of intranasal fentanyl and PCAs. Our goal of increased percentage of patients receiving pain medication within 30 minutes and decreased time to first analgesic was not achieved, however this is an ongoing project and with education in implementation of the clinical pathway we hope to continue to see long term progress. Additionally, in the future, we plan to expand use of this pathway to additional sites within our health care system.

Alterations of Cerebral Metabolites Are Associated with Frequency of Vasoocclusive Crises and Pain Sensitivity in Patients with Sickle Cell Disease

Purpose Sickle cell disease (SCD) is an inherited hemolytic disorder complicated by acute and chronic pain. Acute vasoocclusive crises (VOCs) associated with SCD are extremely painful episodes that are recurrent, unpredictable, and frequently require hospitalization and opioids for pain control. Changes in brain metabolites were identified in other chronic pain populations but haven't been well studied in SCD. Our ongoing trial (ClinicalTrials.gov Identifier: NCT05045820) aims to evaluate the characteristics of brain metabolites in SCD and understand the relationship between the altered cerebral metabolite(s) and clinical pain in patients with SCD. Materials and Methods Metabolite measurements from a single voxel (size: 2×3×3 cm 3) located within the posterior insula cortex (PIC) were acquired from 26 patients with SCD (31.9 ± 13.9 years, 14-73; 14 females) and 19 healthy controls (HCs) (37.9 ± 16.4 years, 17-62; 10 females) with PRESS (TR/TE = 3000/25 ms, Averages =128) and MEGA-PRESS (TR/TE = 3000/68 ms, Averages =256) sequences using a Siemens Prisma 3T scanner. Written consent was obtained from each participant before scanning. LCModel was used for PRESS analysis to obtain concentration values of glutamine + glutamate (Glx), total creatine (tCr), N-acetylaspartate (NAA), total choline (tCho), and myoinositol (MI). Gannet was used for processing MEGA-PRESS data to estimate GABA+. Ratios of each metabolite to tCr were also quantified. Tissue correction for cerebrospinal fluid was performed for each voxel using the tissue composition estimated from SPM12. The Cramer-Rao Lower Bounds of each metabolite analyzed with LCModel was less than 20%. The frequency of VOCs in the preceding 12 months was recorded for each participant. A moderate pressure pain stimuli (using a 0-100 scale with “0” representing “no pain” and “100” representing “most intense pain imaginable”, pain rating at 40-60 abbreviated as P40 is considered as moderate pain) was delivered via a pressure cuff to the gastrocnemius area of the non-dominant leg using a validated MR-compatible air compressor to induce a tonic pressure pain for 8 min right before MRS scan. Higher pressure intensity (mmHg) of P40 indicated higher pain tolerance and lower pain sensitivity. Correlation between the brain metabolites and pain-related outcomes was studied. Results Due to the large range of age in the SCD group, the brain metabolite profile was compared between 17 SCD patients and 17 ethnicity-, age- and gender-matched HCs. The concentration of Glx (p =0.012) and ratio of Glx to tCr (p =0.034) in PIC were significantly higher in patients with SCD compared to HCs (Figure 1). Within the SCD patient group, there was a significant positive correlation between frequency of VOCs in the preceding 12 months and Glx/tCr (r= 0.39, p=0.047, Spearman's), a significant negative correlation between P40 and Glx (r= -0.46, p=0.019, Spearman's). There were no group differences in any other metabolites. Conclusion We find increased Glx in the PIC in patients with SCD. Previous studies have also found increased Glx and/ or Glx/tCr in the PIC as well as other brain regions including the amygdala, the posterior cingulate, the ventral lateral prefrontal cortex and the anterior insula in fibromyolgia. The PIC is thought to be involved in discriminative activities of sensory pain, which suggests that Glx in PIC is related to pain processing in patients with SCD. Glx/tCr was correlated with frequency of VOCs in patients with SCD, indicating that the SCD patients with higher level of Glx/tCr had more VOCs in the preceding 12 months. In addition, the SCD patients with higher level of Glx had lower pressure intensity of P40, suggesting that elevated Glx in the PIC was related to higher pain sensitivity. Our preliminary data provide the first evidence of a link between alterations in excitatory neurotransmitter levels in the PIC in patients with SCD and indicates new information of potential brain markers for pain in SCD, which may guide treatment. Clinical Relevance Statement: Treatment of pain in SCD remains very challenging in part due to a lack of understanding of the underlying mechanisms and pathophysiology of pain. Brain excitatory neurotransmitters and their relationship with pain have been largely unexplored in SCD. These findings indicate that the relationship between clinical outcomes and excitatory brain neurotransmitters may be a potential objective outcome measure 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<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>0.05). Conclusions: Exposure to air pollutants increased respiratory complications among children living in deprived neighborhoods.

