Acute Pain Crisis Research Articles

ID: 194317 Prolonged Dorsal Root Ganglion (DRG) Trial Adequately Treats Neuropathic Pain Due to Malignant Lumbosacral Mass

63-year-old female with PMH significant for Stage 1a endometrial adenocarcinoma s/p robotic total hysterectomy, had a fall 2 months prior to presentation, with subsequent development of left gluteal and labial numbness. She presented with subacute onset of urinary retention, constipation, weight loss, and radiating left lower extremity pain associated with dysesthesia and impaired gait. Conservative measures were ineffective (combination of NSAIDs, opioids and gabapentin). Typically, the diagnosis of Lumbosacral plexopathy (LSP) requires a thorough clinical evaluation due to a wide differential. However, our patient’s diagnosis was rather brisk due to an aggressive carcinoma causing severe localized pain. In cases of tumor compression, the L4-S1 segment is commonly affected (>50% of cases) followed by L1-L4 segment (31%) and pan-plexopathy (about 10%). At 42-month follow-up, 86% of patients diagnosed with malignancy-induced LS plexopathy had expired. DRG stimulation is approved for CRPS, persistent post-surgical pain syndrome, and peripheral neuropathy for T10-below. To our knowledge, this is the first report of successful application of DRG stimulation trial in the acute malignant pain crisis and palliative care setting.

Red blood cell transfusions may have the stongest analgesic effect during acute painful crises in sickle cell diseases

Background: The hardened red blood cells (RBC)-induced capillary endothelial damage, inflammation, edema, and fibrosis are initiated at birth, and terminate with disseminated tissue hypoxia, acute painful crises, multiorgan failures, and sudden death even at childhood in the sickle cell diseases (SCD). Methods: All cases with the SCD were included into the study. Results: We studied 222 males and 212 females with similar mean ages (30.8 vs 30.3 years, p>0.05, respectively). Disseminated teeth losses (5.4% vs 1.4%, p<0.001), ileus (7.2% vs 1.4%, p<0.001), cirrhosis (8.1% vs 1.8%, p<0.001), leg ulcers (19.8% vs 7.0%, p<0.001), digital clubbing (14.8% vs 6.6%, p<0.001), coronary heart disease (18.0% vs 13.2%, p<0.05), chronic renal disease (9.9% vs 6.1%, p<0.05), chronic obstructive pulmonary disease (25.2% vs 7.0%, p<0.001), and stroke (12.1% vs 7.5%, p<0.05) were all higher but not acute chest syndrome (2.7% vs 3.7%, p>0.05) or pulmonary hypertension (12.6% vs 11.7%, p>0.05) or deep venous thrombosis and/or varices and/or telangiectasias (9.0% vs 6.6%, p>0.05) in males, significantly. Conclusion: Infections, medical or surgical emergencies, or emotional stress-induced increased basal metabolic rate aggravates the sickling and capillary endothelial inflammation and edema, and may terminate with disseminated tissue hypoxia, acute painful crises, multiorgan failures, and sudden deaths in the SCD. RBC support may have the stongest analgesic effect, and decrease the risk of multiorgan failures and sudden death by decreasing the density of causative hardened cells from the circulation during such severe crises.

Clinical Profiles of Children With Sickle Cell Anaemia Presenting With Acute Clinical Events: A Single-Center Study.

Sickle cell disease is a common genetic disorder characterised by chronic haemolytic anaemia and vaso-occlusive crisis. Sickle cell anaemia (SCA) has both short-term effects in the form of acute clinical events and long-term repercussions seen with chronic multiorgan involvement. It is associated with significant morbidity and mortality. In India, the disease is largely undocumented. Thus, there is an urgent need to highlight the features of the disease so that locally appropriate models of care may be implemented. This study aims to evaluate acute clinical events in SCA and to provide data that may help to reduce the rate of morbidity and mortality associated with this disease by early interventions. A cross-sectional observational study was conducted between November 2020 and May 2022 at Indira Gandhi Government Medical College and Hospital, Nagpur, Central India. The inclusion criteria included previously diagnosed patients of SCA (homozygous sickle cell disease) on high-performance liquid chromatography (HPLC) between the age groups of six months and 12 years, presenting with acute clinical events. The exclusion criteria included patients younger than six months and older than 12 years of age, and all patients with other haemoglobinopathies and sickle cell trait. The study was approved by the Institutional Ethical Committee. All the data was entered into a well-designed Microsoft Office Excel spreadsheet (v 2019, Microsoft, Washington, USA). All the clinical, biochemical, and haematological data were tabulated and analysed. A total of 100 children with sickle cell disease diagnosed by HPLC were enrolled during the study period. About 215 acute clinical events among the 100 cases were recorded, for which they were admitted to the paediatric ward or PICU. The majority (35%, n=35) were seen in the age group of six to nine years (school-going age). About 52% were male and 48% were female (male-to-female ratio= 1.08:1). Pain was the most common symptom. The highest incidence of 36.75% (n=79) was seen with acute painful crises and was the most common indication of hospitalisation, followed by acute febrile illness (AFI) (34.42%, n=74), aplastic crisis (10.23%, n=22), splenic sequestration crisis (9.77%, n=21), hepatobiliary involvement (3.72%, n=8), acute chest syndrome and haemolytic crisis (each 1.86%, n=4), and stroke (1.40%, n=3). In cases of having foetal haemoglobin (HbF) ≥20%, the incidence of acute painful crisis (p=0.0001), hand-foot syndrome (p=0.047), aplastic crisis (p=0.033), splenic sequestration crisis (p=0.039), and AFI (p=0.035) was low as compared to cases having HbF ≤20% which was statistically significant. The incidence of acute painful crisis, hand-foot syndrome, and an aplastic crisis was significantly low in patients receiving hydroxyurea therapy as compared to patients who were not on hydroxyurea. Out of 100 cases, four died during the study period, three died because of splenic sequestration crisis with septic shock, and one died due to hepatic encephalopathy due to haemolytic crisis with septic shock. Acute clinical events in sickle cell disease can have significant morbidity and mortality in the paediatric age group. The nutritional status of sickle cell disease children must be given due importance. Early initiation of hydroxyurea must be encouraged to maintain higher HbF levels, which plays a significant role in reducing morbidity.

