Episodes In Sickle Cell Disease Research Articles

Early Administration of Intravenous Hydration and Opioid Analgesics Is Correlated with Decreased Admission Rates during Vaso-Occlusive Episodes in Sickle Cell Disease.

Background: Painful vaso-occlusive episodes (VOEs) are the hallmark of sickle cell disease (SCD) and account for frequent visits to the emergency department (ED) or urgent care (UC). Currently, the early administration of analgesics is recommended as initial management; however, there is a need for further understanding of the effect of prompt analgesics and hydration during VOEs. The objective of this study is to analyze the factors associated with the rate of hospital admission in the setting of time to intravenous (IV) analgesics and hydration. Method: This retrospective single-institution study reviewed adult and pediatric patients with SCD who presented with VOEs from January 2018 to August 2023. Results: Of 303 patient encounters, the rates of admission for the overall group, the subgroup which received IV hydration within 60 min of arrival, and the subgroup which received both IV analgesics and hydration within 60 min were 51.8%, 25.6% (RR = 0.46), and 18.2% (RR = 0.33), respectively. Further, factors such as gender and the use of hydroxyurea were found to be significantly associated with the rate of admission. Conclusions: This signifies the importance of standardizing the management of VOEs through the timely administration of IV analgesics and hydration in both adult and pediatric ED/UC.

Inpatient Use of Extended-Release (ER) Opioids for Vaso-Occlusive Crisis Associated with Increased Length of Stay for ER Opioid-Naïve Patients

Background: The intermittent acute pain syndrome associated with sickle cell disease (SCD) is a poorly understood phenomenon with complex pathophysiology. Given the broad spectrum of analgesic interventions, including immediate-release (IR) and extended-release (ER) opioids, healthcare providers are challenged with the task of safely and effectively escalating inpatient opioid regimens, especially in the setting of limited guidelines outlining the combination of different opioid formulations. Despite SCD being the most common genetic disorder in the United States, more research is required to improve physician expertise with appropriate and timely pain management of vaso-occlusive crisis. Methods: This study was a retrospective chart review (n=200) of patients with known SCD requiring hospitalization for acute pain secondary to vaso-occlusive crisis without an alternative etiology of pain symptoms. The review included a patient population aged 18-67 years old with 43.5% males and 56.5% females hospitalized from 2/1/2022 to 5/6/2022. The primary outcome measure was hospital length of stay (LOS) for adequate pain control compared against varying factors of inpatient opioid-prescribing practices, including initiation or continuation (if prescribed within 6 months prior to admission encounter per PDMP review) of an ER opioid formulation, degree of morphine milligram equivalents (MME) escalation from outpatient regimen, utilization of a sickle cell analgesic order set, and initiation of patient-controlled analgesia pump (PCA). A secondary outcome measure investigated was the quantitative comparison of highest daily prescribed MME in relation to the aforementioned inpatient variables. Data analysis was completed using Wilcoxon Rank Summary analysis, with a significant p-value set to < 0.05. Results: Among the primary outcome analysis, the only significant factor affecting LOS was the introduction of an ER opioid. The results show that within the patient cohort naïve to an outpatient ER opioid (n=105), ER opioid-incorporated inpatient analgesic regimens resulted in a significantly increased mean LOS compared to IR opioid monotherapy regimens, with an average of 8.8 inpatient days as compared to 5.3 days, respectively (p-value < 0.001). For the patients prescribed an outpatient ER opioid at baseline (n=95), the continuation of an inpatient ER opioid did not result in a significant change in mean LOS, calculated as 6.7 days vs. 6.0 days in the continued and non-continued groups, respectively (p-value = 0.716). Among the secondary outcome measures, utilization of a sickle cell order set and PCA did not significantly affect degree of MME escalation. Conclusions: Limited evidence-based recommendations for the treatment of acute pain episodes in SCD has resulted in widely varying opioid regimens prescribed by inpatient providers and has created clinical challenges regarding the optimization of pain management. This study investigated inpatient opioid regimens utilized in treatment of vaso-occlusive crisis and found that the initiation of ER opioids resulted in increased length of stay for ER opioid-naïve patients as compared to treatment with IR opioids alone. These results question the benefit of inpatient ER opioids in relation to the risk of opioid dependence and MME escalation.