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.

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 <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 [<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.

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 < .001). LOS positively correlated with pain scores (r 2 = .272, p = .002), number of blood transfusions (r 2 = .229, p < .001) and total units of blood transfused during admission (r 2 = .230, p < .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.

Use of Conventional Transfusion Thresholds Contributes to Ongoing Iron Overload Issues in Patients with Homozygous (SS) Sickle Cell Disease

Introduction: Homozygous sickle cell disease is characterized by chronic anemia which contributes to a clinical course characterized by recurrent pain crisis episodes. These episodes are usually managed with the use of packed red blood cell products. Randomized data is currently available that supports lower transfusion thresholds in non-sickle cell related conditions including but not limited to patients undergoing orthopedic procedures, cardio-vascular interventions and those needing intensive care. Due to lack of similar randomized trials in patients with sickle cell disease, recommendations from other trials are applied to patients with sickle cell diseases as well. However, this has the potential of worsening iron overload states that patients with sickle cell disease usually suffer from. Methods: Patients with homozygous SS sickle cell disease were evaluated with regarding to transfusion support given during hospitalization for vaso-occlusive pain crisis episodes. The hemoglobin threshold that was used for deciding whether or not to give packed red cell transfusion was studied in patients who were previously getting periodic red blood cell exchange procedures for chronic sickle cell related pain. Serum ferritin levels during the period of exchange transfusion support was compared with levels during simple transfusions. 8 patients were selected from the cohort of patients with homozygous sickle cell disease who had been receiving elective packed red blood cell exchanges. Patients with ferritin levels persistently remaining above 1000 ng/ml were then evaluated with regard to transfusion thresholds used for simple transfusion support during hospitalization for pain crisis episodes. Results: Six patients had persistently high ferritin levels. Thresholds for simple transfusion in this group were studied. A total of 30 units of packed red blood cells were found to be transfused over a 6-month period. During this period only one patient required an exchange transfusion session. 2 out of 30 units were given for a Hgb level above 7 g/dl. The majority, representing 24 out of the total 30 pack red blood cell units were given above a Hgb threshold of 6.0 g/dl. Only 4 units were given using a Hgb threshold less than 6 g/dl. Mean ferritin level before and after the period of simple transfusion support was 6097 ng/ml and 6076 ng/ml respectively. Mean Hgb level in while on exchange transfusion was 7.4 g/dl and it was 6.9 g/dl in those receiving a simple transfusion protocol. Conclusions: Transfusion threshold used in patients with homozygous SS sickle cell disease appears to be similar to patients without sickle cell disease. Current practice based on studies including TRICC and TRISS is to keep the Hgb level above 7 g/dl. This has been shown to be safe and in fact even improves patient outcomes. However, in patients with sickle cell disease this may not be appropriate since their baseline Hgb levels are lower to begin with. Also, transfusions don't appear to improve Hgb levels considerably. These patients also tend to have iron overload at baseline which likely will not improve unless all transfusions are limited. Therefore, applying a lower transfusion threshold would be recommended to avoid acute transfusion related issues and long-term iron overload problems in patients with SS disease.