E058 The effects of a pain management programme for patients with an inflammatory arthritis

Abstract Background/Aims This study examines the benefits of Pain Management Programmes (PMPs) for patients with inflammatory arthritis who still report pain and fatigue despite optimal medical management. PMPs are widely recommended (e.g. NICE 2021) for people living with persistent pain, using cognitive behavioural therapy and acceptance and commitment therapy. Programmes aim to enable participants to develop self-management ways of living with their pain, so that pain interferes less in their lives and people feel more confident, and positive about the future. We developed a PMP for patients with an inflammatory rheumatological condition with the additional aim of helping participants to identify when they could self-manage their pain and when they needed healthcare to treat their condition and manage acute pain crises. Methods Patients were offered the programme in an information session, followed by assessment with a psychologist and physiotherapist where treatments options were discussed, among them the PMP. Selection criteria were: any type of inflammatory rheumatological condition and persistent pain diagnosed at least 18 months earlier and relatively stable in terms of current treatment; over the age of 18; and able to speak English. The programme ran for eight weekly, 5-hour sessions, with reviews at one and 9 months afterwards. Groups of between 3-11 patients were run in person by a multidisciplinary team of specialists from both outpatient pain management and rheumatology services. Between April 2016 and September 2020, 45 patients (8 men, 37 women) attended 6 programmes and 33 completed outcome measures on pain, disability and distress on the first and last day and at reviews. Results Post-treatment results showed significant improvement in confidence in managing pain, less interference of pain with everyday life, less fear, greater acceptance and a more positive outlook. Mood, pain intensity and relief from the pain did not change. Improvements gained post-treatment were sustained at one month and nine-months. The effect size of the improvements was medium or large. Conclusion This study shows that attending a PMP can improve quality of life for people with inflammatory arthritis even without reducing pain intensity. Across the programme, patients grew in confidence to engage in life alongside their pain; with significant changes sustained at nine months. However, follow-up outcomes were not returned by two thirds of those who completed the programme, in part due to the pandemic, making it hard to generalise to the wider population of patients. Disclosure K. Corcoran: None. I. Hung: None. R. Stovell: None. J. Manson: None. S. Moore: None. A. Soni: None. A. Williams: None.

5610823 TRIAL IN PROGRESS: THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 1B CROSSWALK-A TRIAL EVALUATING THE SAFETY OF CROVALIMAB FOR THE MANAGEMENT OF ACUTE UNCOMPLICATED VASO-OCCLUSIVE EPISODES (VOES) IN PATIENTS (PTS) WITH SICKLE CELL DISEASE (SCD)

Background: SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S (HbS). HbS polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions, which may present as acute, painful episodes called VOEs. Although most VOEs are managed at home, >70% of emergency department visits and >90% of hospitalizations for SCD are VOE-related.1,2 Additionally, acute chest syndrome is one of the most severe complications of VOEs and is a leading cause of mortality.3,4 As there are no targeted therapies for the management of VOEs, treatment is currently limited to pain management, blood exchange transfusion (with the risk of complications), and other supportive care, which represents a significant unmet medical need. Overall, accumulating nonclinical data suggest a multimodal role for complement dysregulation in the pathophysiology of SCD including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage.5 Complement pathway activation has been described in pts with SCD at baseline, in acute pain crises, and in pts with delayed hemolytic transfusion reaction. The complement pathway can be targeted with crovalimab, which is a novel, engineered, anti-complement C5 monoclonal antibody. In a Phase 1/2 study in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder, crovalimab showed rapid and sustained complement inhibition with promising efficacy and safety.6 Aims: CROSSWALK-a (NCT04912869) is a randomized, double-blind, placebo-controlled, Phase 1b study evaluating the safety of crovalimab in managing acute uncomplicated VOEs in pts with SCD. Methods: Pts aged 12 to 55 years, weighing ≥40 kg, and with a confirmed diagnosis of SCD homozygous hemoglobin S (HbSS) or sickle cell β0 thalassemia (HbSβ0) will be enrolled (Figure). Pts must present with an acute uncomplicated VOE, requiring hospitalization and treatment with parenteral opioid analgesics. Vaccinations against Neisseria meningitidis, Hemophilus influenzae type B, and Streptococcus pneumoniae must be current. Eligible pts will be randomized 2:1 to receive either a single intravenous weight-based tiered dose of crovalimab or placebo. All pts will continue with pain management and other supportive care for their VOE, and may continue concurrent SCD-directed therapies. Pts will be followed during hospitalization until discharge and will also be followed post-discharge during an observational period. The study duration for an individual pt, including the hospitalization and observational periods, will be 12 weeks. The primary objective is to evaluate the incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0, incidence and severity of infusion-related reactions and hypersensitivity, and change from baseline in targeted vital signs and clinical laboratory test results. Efficacy, pharmacokinetic, pharmacodynamic, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Protocol updates are in progress. Results: CROSSWALK-a is scheduled to be completed in September 2023. Summary: CROSSWALK-a is enrolling pts with SCD in five countries.