Trials in Progress: The Randomized, Double-Blind, Placebo-Controlled Phase 1b CROSSWALK-a and Phase 2a CROSSWALK-c Trials - Crovalimab for the Treatment and Prevention of Vaso-Occlusive Episodes in Sickle Cell Disease

Background and Significance In sickle cell disease (SCD), a single point mutation in the beta-globin gene results in hemoglobin S (HbS) production, which can polymerize upon deoxygenation. Polymerization distorts the red blood cell (RBC) membrane and generates sickled RBCs, contributing to microvascular occlusions, which may present as acute, painful vaso-occlusive episodes (VOEs). For patients (pts) with SCD, 70% of emergency department visits and 90% of hospitalizations are VOE-related. 1,2 Despite existing treatments for VOE prevention, considerable morbidity and mortality remain; acute VOE treatment is limited to supportive care due to a lack of targeted therapies. Accumulating nonclinical data suggest a multimodal role for complement dysregulation in SCD pathophysiology, including in vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage. 3 Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody that allows for small-volume subcutaneous (SC) injection after an initial intravenous (IV) loading dose. 4 Here, we describe two randomized, double-blind, placebo-controlled trials evaluating crovalimab in pts with SCD: CROSSWALK-a (Phase 1b; NCT04912869) and CROSSWALK-c (Phase 2a; NCT05075824). Study Design and Methods CROSSWALK-a evaluates the safety of crovalimab in managing acute uncomplicated VOEs. CROSSWALK-c evaluates the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs. Pts 12-55 years old, weighing ≥40 kg with a confirmed diagnosis of sickle cell anemia (homozygous HbSS or heterozygous HbS/β 0 thalassemia) and vaccinated against N. meningitidis, H. influenzae type B and S. pneumoniae are eligible (Fig. 1 and 2). Concurrent SCD-directed therapies are allowed. CROSSWALK-a Pts must present with an acute uncomplicated VOE requiring hospitalization and parenteral opioid analgesics, and have had ≤10 VOEs in the 12 months prior to randomization. Eligible pts will be randomized 2:1 to receive a single IV weight-based tiered dose of crovalimab or placebo, and monitored during hospitalization and in an 84-day observational period followed by a safety follow-up period for a total study duration of 322 days (10.5 months). The primary objective of CROSSWALK-a is to evaluate safety up to Day 84, including: Incidence and severity of adverse eventsIncidence and severity of infusion-related reactions and hypersensitivityChange from baseline in targeted vital signs and clinical laboratory test results Efficacy, pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and exploratory biomarker endpoints will also be evaluated. CROSSWALK-c Pts with 2-10 VOEs in the 12 months prior to randomization are eligible. Eligible pts will be randomized 1:1 to receive weight-based tiered doses of crovalimab or placebo, consisting of initial loading doses (IV: Day 1; SC: Day 2 and weekly for Weeks 2-4) and monthly maintenance SC doses Weeks 5-49 for 48 weeks of treatment. The primary objective of CROSSWALK-c is to evaluate crovalimab efficacy vs placebo up to 48 weeks, on the basis of: The annualized rate of medical facility VOEs Key secondary efficacy objectives are: Annualized rate of home VOEsAnnualized rate of acute chest syndromeAnnualized rate of days hospitalized for medical facility VOEsPt-reported fatigue in adults Safety, PK, PD, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Primary results will be published upon trial readout.