Optimizing Acute Sickle Cell Care at Community Health Partners Medical Center

CONCLUSION Sickle cell disease (SCD) is an inherited disease affecting more than 100,000 Black and Hispanic patients in the US. An adult with SCD has an average life expectancy of 54 years compared to 76 years in a typical US adult. This poor survival rate can be attributed to disease and race-related biases, a lack of standardized procedures and dedicated care providers, and delayed or insufficient pain management in the acute care setting. Delays and disparities in care, particularly pain management in acute care setting, have been identified as one of the key deficiencies leading to a decreased quality of care and patient reported outcomes. This SCD quality improvement project seeks to improve the quality and timeliness of acute sickle cell vaso-occlusive care by utilizing an ED pain pathway, SCD-specific inpatient order sets, and educating providers on care-related biases for patients seeking acute care at Community Health Partners Medical Center (CHP). The primary objective is to improve efficacy, timeliness and patient-centered care in order to optimize health outcomes for patients with SCD seeking acute care at CHP. This is a collaborative effort between ED, Hospitalist and Pain Management teams. By identifying areas of strength and areas for improvement, we can work towards delivering more efficient, effective, and patient-centered care, ultimately leading to better health outcomes for patients with SCD disease in need of emergency services. Using the Epic EMR, a metric dashboard was created for SCD patients to measure time from arrival to ED order placement, time from arrival to medication administration, number of inpatient admissions, and length of stay. We focused on crucial time metrics and patient outcomes to gauge the department's efficiency and quality of care for SCD Vaso-occlusive pain crisis. Our intervention included delivering an educational presentation to the ED providers regarding appropriate recognition and treatment of SCD pain episodes, and by creating ED and inpatient SCD-specific order sets. The baseline data was evaluated from 3/1/2021-2/28/2022, and metrics were followed for one year after implementation of the intervention from 3/1/22-2/28/23. After implementation, the average time from arrival to ED order placement improved from 94.9 minutes to 69.4 minutes, a difference of 25.5 minutes or 27%. The average time from arrival to medication administration improved from 158.5 minutes to 135.3 minutes, a difference of 23.2 minutes or 14.6%. The average length of stay increased from 5.7 days to 8.4 days, an increase of 2.7 days or 32.2%. By providing education and SCD-specific order sets, we were able to significantly decrease the total amount of time to medication administration for SCD patients experiencing acute pain crises. While our methods were aimed at ED providers to simplify the input of orders, it did not address the time for nursing to obtain and administer the medication; future improvements could be made towards educating nursing staff to help administer medications sooner. One complicating factor is that these metrics were evaluated during the COVID pandemic, which was responsible for an overall increase in patient admissions and length of stay during this time period. These additional burdens have strained the ability of providers and nurses to provide timely care to SCD patients, though this will hopefully continue to improve as the pandemic recedes. Additionally, the proportion of ED patients who were admitted for further management decreased marginally from 25/39(61%) to 36/63(57%) though the overall number of patients seeking care in our acute care setting has increased. This increase in the number of patients utilizing our acute care may be partly due to an expanding Sickle Cell program at our facility. This analysis shows that by providing appropriate education and using a standardized order set and pathway, we observed a significant decrease in time to order placement to facilitate a faster administration of medications. While the results indicate positive changes in the acute setting, there are opportunities for continued improvement, particularly in reducing the time from order placement to medication administration to ensure more efficient, effective, and patient-centered care.

Crizanlizumab in sickle cell disease.

Vaso-occlusion in sickle cell disease (SCD) leads to a myriad of manifestations driving morbidity and mortality in patients with SCD. Increased leucocyte adhesion and P-selectin expression on platelets and endothelial cells is an inciting eventthat leads to obstruction of microcirculation by adhesion with rigid sickled red blood cells. Crizanlizumab is a first-in-class monoclonal antibody that inhibits P-selectin and has been shown to decrease the frequency of vaso-occlusive pain crises in patients with SCD in clinical trials. The role of crizanlizumab in other manifestations of SCD still needs further investigation.

Hospitalizations among children with sickle cell disease enrolled in the Kumasi Sickle Cell Pan African Consortium (SPARCo) database: A cross sectional study.

Sickle cell disease (SCD) is the commonest monogenic haemolytic disorder in Africa. Despite strides made in its management, a significant proportion of patients are hospitalized from the various complications of the disease. This study set out to describe the main causes and outcomes of hospitalizations among pediatric patients with SCD. A cross-sectional study was conducted at the Pediatric Emergency Unit of Komfo Anokye Teaching Hospital within a period of 12 months to recruit pediatric SCD patients. This study looked at causes of admission, length of hospital stay (LOS), and outcome of admission. Of the 201 SCD patients recruited, 57.2% were males and majority were of SCD-SS phenotype 83.1%. The median age was 6 years. The three leading causes of hospitalization were Vaso-occlusive pain events (VOPE) (39.8%), acute chest syndrome (ACS) (25.9%), and infections (12.4%). Ten (5.0%) of the patients presented with a stroke. High admissions were observed in June (12.4%) and November (16.9%). The median (interquartile range [IQR]) LOS was 6 days (IQR: 4-10). Six (3.0%) of the patients died from complications of the disease during hospitalization. VOPE, ACS, infections, and acute anaemia from hyperhaemolysis were observed as the most common causes of admissions among SCD patients. A good outcome of discharge was seen in most of the patients that were hospitalized with a median length of stay of 6 days. This study also strengthens the importance of a good SCD database with patient follow-ups for better outcomes in SCD patients.