5612539 TRIAL IN PROGRESS: THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 2A CROSSWALK-C TRIAL EVALUATING THE EFFICACY OF CROVALIMAB AS ADJUNCT TREATMENT IN THE PREVENTION OF VASO-OCCLUSIVE EPISODES (VOES) IN PATIENTS (PTS) WITH SICKLE CELL DISEASE (SCD)

Background: SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, with either homozygous inheritance or heterozygous co-inheritance with other pathogenic variants of the β-globin gene. Hemoglobin S, produced as a result of this point mutation, polymerizes within RBCs under certain conditions, distorting them and generating dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions, which may present as acute painful episodes called VOEs. Pts with SCD may also have severe chronic anemia, chronic pain, immune dysfunction, and progressive multi-organ damage. Current therapies for SCD include hydroxyurea, as well as newer treatments such as L-glutamine, crizanlizumab, and voxelotor. Despite these treatments, considerable morbidity and mortality among pts with SCD represents a significant unmet medical need. Complement pathway activation has been reported in pts with SCD at baseline, in acute pain crises, and in delayed hemolytic transfusion reaction. Accumulating nonclinical data suggest the potential multimodal role for complement dysregulation in the pathophysiology of SCD, including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage.1 The complement pathway can be targeted with crovalimab, a novel anti-C5 monoclonal antibody that allows for small-volume subcutaneous (SC) self-injection. In a Phase 1/2 paroxysmal nocturnal hemoglobinuria (a complement-mediated disorder) study, crovalimab showed rapid and sustained complement inhibition with promising efficacy and safety.2 Aim: CROSSWALK-c (NCT05075824) is a randomized, double-blind, placebo-controlled, Phase 2a study evaluating the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs in pts with SCD. Methods: Pts aged 12 to 55 years, weighing ≥40 kg, with a confirmed diagnosis of SCD, homozygous hemoglobin S (HbSS) or sickle cell β0 thalassemia (HbSβ0), and presenting with 2 to 10 VOEs are eligible, including pts on concurrent SCD-directed therapies. Vaccinations against Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumoniae are required. Pts with a history of hematopoietic stem cell transplant will be excluded. Eligible pts will be randomized 1:1 to the crovalimab or placebo arms (Figure). An initial intravenous loading dose of crovalimab or placebo will be given on Week 1, Day 1, followed by SC dose on Week 1, Day 2, and then weekly SC doses on Weeks 2–4. Starting Week 5, a maintenance dose will be given every 4 weeks for 48 weeks. All study treatment will be given according to a weight-based tiered dosing schedule (pts weighing ≥ 40 kg to < 100 kg and pts ≥ 100 kg). The primary objective is to evaluate the efficacy of crovalimab vs placebo based on the annualized rate of medical facility VOEs. Key secondary efficacy objectives are the annualized rate of acute chest syndrome, the annualized rate of home VOE, and change in urinary albumin–creatinine ratio, tricuspid regurgitant jet velocity, and Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue score in adults, from baseline to Week 49. Safety, pharmacokinetic, immunogenicity, and exploratory biomarker objectives will also be evaluated. Protocol updates are in progress. Results: Primary results are expected in July 2024. Summary: CROSSWALK-c is enrolling pts with SCD and chronic VOEs in six countries.

5613082 CD34+ HEMATOPOIETIC STEM CELL COUNT AS NOVEL BIOMARKER FOR PREDICTING VASCULAR EVENTS IN EGYPTIAN CHILDREN WITH SICKLE CELL DISEASE

Background: Vasoocclusion is the major clinical feature of sickle cell disease (SCD). It results in acute painful vasoocclusive crises and progresses to multiple organ failure (1). Severe SCD is defined as frequent pain, recurrent Acute Chest Syndrome (ACS), stroke and death(2). Therefore, it is essential to identify relevant predictive markers for clinical vascular events. Aim: Evaluation of circulating CD34 as a novel predictive marker of occurrence of vascular events in children with sickle cell disease in their steady state and to relate its levels to other clinical and laboratory parameters of SCD. Methods: 50 patients diagnosed with SCD aged 0.3-13 years old (median 2 years) in their steady state for at least 3 month were enrolled. History with emphasis on neurovascular and peripheral vascular events was taken then hematology, hemolysis, coagulation markers and flow cytometery for quantification of circulating CD34 were withdrawn at inclusion and compared to age and sex matches control then patients were prospectively followed up for 6 months where 2 groups of patients were compared depending on development of vascular events. Results: Results showed statistically significant higher level of circulating CD34+ in patients with SCD compared to control (p <0.001). Patients who developed peripheral vascular events on follow up (n=29) has statistically significant higher level of previous neurovascular events, previous history of vasooclussive crisis(VOC) and previous hospitalization for VOC (p-value 0.015, 0.001 and 0.001 respectively).As for laboratory markers, they have statistically significant higher level of total leucocytic count(TLC), neutrophil count, platelet count and CD34+ level with cut off value of >4340 cell/ ml and higher Time Averaged Mean Flow (TAMMAX)>115cm/sec(p-value 0.015, 0.008, 0.042 and 0.022, 0.028 respectively). There was negative correlation between CD34 and age of diagnosis (p<0.006), hemoglobin level at inclusion (p=0.045), while positively correlated with peripheral vascular events on follow up, TLC, platelet count and bilirubin level at inclusion(p=0.022, 0.01, 0.044, <0.001). Conclusion: Our data showed that circulating CD34 is a potential biomarker for predicting vascular events in children and adolescents with SCD at steady state.

Urinary Biomarkers for the Assessment of Acute Kidney Injury of Pediatric Sickle Cell Anemia Patients Admitted for Severe Vaso-occlusive Crises.