Correlation of a Shape Factor and Degree of Saturation of Sickle Cell Red Blood Cells to Vaso-Occulsive Episodes in Sickle Cell Disease

Introduction: Patients with sickle cell disease (SCD) can experience intermittent episodes of vaso-occlusive episodes (VOE) leading to acute pain. Additionally, patients can experience changes in pain over their lifetime such that they can have nociceptive, neuropathic, and opiate induced hyperalgesia, all contributing to the development of chronic pain. Developing a test that can delineate VOE from steady state and also differentiate it from chronic pain continues to pose an elusive problem in SCD. It not only impacts endpoints in clinical studies, it can pose a significant challenge for the patient in terms of timely clinical diagnosis and treatment of pain. Cell Tracking Velocimetry, (CTV), tracks cells on a single cell basis in a very high magnetic energy gradient. This instrument allows us to use the cell's magnetic, v x, and settling velocities, v y, to be transformed into estimates of the oxygen saturation and deformity of the red blood cells, (RBCs). Based on statistical correlations of these measurements to patient status, VOE can be independently identified. Results: Patients were consented in a single center Institutional Review Board, (IRB) approved study. Clinical data including genotype of the patients were collected in 5 clinical states, including healthy donors (0). Steady State no chronic pain ≤ 3 crisis/year (1), Steady state with chronic pain 3 ≤ crisis/year (2), Steady state with no chronic pain > 3 crisis/year (3), Steady state with chronic pain > 3 crisis/year (4), and during acute pain crisis (5). Steady state was defined as no VOC requiring health care intervention for > 4 weeks and no VOE crisis on day of clinic. The patients' samples (n=49; distributed between each state) and clinical state was deidentified for initial laboratory evaluation. The CTV instruments returns two types of data: magnetic velocity and settling velocity. It was demonstrated that the range of the magnetic velocity of the top and bottom 1 percent of the measured velocities (i.e the fastest and slowest moving RBCs) correlates to a patient in VOE, when compared to normal, healthy RBCs and SCD patients in steady state (p > 0.0168). Further, the ratio of the magnetic to settling velocity of the top and bottom 1 percent of these ratios correlates to a patient in VOE, when compared to normal RBCs and SCD patients in steady state (p > 0.0003). These correlations are significant for both RBCs under deoxygenated and ambient air conditions. Discussion: We suggest that these correlations have physical significance since further mathematical modeling of these experimental velocities can be reduced to two factors: a shape factor, fe-x/fe-y, (velocities are proportional to the effective diameter of the cells) and the oxygen-hemoglobin saturation of the RBCs. This ratio of this shape factor can be considered as a measure of how “deformed” the RBC is, while the degree of oxygen-hemoglobin saturation is consistent with the traditional oxygen saturation measurement. Conclusion: While further studies on a larger patient population are warranted, these data suggests that the CTV instrument could potentially provide a biological point of care test to help diagnose VOE. Furthermore, this seems to delineate chronic pain and steady state from acute VOE. A longitudinal study in a consistent patient population would help further delineate and refine this for the specific patient but may offer significant insight over time to correlate the clinical phenotype with a laboratory correlation.

Pklr Variants Associated with Acute Pain in Sickle Cell Disease Influence ATP Concentrations in Red Blood Cells