Nurses’ Attitudes Concerning Analgesia Administration for Pediatric Patients with Sickle Cell Disease in Jordan: A Cross-Sectional Study

BackgroundPain management of vaso-occlusive crises is a fundamental priority in the lifelong care of children and adolescents with sickle cell disease. AimThis study examined nurses' attitudes towards caring for children with sickle cell disease (SCD) and SCD pain management in those with vaso-occlusive pain. MethodA structured, self-reporting survey was provided to a convenience sample of 298 nurses across 10 hospitals serving Jordan's northern and middle regions. Descriptive and inferential statistics were applied for data analysis. ResultsMost nurses (77%) perceived their experience caring for children with SCD as positive. Many nurses (65%) felt frustrated about caring for these children during painful episodes. Participants identified workload and inadequate time as limiting their ability to address the analgesic needs of children with SCD. Receiving structured education specialized in pain management and more years of experience in nursing significantly predicted less hesitancy in administering opioid-based analgesia. ConclusionsThe results of this study provided further insight into factors that potentially contribute to vaso-occlusive pain crises frequently being poorly managed and inadequately addressed among pediatric patients. Nurses' attitudes and understanding of SCD pain management must be addressed to advance the clinical practice of managing pain in children with SCD.

Education Liaison improves implementation of school accommodations for students with sickle cell disease.

Children with sickle cell disease (SCD) have lower academic attainment than healthy peers. Many benefit from neuropsychological testing (NPT) and educational accommodations, including Individualized Education Programs (IEPs) and Section 504 plans (504s). Despite medical barriers to academic attainment, many children with SCD do not receive indicated NPT or accommodations. We hypothesize that a dedicated Education Liaison (EL) embedded in the SCD team increases implementation of NPT and accommodations. This retrospective study included children aged 5-20years with SCD receiving care at a single center from 2017 through 2020. Univariate analysis and multiple logistic regression were performed. Total 316 children with SCD were included. At baseline, 52.8% had accommodations (IEP: 24.4%, 504: 38.0%). The EL interacted with 62.0% of children. Children with EL contact were more likely to undergo NPT (odds ratio [OR]: 5.385), have an IEP (OR: 4.580), and have a 504 (OR: 2.038) (p<.001 for all). At the end of the study period, 64.6% had accommodations (IEP: 33.5%, 504: 54.4%), which increased from baseline (p<.001 for all). EL interaction was associated with overt or silent stroke history (OR: 1.911), acute chest syndrome history (OR: 2.257), hospitalizations since age 5 (OR: 3.216), and hospitalization for vaso-occlusive pain since age 5 (OR: 2.226) (p<.001 for all). EL interaction improves access to NPT and educational accommodations among children with SCD. SCD centers should incorporate ELs in comprehensive care teams to improve access to appropriate educational accommodations.

Timing matters: An analysis of the relationship between red cell transfusion timing and hospitalization outcomes in sickle cell crisis patients using the National Inpatient Sample database.

Vaso-occlusive pain crisis is a debilitating complication of sickle cell disease (SCD) and it is the most common cause of hospitalization among these individuals. We studied the inpatient outcomes among patients admitted with sickle cell crisis based on the timing of red blood cell transfusion. In this retrospective study, we used the United States National Inpatient Sample (NIS) data for the year 2019, to identify adult patients hospitalized with the principal diagnosis of sickle cell crisis who received simple red blood cell transfusion during their hospitalization. Patients were divided into two groups. Those who received simple red cell transfusion within 24hours of admission were classified as early transfusion. After adjusting for confounders, the mean adjusted length of stay for patients with early transfusion was significantly lower than those who received a late blood transfusion by 3.51days (p-value < 0.001) along with a decrease in mean adjusted hospitalization charges and cost, by 25,487 and 4,505 United States Dollar (USD) respectively. The early red cell transfusion was also associated with a decrease in inpatient mortality, demonstrated by an adjusted odds ratio (aOR) of 0.19 (p-value 0.036), and a reduction in in-hospital sepsis, with an aOR of 0.28 (p-value < 0.001), however, no statistically significant difference was found between the two groups regarding acute respiratory failure requiring intubation, vasopressors requirement, acute kidney injury requiring dialysis and intensive care unit (ICU) admission. We recommend timely triage and reassessment to identify sickle cell crisis patients requiring blood transfusion. This intervention can notably affect the inpatient length of stay, resource utilization, and hospitalization outcomes.