Sickle cell nephropathy is a progressive morbidity, beginning in childhood, which is incompletely understood partially due to insensitive measures. We performed a prospective pilot study of pediatric and young adult patients with sickle cell anemia (SCA) to assess urinary biomarkers during acute pain crises. Four biomarkers were analyzed with elevations potentially suggesting acute kidney injury: (1) neutrophil gelatinase-associated lipocalin (NGAL), (2) kidney injury molecule-1, (3) albumin, and (4) nephrin. Fourteen unique patients were admitted for severe pain crises and were found to be representative of a larger SCA population. Urine samples were collected at the time of admission, during admission, and at follow-up after discharge. Exploratory analyses compared cohort values to the best available population values; individuals were also compared against themselves at various time points. Albumin was found to be moderately elevated for an individual during admission compared with follow-up ( P = 0.006, Hedge g : 0.67). Albumin was not found to be elevated compared with population values. Neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and nephrin were not found to be significantly elevated compared with population values or comparing admission to follow-up. Though albumin was found to be minimally elevated, further research should focus on alternative markers in efforts to further understand kidney disease in patients with SCA.

Clinical outcomes among young patients with Fabry disease who initiated agalsidase beta treatment before 30 years of age: An analysis from the Fabry Registry.

Clinical manifestations of classic Fabry disease (α-galactosidase A deficiency) usually occur in childhood, while complications involving major organs typically develop in adulthood. Outcomes of Fabry-specific treatment among young patients have not been extensively reported. Our aim was to analyze clinical outcomes among patients aged 5-30 years at initiation of treatment with agalsidase beta using data from the Fabry Registry (NCT00196742, sponsor: Sanofi). Reported GLA variants were predicted to be associated with the classic phenotype or not classified in fabry-database.org. Linear mixed models were conducted to assess changes over ≥2-year follow-up in the estimated glomerular filtration rate (eGFR) stratified by low (LRI) and high (HRI) renal involvement (defined by proteinuria/albuminuria levels), and changes in interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) Z-scores stratified by median age at first treatment. Self-reports ('yes'/'no') of abdominal pain, diarrhea, chronic peripheral pain (denoting neuropathic pain), and acute pain crises at baseline were compared with reports after ≥0.5-year and ≥2.5-year follow-up using McNemar's test. Male (n = 117) and female patients (n = 59) with LRI initiated treatment at a median age of 19.9 and 23.6 years, respectively, and were followed for a median of 6.3 and 5.0 years, respectively. The eGFR slopes were -1.18 (Pfrom 0 <0.001) and -0.92 mL/min/1.73 m2/year (Pfrom 0 = 0.040), respectively. Males with HRI (n = 23, median UPCR 1.0 g/g), who started treatment at a median age of 26.7 years, had an eGFR slope of -2.39 mL/min/1.73 m2/year (Pfrom 0 <0.001; Pdifference = 0.055, as compared with the slope of -1.18 mL/min/1.73 m2/year for LRI males) during a median follow-up of 5.6 years. Echocardiographic variables were stable among males, regardless of age, and among young females (median follow-up >5.5 years and ≥4.5 years, respectively). Older females (treatment initiation at median age 27.5 years) had a slope of LVPWT Z-scores of 0.18/year (n = 12, Pfrom 0 = 0.028), whereas IVST Z-scores remained stable (n = 13, 0.10/year, Pfrom 0 = 0.304) during a median follow-up of ≥3.7 years. These slopes did not significantly differ from slopes of younger females. Reports of chronic peripheral pain and acute pain crises by males, and of diarrhea and acute pain crises by females, significantly reduced after a median follow-up of ≥4.0 years. After a median follow-up of ≥5.4 years, reports of all four symptoms significantly decreased among males, whereas among females only reports of abdominal pain significantly decreased. During sustained treatment with agalsidase beta in young Fabry patients with a predicted classic phenotype or with unclassified GLA variants with similar characteristics, the decline in eGFR was modest among male and female patients with LRI. The greater decline in eGFR among older, proteinuric (i.e., HRI) males may suggest a benefit of earlier treatment. Overall, echocardiographic variables remained stable, particularly among males and younger females. Significant reductions in symptom reports occurred primarily among males after longer follow-up and were less noticeable among females. These observed trends are suggestive of an overall improvement after treatment in young patients, but warrant larger longitudinal studies.

How does sickle cell disease affect the peri-operative outcome in patients undergoing total knee arthroplasty? A large-scale, National Inpatient Sample-based study.

In view of the vaso-occlusive pathophysiology affecting osseous micro-circulation, sickle cell disease (SCD) is well known to present with diverse skeletal and arthritic manifestations. With prolonged life-expectancy over the past decades, there has been a progressive increase in the proportion of SCD patients requiring joint reconstructions. Owing to the paucity of evidence in the literature, the post-operative complication rates and outcome in these patients following total knee arthroplasty (TKA) are still largely unknown. Based on the National Inpatient Sample (NIS) database (using ICD-10 CMP code), patients who underwent TKA between 2016 and 2019 were identified. The cohort were classified into two groups: A-those with SCD; and B-those without. The data on patients' demographics, co-morbidities, details regarding hospital stay including expenditure incurred, and complications were analyzed and compared. Overall, 558,361 patients underwent unilateral, primary TKA; among whom, 493 (0.1%) were known cases of SCD (group A). Group A included a significantly greater proportion of younger (60.14 ± 10.87 vs 66.72 ± 9.50years; p < 0.001), male (77.3 vs 61.5%; p < 0.001); and African-American (88.2 vs 8.3%B; p < 0.001) patients, in comparison with group B. Group A patients were also at a significantly higher risk for longer duration of peri-operative hospital stay (p < 0.001), greater health-care costs incurred (p < 0.001), and greater need for alternative step-down health-care facilities (p < 0.001) following discharge. Among the SCD patients, 24.7%, 20.9% and 24.9% developed acute chest syndrome, pain crisis and splenic sequestration crisis, respectively during the peri-operative period. Group A patients had a statistically greater incidence of acute renal failure (ARF; p = 0.014), need for blood transfusion (p < 0.001) and deep vein thrombosis (DVT; p = 0.03) during the early admission period. The presence of SCD substantially lengthens the duration of hospital stay and enhances health care-associated expenditure in patients undergoing TKA. SCD patients are at significantly higher risk for systemic complications including acute chest syndrome, pain crisis, splenic sequestration crisis, acute renal failure, higher need for blood transfusions and deep venous thrombosis during the initial peri-operative period following TKA.