Background: We previously demonstrated association of PKLR intron 2 variants with hospitalization rate for acute pain in people with sickle cell disease (SCD) and utilized allele-specific expression analysis to show that these variants influence PKLR activity (Wang et al, 2022). Pyruvate kinase (gene PKLR, protein PKR) is a rate-limiting enzyme in glycolysis. Reduced PKR activity leads to an increase in intracellular 2,3-diphosphoglycerate (2,3-DPG), and a concomitant decrease of adenosine triphosphate (ATP), factors that promote sickle hemoglobin (HbS) polymerization and red blood cell (RBC) sickling. On this basis, we explored how the "high risk" PKLR intron 2 variants affect levels of PKR protein expression, 2,3-DPG, ATP, oxygen dissociation (p50) and sickling kinetics (t50). Methods: We studied a total of 416 subjects which included 125 HbSS, 89 HbAS, and 202 ethnic-matched healthy controls (HbAA) enrolled under protocol NCT03685721 approved by the NHLBI Institutional Review Board. DNA was genome scanned using Ilumina's Infinium "MEGA" chip (1.7m markers). The results were quality controlled followed by genotype imputation based on the 1000 Genomes Project phase 3 data using the Michigan Imputation Server. Whole blood levels of ATP and 2,3-DPG were measured using LC-MS/MS with LLOQ at 50.0 μg/mL and converted to intracellular concentrations by dividing by the hematocrit (as a fraction). PKR was detected by antibody-based capture and detection using an electrochemiluminescence immunoassay (Meso Scale Discovery, Rockville, MD, USA) and the signal normalized to a control sample. A Hemox Analyzer [TCS, Scientific Corp, New Hope, PA] was used to obtain p50 values (defined as the partial pressure of oxygen at which Hb is 50% saturated with oxygen). t50 is single parameter measure of sickling kinetics (Dunkelberger et al, 2018). Single variant analyses (under additive genetic model adjusted for age and sex) were conducted in each of the Hb sub-populations for associations between the 7 PKLR variants (intron 4 - rs2071053, and intron 2 -rs8177970, rs116244351, rs114455416, rs12741350, rs3020781, and rs8177964) and the 5 parameters (PKR, 2,3-DPG, ATP, p50 and t50). False-discovery rate (FDR) adjusted p-values were calculated to account for the multiple testing issue. Results: Table 1A shows levels of the 5 parameters (ATP/HCT, 2,3-DPG/HCT, PKR, p50 and t50) in the 3 Hb genotypic groups (HbAA, HbAS and HbSS). Because patients with SCD have variable anemia, ATP and 2,3-DPG were normalized against HCT. The observed trending higher ATP / HCT and significantly elevated 2,3-DPG /HCT in HbSS compared to HbAS and to HbAA are consistent with previous reports (Poillon et al, 1990). HbSS subjects also had higher PKR protein expression, as well as right-shifted p50 values, compared to HbAS and HbAA (Table 1A), which suggest HbSS RBCs have lower specific activity of PKR. A one-way ANOVA showed that the differences in these mean values were highly significant (Table 1A). All 7 PKLR variants were associated with ATP levels in the HbAS group, of which 4 (rs8177970, rs116244351, rs114455416 and rs8177964) in intron 2 remained statistically significant after multiple testing adjustment (Table 1B). We also identified association between 3 variants (intron 2 - rs12741350, rs3020781, intron 4 - rs071053) and 2,3-DPG levels in the HbSS, as well as t50 in the HbAS group. Conclusion: ATP is essential for maintaining RBC membrane integrity and shape; reduced ATP dehydrates RBCs and promotes sickling. In a previous report, a PKLR intron 2 'high-risk" haplotype was implicated in acute sickle pain by affecting PKLR expression (Wang et al, 2022). In this follow-up study, we show that the same intron 2 "high-risk" haplotype negatively affects ATP levels when accounting for PKR expression, thus providing a biological basis for PKLR as a genetic modifier of SCD pain presentation. 3 of the 7 variants are also associated with elevated 2,3-DPG levels in HbSS as well as t50 (a single parameter that depends primarily on sickling kinetics) in HbAS. The variant associations are observed more clearly in HbAS but not in HbSS, possibly because of the much more homogeneous cell population in HbAS. We conclude that PKLR intron variants may directly contribute to the severity and frequency of acute pain episodes in SCD, thus additional studies with larger sample sizes are warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hydroxyurea Is Associated with Later Onset of Occurrence of Acute Splenic Sequestration Episodes in Sickle Cell Disease: Lessons from the European Sickle Cell Disease Cohort - Hydroxyurea (ESCORT-HU) Study

Hydroxyurea Is Associated with Later Onset of Occurrence of Acute Splenic Sequestration Episodes in Sickle Cell Disease: Lessons from the European Sickle Cell Disease Cohort - Hydroxyurea (ESCORT-HU) Study

Web Exclusive. Annals for Hospitalists Inpatient Notes - Clinical Pearls-Acute Pain Episodes in Sickle Cell Disease.

Web Exclusive. Annals for Hospitalists Inpatient Notes - Clinical Pearls-Acute Pain Episodes in Sickle Cell Disease.