The evolution of the COVID-19 pandemic in paediatric patients with sickle cell disease: From Alpha to Omicron.

We compare the impact of SARS-CoV-2 variants on healthcare utilization and clinical presentation in paediatric patients with sickle cell disease (SCD). One hundred and ninety-one unique patients with SCD and positive SARS-CoV-2 polymerase chain reactions were identified between March 2020 and January 2022. Hospitalizations, which accounted for 42% (N = 81) of cases, were highest during the Delta dominant era (48%) and lowest during Omicron (36%) (p = 0.285). The most common SCD-related complication was vaso-occlusive pain (37%, N = 71), which accounted for 51% of all hospital admissions (N = 41), and acute chest was highest in the Alpha variant era (N = 15). Overall, COVID-19 remained mild in clinical severity within most paediatric SCD patients.

Longitudinal Predictors of Pain in Pediatric Sickle Cell Disease.

Despite the identified pathophysiology of vaso-occlusive pain in sickle cell disease (SCD), predictors of pain in youth with SCD remain elusive. In this study, we measured changes in pain frequency, intensity, and interference over 1 year and examined biopsychosocial risk factors (SCD disease severity, age, female, depression, and sleep quality) as possible longitudinal predictors. Medical history was obtained from retrospective chart review for 79 children with SCD (ages 2-18 years; 48.1% female; 100% Black/African American; 83.5% SCD, SS genotype). As part of a clinical screening protocol, caregivers (n = 79) and youth 8-18 years (n = 43) completed psychosocial questionnaires approximately 1 year apart (M = 15.52 months, SD = 5.69). Zero-order correlations, paired t-tests, and hierarchical linear models examined longitudinal predictors of pain. The longitudinal bidirectional relationship between pain and sleep was also examined. The rate of severe SCD disease increased from 41.8% to 55.7% across the year, while most hematologic medical parameters remained stable. Increased depression and pain interference at survey 1 significantly predicted increased pain interference at survey 2. Poor sleep quality and increased pain frequency at survey 1 predicted increased pain frequency at survey 2. Finally, increased pain interference at survey 1 predicted poor sleep quality at survey 2. History of pain, depression, and sleep quality were longitudinal predictors of pain over 1 year in youth with SCD. Identifying longitudinal predictors of pain may lead to earlier identification of patients with a high-risk SCD pain phenotype and earlier medical, psychological, and behavioral interventions.

Adherence to hydroxyurea and clinical outcomes among children with sickle cell anemia.

Hydroxyurea lowers the incidence of vaso-occlusive pain crises (VOC) and acute chest syndrome (ACS) among children with sickle cell anemia (SCA). Our objective was to assess the relationship between levels of adherence to hydroxyurea and clinical outcomes among children and adolescents with SCA. This retrospective cohort study included Medicaid data (2005-2012) from Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. The study population consisted of children 1-17 years old with SCA enrolled in Medicaid for 3 years. Among children that initiated hydroxyurea, the medication possession ratio (MPR) was calculated as the proportion of days covered by hydroxyurea. Six months after initiation of hydroxyurea, clinical outcomes were assessed through the end of the study period: numbers of VOC-related inpatient admissions and emergency department visits, and encounters for ACS. Multivariable Poisson models were used to predict outcomes by MPR quartile adjusting for previous healthcare utilization, state, and age. Hydroxyurea was initiated by 515 children. The median MPR was 0.53 (interquartile range=0.3-0.8). The annual median number of visits was 0.0 for ACS, 1.3 for VOC-related emergency department, and 1.4 for VOC-related inpatient admissions. For each outcome, the highest quartile of MPR had the lowest predicted count; this difference was significant for ACS visits when compared with the lowest quartile of MPR. This study demonstrated a high level of adherence (>75%) was essential to achieve a lower incidence of common negative clinical outcomes. Further, moderate and severe hydroxyurea nonadherence may be more common than previously appreciated among children, emphasizing the importance of developing and testing innovative strategies to increase adherence.