Acute painful crises may be causes of sudden deaths in sickle cell diseases

Background: Sickle cell diseases (SCDs) are severe inflammatory processes on vascular endothelium, especially at the capillary level because the capillary system is the actual distributor of hardened red blood cells (RBCs) into the tissues. Methods: All cases with the SCDs were included. Results: We studied 222 males and 212 females with similar mean ages (30.8 vs 30.3 years, p&gt;0.05, respectively). Disseminated teeth losses (5.4% vs 1.4%, p&lt;0.001), ileus (7.2% vs 1.4%, p&lt;0.001), cirrhosis (8.1% vs 1.8%, p&lt;0.001), leg ulcers (19.8% vs 7.0%, p&lt;0.001), digital clubbing (14.8% vs 6.6%, p&lt;0.001), coronary heart disease (18.0% vs 13.2%, p&lt;0.05), chronic renal disease (9.9% vs 6.1%, p&lt;0.05), chronic obstructive pulmonary disease (25.2% vs 7.0%, p&lt;0.001), and stroke (12.1% vs 7.5%, p&lt;0.05) were all higher in males but not acute chest syndrome (2.7% vs 3.7%), pulmonary hypertension (12.6% vs 11.7), deep venous thrombosis and/or varices and/or telangiectasias (9.0% vs 6.6%), or mean age of mortality (30.2 vs 33.3 years) (p&gt;0.05 for all). Conclusion: The hardened RBCs-induced capillary endothelial damage, inflammation, edema, and fibrosis are initiated at birth, and terminate with disseminated tissue hypoxia and multiorgan failures even at childhood in the SCDs. Although RBCs supports and corticosteroids in acute phase and aspirin plus hydroxyurea both in acute and chronic phases decrease severity of the diseases, survivals are still shortened in both genders, dramatically. Infections, medical or surgical emergencies, or emotional stresses-induced increased basal metabolic rate aggravates the sickling and capillary endothelial edema, and may terminate with acute painful crises, multiorgan failures, and sudden deaths. Key words: Sickle cell diseases, acute painful crises, sudden deaths, capillary endothelial inflammation, capillary endothelial edema, atherosclerosis, aging

Corticosteroids during Acute Painful Crises of Sickle Cell Diseases

Background: Sickle cell diseases (SCD) are severe inflammatory processes on vascular endothelium, particularly at the capillary level since the capillary system is the main distributor of hardened red blood cells (RBC) into the tissues. Methods: All patients with the SCD were included. Results: The study included 222 males and 212 females with similar ages (30.8 vs 30.3 years, p&gt;0.05, respectively). Disseminated teeth losses (5.4% vs 1.4%, p&lt;0.001), ileus (7.2% vs 1.4%, p&lt;0.001), cirrhosis (8.1% vs 1.8%, p&lt;0.001), leg ulcers (19.8% vs 7.0%, p&lt;0.001), digital clubbing (14.8% vs 6.6%, p&lt;0.001), coronary heart disease (18.0% vs 13.2%, p&lt;0.05), chronic renal disease (9.9% vs 6.1%, p&lt;0.05), chronic obstructive pulmonary disease (25.2% vs 7.0%, p&lt;0.001), and stroke (12.1% vs 7.5%, p&lt;0.05) were all higher but not acute chest syndrome (2.7% vs 3.7%), pulmonary hypertension (12.6% vs 11.7), deep venous thrombosis and/or varices and/or telangiectasias (9.0% vs 6.6%), and mean age of mortality (30.2 vs 33.3 years) in males (p&gt;0.05 for all). Conclusion: Although the hardened RBC-induced capillary endothelial damage is present in whole body even at birth, severe exacerbations during additional stresses are called as acute painful crises. An increased basal metabolic rate, exaggerated sickling, diffuse capillary endothelial damage, exaggerated capillary endothelial inflammation and edema, generalized tissue hypoxia, and multiorgan insufficiencies may be the main causes of mortality during the crises. Although rapid RBC supports are the main treatment option, corticosteroids should also be added to decrease severity of endothelial inflammation and edema, and to prevent tissue hypoxia and multiorgan insufficiencies during such crises. Key words: Sickle cell diseases, acute painful crises, capillary inflammation, capillary edema, corticosteroids, metabolic syndrome, atherosclerosis

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 \&amp;quot;Ketamine Administration for Acute Painful Sickle Cell Crisis: A Randomized Controlled Trial,\&amp;quot; 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 (&amp;gt; 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.

Improving the Emergency Department Management of Sickle Cell Vaso-Occlusive Pain Crisis: The Role and Options of Sublingual and Intranasally Administered Analgesia.

Vaso-occlusive crisis (VOC), characterized by periods of excruciating pain is the most common clinical manifestation of sickle cell disease (SCD), often resulting in emergency room presentation. These patients often experience long wait times in the emergency department before receiving their first dose of analgesia. This delay results from the complexities of the emergency care system. Using the intranasal or sublingual approach to administering analgesia to SCD patients with VOC offers a fast, safe, noninvasive, atraumatic, and easily accessible route of administration which could reduce the time to first dose of analgesia. With the evolving advances in the development and delivery of analgesic medications, providers should be conversant with the nuances of intranasal and sublingual analgesia in the management of acute vaso-occlusive pain crisis. This review explores the pharmacokinetic profiles, dosages, and administration of intranasal and sublingual analgesics with relevance to the SCD population.