P-Selectin Deficiency Reduces Acute Vascular Complications but Not Chronic Organ Damage in Sickle Cell Mice

P-selectin (Psel) is an adhesion molecule expressed on platelets and endothelial cells, which interacts with its ligand PSGL-1 on leukocytes and a PSGL-1-like molecule on sickle red blood cells (RBCs). Psel mediates the formation of the multicellular aggregates that promote vaso-occlusive crisis (VOC) and acute painful episodes in sickle cell disease (SCD). Crizanlizumab, a monoclonal antibody blocking Psel, reduces the frequency of VOC in SCD patients. In SCD mice, Psel contributes to heme-induced microvascular stasis, and thrombus and platelet-neutrophil aggregate formation in the lung and liver. Unexpectedly, Psel deficiency promotes liver senescence in a mouse model of SCD, suggesting a possible detrimental effect of Psel inhibition. In this study, we further investigated the long-term effects of Psel deficiency on thromboinflammation and end-organ damage in murine SCD.We used Townes wild type (AA) and sickle (SS) mice (n=12-27) that either express Psel (Psel +/+) or lack Psel (Psel -/-) at 11-12 months of age. Kidney damage was evaluated by histology and urine analysis. Heart function was determined using echocardiography. Complete blood counts and plasma biomarkers of thrombin generation (thrombin anti-thrombin [TAT] complexes) and inflammation (interleukin [IL]-6) were also analyzed. In addition, in a pilot experiment, we analyzed the effect of Psel deficiency on experimental venous thrombosis in SS mice.SS Psel +/+ mice exhibited renal damage, urinary concentrating defect, and reduced creatinine clearance, which was not improved in SS Psel -/- mice. Psel deficiency attenuated glomerular (GLM) congestion (0.17±0.05 vs 0.39±0.06, p<0.05) but failed to prevent GLM injury, as evidenced by similar extent of GLM sclerosis, hypertrophy and podocyte loss in SS mice. Interestingly, only SS P-sel -/- mice presented withdistinct differences in GLM structure, demonstrated by extensive hypercellularity, mesangial expansion and mesangiolysis. We also observed tubular injury concomitant with brush border loss and interstitial fibrosis in SS mice, regardless of Psel expression. Additionally, there was a significant reduction in CD3 + T cells (5.0±1.2 vs 9.5±1.6 cells/field; p<0.05) and macrophages (1.0±0.1 vs 1.6±0.2 % of area; p<0.05) infiltration in the kidney cortex of SS Psel -/- compared to SS Psel +/+ mice. This corresponded to a greater renal iron accumulation in SS Psel -/- mice (59.9±4.2 vs 48.2±3.2 Mpix/μm; p<0.05).We observed cardiac hypertrophy (elevated heart weight to tibia length ratio) in SS mice, regardless of Psel expression. Echocardiography of left ventricle (LV) revealed that SS mice had increased LV mass and LV internal diameter with no change in ejection fraction or fractional shortening compared to AA mice. None of these parameters were affected by Psel expression. Furthermore, hypertrophy observed in other organs (kidney, liver, lung and spleen) of SS Psel +/+ mice was also not affected by Psel deficiency.Consistent with previous studies, SS Psel +/+ mice had elevated plasma levels of TAT and IL-6 compared to AA Psel +/+ mice. Psel deficiency significantly reduced IL-6 (47±15 vs 20±10 ng/mL, P<0.05), but had no effect on elevated plasma TAT levels in SS mice. Despite the lack of effect of Psel deficiency on systemic thrombin generation in SS mice, femoral vein thrombi formed after electrolytic injury exhibited a strong trend in reduced fibrin and platelet content compared to SS Psel+/+ mice (n=5 per group).As expected, SS Psel +/+ mice exhibited anemia as shown by reduced RBC number, hemoglobin (Hb) and hematocrit (Hct) compared to AA Psel +/+ animals. Interestingly, these parameters were further decreased in SS Psel -/- mice (p<0.01 for all); RBC (5.6±0.2 vs 4.4±0.4 x 10 6/mL), Hg (6.7±0.2 vs 5.7±0.2 g/dL) and Hct (25.1±1.1 vs 19.7±1.1%). This was accompanied by a significant increase in mean corpuscular Hb concentration (26.9±0.5 vs 29.2±0.5 g/dL p< 0.01) but no changes in RBC mean corpuscular volume in SS Psel -/-mice compared to SS Psel +/+ mice.Our data suggest that despite improving acute vascular pathologies, including VOC and thromboinflammation, long term deficiency of Psel does not prevent end-organ damage. If fact, it may contribute to organ dysfunction and enhanced anemia. More mechanistic studies are needed to better understand the long-term effects of anti-Psel treatment in SCD patients. DisclosuresReeves: Incyte Corporation: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Pharma Essentia: Consultancy, Honoraria. Sundd: CSL Behring Inc: Research Funding; Bayer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Distinct Mechanisms Account for In Vitro Activation and Sensitization of TRPV1 by the Porphyrin Hemin.