5613480 REAL WORLD APPLICATIONS OF CLINICAL WHOLE BLOOD ADHESION (VCAM AND P-SELECTIN) BIOMARKERS IN A PEDIATRIC SCD POPULATION

Background: Vaso-occlusive (VOC) pain is the most common complication in sickle cell disease (SCD) and is associated with increased morbidity and early mortality. VOC results from intravascular sickling, and decreased red blood cell deformability with increased inflammation and adhesion in the vessel bed. Recent data has demonstrated the ability of whole blood adhesion to vascular cell adhesion molecule (VCAM) and P-selectin (Psel) to stratify individuals with SCD according to their risk of developing a self-reported VOC. Literature regarding the clinical utility of whole blood adhesion biomarkers in pediatric patients with SCD is limited. Aims: We describe our real-world application of the flow adhesion of whole blood to VCAM-1(FA-WB-VCAM) and flow adhesion of whole blood to P-selectin(FA-WB-Psel) assays in pediatric patients with SCD. Methods: This was a cross-sectional analysis of baseline flow adhesion of whole blood to VCAM-1 and flow adhesion of whole blood to P-selectin indices obtained in children (<18 y/o) and young adult patients (18-21 y/o) with SCD at Children’s National Hospital in Washington, D.C. between January 2020 and March 2022. Both FA-WB-VCAM and FA-WB-Psel were performed by the Functional Fluidic laboratory in Detroit, MI. Changes in disease severity included increased VOC pain rate (home, emergency department, or hospital management), acute chest syndrome, priapism, and nephropathy. Statistical analysis included descriptive statistics, Pearson’s correlation, and categorical analysis by t-test(GraphPad, v9, 2021). P value <0.05 was statistically significant. Results: We identified 109 unique pediatric patients with FA-WB-VCAM and FA-WB-Psel assays performed as part of the standard of care. Eighty-seven percent were children (N=95), and 13% were young adults (N=14). The median age was 11 years(IQR 7-15 years), with 47% males (N=51) and 53% females (N=58). Sixty-two percent of patients were on hydroxyurea (N=68), 4.5% on crizanlizumab (N=5), 5.5% on voxelotor (N=6), and 3% on L-glutamine (N=3). FA-WB-VCAM was similar in children vs young adults [median (IQR): 242 (142-500) cells/m2 vs. 239 (134.8-324.8) cells/m2,p=0.0856] while FA-WB-Psel was higher in the young adult population [median (IQR):32 (11-52) cells/m2 vs. 45 (20-76.5) cells/m2, p=0.8681]. Seventy-four percent of patients were HgbSS, 22% Hgb SC, 2% HgbS Beta Thalassemia Zero, 1% Hgb SBeta Thalassemia Plus, and 1% Hgb SE. Baseline FA-WB-P-Sel and FA-WB-VCAM were performed as part of our standard of care. The most common indication for testing was for baseline evaluation (N=76, 70%), followed by a change in disease severity(N=18, 16%), pre-initiation of DMT/change in DMT (N=5, 4.5%), and a combination of change in disease severity and DMT (N=8, 7%). There were FA-WB-Psel values in patients with a change in disease severity vs. without (55.8 vs. 37.28 cells/m2, p=0.036), but no difference in FA-WB-VCAM (299.7 vs. 329.2 cells/m2, p=0.729). There was an inverse correlation between FA-WB-VCAM-1 and HgbF levels (Pearson’s R = 0.483, p<0.001). Conclusions: We established preliminary mean values of FA-WB-Psel and FA-WB-VCAM adhesion indices within all SCD genotypes. FA-WB-VCAM was higher in children while FA-WB-Psel was higher in young adults. Our data represents the expected differences in HgbSS and HgbSC phenotypes. FA-WB-Psel values were most reflective of a recent change in disease severity and may represent an attractive target to monitor SCD clinical severity.