664: A RARE CASE OF NEUROPSYCHIATRIC LUPUS VASCULITIS: TREATING A DIAGNOSTIC DILEMMA

Introduction: Fat emboli syndrome (FES) in the setting of sickle cell disease (SCD) occurs secondary to bone ischemia, releasing fatty acids into the blood, and leading to infarct and microhemorrhages to the brain through either pulmonary or cardiac shunt. The characteristic MRI findings of cerebral FES are a “starfield” appearance of scattered micro-infarcts. Cerebral FES is uncommon in pediatrics, in patients without evidence of a shunt and in patients without inciting bone injury. Description: 16 year old male with HbSS presented with low back pain concerning for acute vaso-occlusive pain crisis that progressed to acute chest syndrome, respiratory failure and ARDS requiring intubation. He had respiratory acidosis and prolonged hypoxia on arrival. His initial HgbS fraction was 76%, requiring multiple exchange transfusions. He developed multiorgan dysfunction including acute renal failure, bilateral cortical renal infarcts, and biventricular cardiac dysfunction with ejection fraction of 35-40% and no shunt. He received therapeutic plasma exchange (TPE) in the setting of thrombocytopenia with schistocytes. A week later, his respiratory failure had improved and sedation was lifted for extubation when he was found to have increased tone, myoclonic movements, clonus, extensor posturing, gaze deviation and bilateral Hoffman sign. EEG showed no evidence of seizures. MRI demonstrated diffuse microhemorrhages and diffusion restriction in the white matter of the brain, localized heavily in the corpus callosum, as well as extensive bone ischemia of cervical vertebrae consistent with a microvascular occlusive process. The bony changes and starfield pattern seen on MRI were suggestive of cerebral FES. He tested positive for parvovirus B19, commonly seen in FES. He was extubated 6 days after diagnosis of FES and transferred to rehab facility after a month. Discussion: Although well described in adults, we found only a single other case describing FES with SCD in a child. Also notable are his delayed development of FES after recovery from other organ injuries and in the absence of cardiac shunt, and unknown intrapulmonary shunt. Prognosis for this disease, particularly in pediatrics, is unclear and treatment is mostly supportive aside from exchange transfusions.

"Here's What I Wish You Knew": A Qualitative Narrative Analysis of the Adolescent Sickle Cell Pain Experience

Background Bias, stigmatizing language, and social isolation are significant barriers to the optimal care of pain for adolescents and young adults (AYA) with sickle cell disease (SCD). Qualitative studies that include first-person narratives of SCD pain are underrepresented in outcomes research but provide valuable information for clinical education and community care models. Here, we present the interim analysis of an ongoing thematic research study that analyzes narrative experiences of AYA patients with SCD and their journeys- both in and out of the healthcare system- with chronic pain. Methods In this IRB-approved study, a single semi-structured interview is administered to patients ages 13-21 with sickle cell disease (Hemoglobin SS, SC, and SBeta0Thal genotypes) living in a mid-sized metropolitan center and receiving care at an academic teaching hospital. Patients are offered the opportunity to participate from inpatient units, ambulatory continuity clinics, and community advocacy groups. Interviews are conducted either in-person or remotely, recorded, transcribed, and independently checked for accuracy. The interview includes questions about coping with pain in medical and non-medical settings, interactions with the healthcare team, impacts of pain on social and community life, and opportunities to describe what patients wish family members, teachers, friends, and healthcare providers understood about living with SCD pain. Transcripts are analyzed for thematic coding by 2 independent coders using a deductive approach with latent textual analysis (Braun & Clarke, 2013). Codes are translated into themes by key-words-in-context and indigenous categorization methods (Ryan, 2011). Thematic coders are not members of the patients' clinical care teams, and patients do not provide interviews during acute pain crises. Results At the time of submission, 8 interviews were completed and analyzed. The median patient age was 17 years. Concordant coding revealed five primary themes: the relationship between acute and chronic pain, coping with rituals and cycles of care, the unpredictable nature of pain, navigating a biased healthcare system, and social isolation. The majority of patients detailed their experiences with intense, coexistent physical and emotional pain (6/8) that creates a pervasive sense of uncertainty and foreboding (4/8) in their lives. They described navigating a healthcare system that is difficult to understand, while experiencing doubts and dismissals of their pain from healthcare providers, particularly when making the transition to adult care (4/8). Lack of education and awareness about SCD in academic settings (5/8) and "missing out" on social milestones and norms (6/8) were cited as sources of isolation and emotional fatigue. Having a family member or community-based care advocate was viewed as a critical source of support within both the health system and community (4/8). Discussion and Future Directions This ongoing qualitative research study in adolescent and young adults with SCD provides narrative data about the lived experience of sickle cell pain from the patient perspective. Interim analysis suggests several locations in the care trajectory where reports of pain may be particularly vulnerable to bias: in healthcare settings for management of acute-onset pain crisis, in schools and other academic support settings where knowledge of SCD may be incomplete, and in the transition of care from pediatric to adult care models. Particularly during acute pain management and transition care experiences, patients describe the use of stigmatizing language- in conversation and in the electronic health record- that contribute to feelings of isolation, frustration, and emotional suffering. Results of this study are being used to inform community, pastoral, and school-based sickle cell education programs as well as medical education curricula aimed at reducing stigmatizing language. Results are also being used to develop standard criteria for sickle cell patient advocates, and to improve infrastructure for the integration of patient advocates into sickle cell care teams. Future research will measure the impact of patient participation in narrative research on clinical outcomes and attitudes toward engaging the healthcare system, both for routine care and potential SCD clinical research. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Assessment of Emergency Department Care for Patients with Acute Pain Crisis after the Formation of a Multidisciplinary Team