TRPV1 mediates pain occurring during sickling episodes in sickle cell disease (SCD). We examined if hemin, a porphyrin released during intravascular hemolysis modulates TRPV1. Calcium imaging and patch clamp were employed to examine effects of hemin on mouse dorsal root ganglion (DRG) neurons and HEK293t cells expressing TRPV1 and TRPA1. Hemin induced a concentration-dependent calcium influx in DRG neurons which was abolished by the unspecific TRP-channel inhibitor ruthenium red. The selective TRPV1-inhibitor BCTC or genetic deletion of TRPV1 only marginally impaired hemin-induced calcium influx in DRG neurons. While hTRPV1 expressed in HEK293 cells mediated a hemin-induced calcium influx which was blocked by BCTC, patch clamp recordings only showed potentiated proton- and heat-evoked currents. This effect was abolished by the PKC-inhibitor chelerythrine chloride and in protein kinase C (PKC)-insensitive TRPV1-mutants. Hemin-induced calcium influx through TRPV1 was only partly PKC-sensitive, but it was abolished by the reducing agent dithiothreitol (DTT). In contrast, hemin-induced potentiation of inward currents was not reduced by DTT. Hemin also induced a redox-dependent calcium influx, but not inward currents on hTRPA1. Our data suggest that hemin induces a PKC-mediated sensitization of TRPV1. However, it also acts as a photosensitizer when exposed to UVA-light used for calcium imaging. The resulting activation of redox-sensitive ion channels such as TRPV1 and TRPA1 may be an in vitro artifact with limited physiological relevance.

Use of an Emergency Department-Based Intranasal Fentanyl Protocol for Vaso-Occlusive Episodes in Sickle Cell Disease: The Unanticipated Consequences