5613043 THE EVOLUTION OF THE COVID-19 PANDEMIC IN PEDIATRIC PATIENTS WITH SICKLE CELL DISEASE: FROM ALPHA TO OMICRON

Background: Approximately two years ago, COVID-19 was declared a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and through genomic surveillance, we have seen the emergence of variants of SARS-CoV-2. In the United States, over 78 million cases and >900,000 deaths attributable to COVID-19 have been reported. SCD was identified as a risk factor for severe COVID-19 disease in adults and pediatric patients. The emergence of novel SARs-CoV-2 variants has led to challenges in diagnosis, treatment, and prediction of long-term sequelae in individuals with SCD and COVID-19. Aims: We compare the overall seasonal variation of COVID-19 variants and patterns of healthcare utilization and clinical presentation over time in pediatric patients with SCD and COVID-19 at Children’s National Hospital (CNH). Methods: Our single-center, observational cohort study included 193 pediatric patients with SCD (0-21 years) with PCR-confirmed SARS-CoV-2 infection between March 31, 2020, and January 31, 2022. Per the SECURE SCD Registry definitions, clinical severity was classified as asymptomatic, mild, moderate, and severe. Results: A total of 193 unique patients with SCD and positive SARS-CoV-2 PCRs between March 2020-January 2022 were included in our registry. Most patients were female (51.8%), and the mean age was 11.2 years (SD 6.5 years). Most of the cohort resides in Maryland (N=135), and HbSS was the dominant genotype (69.4%). During the alpha dominant variant of the COVID-19 pandemic (March 2020- June 2021) there were 70 cases, followed by 40 cases during the Delta variant (July 2021- December 19, 2021), and 83 cases during the Omicron variant dominance (from December 20, 2021-January 31,2022). There were 149 patients (77%) that presented to the emergency department (ED) or were hospitalized. There were a total of 80 hospitalizations (41.5%), and a relative comparison showed that the percentage of hospitalizations was highest during the delta wave (47.5%) and lowest during the omicron wave (36.1%) (p= 0.407). ED-only utilization was highest in the era of omicron (43.4%, N=36), followed by delta (32.5%, N=13), and then alpha (30%, N=21)(p=0.197). The most common SCD-related complication was vaso-occlusive (VOC) pain (33%, N=64) which accounted for half of all hospital admissions (51%, N=41 of 80). Acute chest syndrome (ACS) was reported in 40% (N=32) of admitted patients and was highest in the alpha era (54.8%, N=17). The use of blood transfusion therapy was highest in the alpha (N=17) and delta (N=14) variants, while Remdesivir use was highest in omicron (N=15). A total of 6 patients received monoclonal antibodies (Delta, N=4; omicron, N=2). Throughout all the variants, there was a significant difference in COVID-19 clinical severity (p>0.005). Of the patients classified as asymptomatic (13%, N=25), seventy-two percent (n=18) were diagnosed during the alpha variant. Mild severity was the most prevalent (69%, N=134), with the omicron variant having the highest cases (51.5%, N=69). Severe cases were observed in all variants (6.7%, N=13) but were most prevalent during the alpha variant (46.2%, N=6). Summary - Conclusion: Interestingly, while the relative percentage of hospitalizations was lowest during the omicron wave, it saw the highest percentages of ER utilization. Overall, COVID-19 remains mild in pediatric patients with SCD, and notably, there was higher health care utilization in the omicron era.

Ketamine use for management of vaso-occlusive pain in pediatric sickle cell disease.

Typical sickle cell disease (SCD) vaso-occlusive pain episode (VOE) management includes opioids, which are often inadequate and can be associated with significant side effects. Ketamine, a dissociative anesthetic, is a potentially effective adjunct to VOE management. This study aimed to characterize ketamine use for VOE management in pediatric SCD. This retrospective case series summarizes a single-center experience regarding the use of ketamine for inpatient management of pediatric VOE in 156 admissions from 2014 to 2020. Continuous low-dose ketamine infusion was most commonly prescribed to adolescents and young adults as an adjunct to opioids (median starting dose 2.0μg/kg/min; median maximum dose 3.0μg/kg/min). Ketamine was started a median of 13.7hours after admission. Median ketamine infusion duration was 3days. In most encounters, ketamine infusion was discontinued prior to opioid patient-controlled analgesia (PCA) discontinuation. The majority of encounters (79.3%) had a reduction in either PCA dose, continuous opioid infusion, or both while receiving ketamine. Low-dose ketamine infusion was associated with side effects noted in 21.8% (n=34) of encounters. The most common side effects included dizziness (5.6%), hallucinations (5.1%), dissociation (2.6%), and sedation (1.9%). There were no reports of ketamine withdrawal. Most patients who received ketamine went on to receive it again during a subsequent admission. Further study is needed to determine the optimal timing of ketamine initiation and dosing. The variability of ketamine administration highlights the need for standardized protocols for ketamine use in VOE management.