Introduction:American Society of Hematology (ASH) guidelines recommend the rapid evaluation and treatment of patients presenting to the Emergency Department (ED) with pain from an acute vaso-occlusive episode (VOE) related to sickle cell disease (SCD). The treatment of severe pain from VOE in SCD is time dependent and time sensitive. Guidelines recommend that treatment for acute VOE with parental opioid analgesia occurs within 60 minutes of ED registration. With respect to the five-level Emergency Severity Index (ESI) triage tool, in which lower numbers indicate higher acuity, patients with SCD are to be assigned an Emergency Severity Index (ESI) of 2 indicating (a) greater disease burden, and (b) the need for high priority bed assignment. Objectives: We aimed to create a multidisciplinary team of providers to assess and address the existing barriers and facilitators to improving guideline adherence for the management of acute crises in our large academic health system. The primary outcome of this initiative was to improve guideline adherence by ensuring 90% or greater adherence to ESI 2 assignment to acknowledge illness severity as well as timely, within 60-minute opioid analgesia. Methods: In March 2020, we convened a multidisciplinary team of stakeholders to discuss the ED care of patients with SCD presenting with an acute VOE. The group comprises ED and infusion center nurse champions, nurse educators, nurse leaders, hematologists, palliative care specialists, primary care physicians, psychologists, advanced practice providers and other allied health professionals including social work and spiritual care. Initial monthly meetings established recommendations based on national guidelines and discussed interventions to improve guideline adherence including 1. a nursing driven pain management orderset with subcutaneous and intranasal opioids, 2. a best practice alert with the recommended guidelines. We conducted a retrospective review of ED visit data including all patients with a known diagnosis of sickle cell disease presenting to the ED with a chief complaint of acute pain related to VOE from January 2018-February 2020 and March 2020 to March 2022. We compared the before and after intervention using descriptive statistics. Results: Of the 760 unique encounters for acute pain related to sickle cell disease from 2018-2022, 406 visits occurred before the group formation and 354 visits occurred after the group formed. Mean age was 30.5 years (+/- 19.5) in the pre-intervention period compared to the 29.5 years (+/- 18.9) in the post intervention period. The time to the first opioid order placed pre-intervention averaged 53.3 mins (+/- 64.9) was not significantly different compared to the post period 75.2 mins (+/- 125.8; p =0.17). The proportion of patients assigned an ESI 2 changed from 49.3% to 50.5%. Conclusion: While there was a marginal increase in the ESI 2 assignment among SCD patients presenting in acute VOE, there was no significant change in the ED time to first opioid after the formation of a multidisciplinary team.

Resolvins Modulate Netosis and Autoimmunity in Sickle Cell Disease

Sickle cell disease (SCD) is a genetically determined hematological disease which is characterized by anemia, chronic hemolysis, and multi-organ chronic inflammatory vasculopathy with acute vaso-occlusive painful crises and chronic organ damage. The pathophysiology of SCD is complex and involves several other cell types and metabolic pathways than erythrocytes, including neutrophils and soluble factors such as cytokines or alternative complement pathway which affect the function of vascular endothelium. An inflammatory vasculopathy with chronically activated neutrophils releasing Neutrophil Extracellular Traps (NETs) is a key component of the pathophysiology of sickle cell disease (SCD). Chiang et al. have recently shown that resolvins (Rv) reduce NETS and improve NETs clearance in a model of sepsis by Staphylococus aureus, a known trigger of NETosis (Chiang N et al. Blood 139 (8): 1222, 2022). We previously reported that targeting pro-resolution mechanisms with Rv improves SCD vasculopathy and organ damage in humanized sickle mice. Here, we studied 23 adult patients with SCD, followed by the Comprehensive center for hemoglobinopathies and rare anemias, University of Verona and AOUI Verona from January 2019 to December 2021. For each patient the presence/absence of concomitant rheumatological condition such as rheumatoid arthritis, other inflammatory arthropathies, immune-mediated dermatological conditions, Sicca syndrome and Raynaud's phenomenon, were assessed. Eight age, and ethnicity matched healthy controls were analyzed. Blood was collected for hematological and biochemical assay as part of the standard clinical care for these patients. Additional blood was collected for research studies on whole blood and on plasma cytokines. SCD patients display significant increase in tumor- necrosis-factor (TNF)- α (p = 0.011) and interleukin (IL)-10, suggesting both active inflammatory state and an upregulated counterregulatory mechanism to limit inflammation. We observed that antinuclear antibodies (ANA), but not extractable nuclear antibodies (ENA), were significantly increased in SCD patients (provide specific data here). Previous reports have reported the presence of this type of autoantibodies in the absence of autoimmune clinical manifestations in patients with SCD (Toly-Ndour C et al J Rheumatol 38: 302, 2011). ANA+ SCDsubjects (defined by a cell nuclei homogenous pattern, and positive dilution in the 1:80 to 1: 160 range) had a higher inflammatory and hemolytic status, as demonstrated by increased WBC and neutrophil counts and LDH values compared to ANA- subjects. NETosis plays a key role in modification and externalization of autoantigens involved in production of autoantibodies such as ANA. Here, we found basal NETosis was higher, though not significant, in ANA+ SCD subjects compared to ANA-SCD patients. This was associated with lower expression of receptors for RvD1 and D2, namely ALX, GPR32/DRV1, and GPR18/DRV2 on PMN, monocytes, and lymphocytes from ANA+ SCD patients when compared to ANA- SCD subjects, who were also characterized by relatively low LDH compared to ANA+ SCD patients. Exogenous treatment of SCD neutrophils with RvD1 and D4 significantly dampened NETs release and enhanced NETs clearance by macrophages. RvD4 along with other pro-resolving mediators also stimulated ex vivo clearance of P. aeruginosa and S. aureus by SCD neutrophils. Our findings provide a novel link between autoimmunity and neutrophil-mediated vasculopathy in SCD and highlight the importance of Rv and their immune-pro-resolution effects in limiting disease progression in SCD but also to modulate the host response to infections and sepsis, which is altered in SCD.