Background: Acute management of pain associated with vaso-occlusive episodes (VOE) in patients with sickle cell disease (SCD) is an on-going challenge in the emergency department (ED) setting. The 2014 National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend rapid evaluation and treatment for moderate-severe VOE, including administration of 1stparenteral opioid within 30 minutes (min) of triage or 60 min from registration, pain reassessment, and repeat opioid delivery within 15-30 min. Despite these recommendations, significant delays in providing optimal pain management is common for patients with SCD. Intranasal fentanyl (INF), a powerful parenteral analgesia with rapid onset is commonly used for pain in the ED, a practice that has recently been extended to treatment of VOE in some institutions. We and others have demonstrated that INF use is effective in helping with sickle-related pain management and achieving better adherence to NHLBI guidelines. However, the utilization of INF may have led to an unanticipated delay in administering intravenous (IV) opioids for this patient population.Objective: To evaluate the utilization of INF in the ED and its effect on the timeliness of 1st IV opioid administration for treatment of VOE in children with SCD.Methods: We conducted a retrospective review of electronic medical records in a single Pediatric ED from January 2017 to June 2017. We evaluated patients with SCD ages ≥ 2 years presenting with moderate-severe VOE (pain scores ≥6 on a severity scale of 0-10) after introduction of a nurse-initiated INF order (1.5 mcg/kg/dose; max 100 mcg/dose X2, 5 min apart) that was added to the standard institutional protocol for VOE treatment. Outcomes included: Time of ED arrival to 1st parenteral opioid, time to first IV opioid, and disposition. We also compared time to 1st IV opioid administration in patients who received INF with historical data of SCD patients treated at this ED with only IV opioids before INF use was standard practice (Jan-Dec 2012, n=231).Results: 250 patients met inclusion criteria. Mean age was 12.5 years, 52% female, and 66% had HbSS, 22% HbSC, 6% HbSB0 and 6% other. Admission rate was 60%. 183 (73%) patients received INF and 204 (82%) received an IV opioid, 141 of whom received both INF and IV opioids, while 42 (17%) patients received INF only. Mean time±standard deviation to first INF dose was 28.5±21 min; mean time to IV opioid delivery was 77±47 min compared to 35±18 min prior to initiation of the INF protocol (historical data, n=231, p<0.0001; Figure 1). In the current cohort, there was no statistically significant difference in time to IV opioid delivery in patients who received IV opioid after INF vs. IV opioid alone. However, only 52 (36%) of patients who received IV opioid after INF received IV opioid within 60 min of ED arrival compared to 36 (57%) who received IV opioids without INF (p<0.01). Of the 42 patients who received INF without any IV opioids, 39 patients (93%) were discharged home, while 5 (13%) of these discharged patients returned to the ED within 72 hours for VOE, similar to the 72 hour return rate in 7/39 (18%) patients discharged from the ED after receiving INF followed by IV opioids.Conclusion: Use of INF in the ED for pediatric patients with SCD and VOE is an excellent strategy to shorten time to administration of 1st dose of parenteral opioid and therefore improve adherence to the NHLBI guidelines recommending rapid administration of parenteral opioids within 60 min of ED arrival. Of interest, INF alone appeared to provide sufficient pain control without IV opioids for disposition home in one out of 6 children with VOE, an observation not previously reported. Whether this reflects adequate pain control or insufficient management requires further investigation. However, our experience also illustrates the potential pitfall of an ED-based INF protocol with respect to delays in delivery of IV opioids after initial administration of INF compared to our historical data prior to the INF protocol implementation. Although the significance of this delay is unknown, quality improvement efforts are underway to address this unanticipated consequence. [Display omitted] DisclosuresMorris:MAST Therapeutics: Research Funding; Calithera Biosciences: Consultancy; Nestle: Consultancy; Lifetrients: Patents & Royalties: I am inventor of IP owned by USCF-Benioff Children's Hospital Oakland, licensed to Lifetrients, generating royalties; Pfizer: Consultancy.

Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease

Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-β0 thalassemia, or S-β+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. ClinicalTrials.gov Identifier: NCT01737814.

Trial design of comparing patient-specific versus weight-based protocols to treat vaso-occlusive episodes in sickle cell disease (COMPARE-VOE)

ObjectivesPainful vaso-occlusive episodes (VOE) are the most common reason for emergency department (ED) visits experienced by patients with sickle cell disease (SCD). The National Heart, Lung and Blood Institute (NHLBI) evidence-based recommendations for VOE treatment are based primarily on expert opinion. In this randomized controlled trial (RCT), we will compare changes in pain scores between patients randomized to a patient-specific analgesic protocol versus those randomized to a weight-based analgesic protocol, as recommended by the NHLBI guidelines. MethodsWe report the rationale and design of a multi-site, phase III, single-blinded, RCT to be conducted in six EDs in the United States. Eligible participants will be randomized after providing consent, anticipating 50% of those randomized would have an ED visit during the enrollment period. A total of 230 participants with one VOE ED visit provides sufficient power to detect a clinically significant difference in pain score reductions of 14 between groups with 0.05 type I error. Uniquely, this trial randomizes participants in a larger population than the study population, given the impossibility of consenting and randomizing participants during emergencies. The primary endpoint is the change in pain scores in the ED from time of placement in treatment area to time of disposition (hospitalization, discharged home, or assigned to observation status) or a maximum treatment duration of 6 hours. Additional outcomes include hospitalizations and ED visits seven days post enrollment, side effects, and safety assessments. ConclusionsThe COMPARE-VOE study design will provide high-level evidence to support the NHLBI VOE treatment guidelines.