Emergency Department Experience and the Use of Non-Pharmacologic Treatment for Acute Pain Among Patients with Sickle Disease

Background: Appropriate management for patients presenting to the Emergency Department (ED) with acute pain from vaso-occlusive episodes (VOE) primarily includes treatment with parenteral opioid and non-opioid analgesia and fluids if the episode is uncomplicated. Non-pharmacological strategies that significantly affect non-physical aspects of behavioral, social, and cultural life, have been studied for pain treatment in sickle cell patients; however, the data on the effectiveness of these methods are limited. Objectives: This work aims to assess the overall ED experience among patients seeking care for acute VOE. We also aim to assess any effective alternative pain management strategies used by patients to treat their acute pain symptoms. Methods: We conducted ED follow up assessments for patients who sought care in the ED for acute pain from vaso-occlusive episodes from January 1, 2022- July 15, 2022. These were brief individual phone interviews. The semi-structured interview guide was created using a hospital specific patient experience questionnaire in addition to questions pertaining to pain management in the acute and day-to-day settings, demographic data including, age, sex, emergency department visit characteristics (length of stay (LOS), emergency severity index assignment (ESI), time to first opioid). The interviews were analyzed using a framework matrix analysis. This qualitative data reduction technique was used to review, summarize, and classify the interview data. NVivo 20 qualitative data analysis software includes a framework matrix tool used to manage data and facilitate this analysis in which participant comments about key content were aggregated and entered for review. Results: Overview: Among the 21 patients who met study criteria, eight participants are included in this analysis. Six participants identified as male, and two participants identified as female. ED Experience: Patients rated their ED care from a 3/10 to a 10/10 (avg 6.4, +/- 2.6). Common themes included prolonged wait times for pain management (6/8 participants). Five of the eight patients interviewed expressed gratitude for the care provided though noted some room for improvement. One participant noted "they could have been nicer to me. It's like they don't talk to each other" (2/8 participants). Patients also expressed frustration when intravenous access issues arise and compounding delays in treatment. Pain management: Three of the eight patients interviewed reported using scheduled opioids (oxycodone-5 patients, and methadone-2 patients) at home every 3-8 hours. One patient declined to answer questions about home opioid use. All patients received hydromorphone for acute management in the ED. Two of the eight patients expressed knowledge of their care coordination pain management plan. Alternative pain management: Five of the eight patients used heat or hot packs as their primary alternative pain management and specifically referenced this as an intervention that they would find helpful in the ED. Two patients prioritized distractions such as video games or other screen time. One patient relied on family support, massages, and meditation. Conclusions: Patients experiencing acute pain from VOE rely on the ED for care. Optimizing that care will not only improve patient's health, but also their well-being. Considering complementary alternatives for acute pain management including heat therapy (packs, blankets) as well as massage (heated chair) or distractions (video games, reading or movies) may provide additional benefits while patients seek care for acute pain crises.

Impact of Hydroxyurea Therapy in Reducing Pain Crises, Hospital Admissions, and Length of Stay Among Sickle Cell Patients in the Eastern Region of Saudi Arabia.

Background In Saudi Arabia, sickle cell disease (SCD) is a major public health issue, especially in the eastern region. Sickle cell patients have major health-related issues, resulting in a poor quality of life and increased morbidity. Abnormal hemoglobin production in SCD causes various complications, such as vaso-occlusive crises, hemolytic episodes, and acute chest syndrome. These disease manifestations increase the need for hospital admission and long-term care. Most therapies for SCD are supportive and include episodic red blood cell transfusions, narcotics, antibiotics, and intravenous fluids. Hydroxyurea is a disease-modifying therapy. This study aimed to assess the effectiveness of hydroxyurea therapy on reducing pain crises, hospital admissions, and length of stay for SCD patients and discern reasons that would prevent SCD patients from using hydroxyurea as a treatment option. Methodology We conducted a descriptive cross-sectional study on SCD patients from the eastern Saudi Arabian province. The study included 202 SCD patients from hematology clinics and medical wards. We used a validated questionnaire tested for reliability after a pilot study of 15 randomly selected patients. We surveyed participants on demographic data, use of hydroxyurea, compliance with the regimen, hospitalization rates, durations, and complications. The study used IBM SPSS Statistics for Windows, Version 22.0. (IBM Corp., Armonk, NY) to analyze the data. All statistical analysis was done using two-tailed tests. P-values < 0.05 were considered statistically significant. Results The study included 202 participants who agreed to participate and completed the study questionnaire. The respondents comprised 150 SCD patients (74.3%) and 52 caregivers of SCD patients (25.7%). Patient ages ranged from one year to older than 36 years (mean age: 26.8 ± 12.3 years). The most common reason for not using hydroxyurea was that it was never offered to patients as a treatment option (40.9% of respondents), followed by respondents who had never heard of it (34.4%), think that they do not need it (24.7%), and fears of long-term consequences (23.7%). More hydroxyurea users (35.1%) suffered no acute painful crises during the last year than nonusers (32%), and more nonusers suffered more than four crises (20%) than hydroxyurea users (9.1%; p=.046). As for hospitalization due to SCD-related complications, 66.2% of hydroxyurea users were never hospitalized, while 51.2% of nonusers were never hospitalized. While 19.5% of hydroxyurea users were hospitalized one to two times, 28.8% of nonusers were hospitalized one to two times (p=.049). Conclusions The study revealed that hydroxyurea is effective in reducing painful vaso-occlusive crises and the number of hospital admissions. The prevalence of hydroxyurea use among SCD patients in the eastern province of Saudi Arabia remains low. Therefore, education campaigns and programs to increase awareness among health care providers regarding the benefits of hydroxyurea use are warranted in our region to help improve patient outcomes.