Warmed Saline for Vaso-oclusive Episodes in Sickle Cell Disease

Warmed Saline for Vaso-oclusive Episodes in Sickle Cell Disease

Prognostic Value of Hyponatremia During Acute Painful Episodes in Sickle Cell Disease

BackgroundLow plasma sodium concentration has been recognized as a prognostic factor in several disorders but never evaluated in sickle cell disease. The present study evaluates its value at admission to predict a complication in adult patients with sickle cell disease hospitalized for an initially uncomplicated acute painful episode. MethodsThe primary outcome of this retrospective study, performed between 2010 and 2015 in a French referral center for sickle cell disease, was a composite criterion including acute chest syndrome, intensive care unit transfer, red blood cell transfusion or inpatient death. Analyses were adjusted for age, sex, hemoglobin genotype and concentration, lactate dehydrogenase (LDH) concentration, and white blood cell count. ResultsWe included 1218 stays (406 patients). No inpatient death occurred during the study period. Hyponatremia (plasma sodium ≤135 mmol/L) at admission in the center was associated with the primary outcome (adjusted odds ratio [OR] 1.95, 95% confidence interval [CI] 1.3-2.91, P = 0.001), with acute chest syndrome (OR 1.95 [95% CI 1.2-3.17, P = 0.008]), and red blood cell transfusion (OR 2.71 [95% CI 1.58-4.65, P <0.001]) but not significantly with intensive care unit transfer (OR 1.83 [95% CI 0.94-3.79, P = 0.074]). Adjusted mean length of stay was longer by 1.1 days (95% CI 0.5-1.6, P <0.001) in patients with hyponatremia at admission. ConclusionsHyponatremia at admission in the medical department for an acute painful episode is a strong and independent prognostic factor of unfavorable outcome and, notably, acute chest syndrome. It could help targeting patients who may benefit from closer monitoring.

Managing Sickle Cell Disease Patients with Acute Pain Crisis in the Most Appropriate Setting

Introduction: Pain is the top concern of individuals with sickle cell disease (SCD). Acute painful vaso-occlusive episodes in SCD are the leading cause of emergency department (ED) encounters and frequent hospital admissions. Well-documented disparities include significant delay and under treatment of SCD patients with acute pain crisis in the ED. An acute care observation unit (ACOU) staffed with SCD specialists can help to address these disparities. SCD patients treated in a dedicated ACOU have a 40% lower admission rate than patients treated in the ED. An expedited transfer and treatment program at our dedicated sickle ACOU at the University of Illinois Hospital (UIH) was implemented with the goal of improving overall care and decreasing the hospital admission rate for SCD patients. Method: This is an outcome study of individuals with SCD &gt;16 years of age who presented with an acute painful episode to UIH. A quality improvement project used the Plan-Do-Study-Act translation method. The following key areas were identified for intervention: 1) established criteria for direct ACOU admission, 2) expedited transfer to the ACOU from the ED, 3) addition of a third provider to expand hours, and 4) establishing a consistent but individualized pain treatment plan across the ED and ACOU. The number of admissions to hospital of patients with SCD was examined from September 2018 through August 2019. Applying the Donabedian triad of Structure, Process, and Outcomes, we demonstrated improved outcome and decrease hospitalization. Results: There were 877 admissions to the ACOU from January to July of 2019, which is an increase of 37% compared to the same period in 2018. Of the 877 admissions, 793 were discharged home (90.4%) as compared to 88.6 % in 2018. The average time to first dose of opioids in the ACOU in 2019 was 55 minutes with and average decrease in the pain score of 2.62 during an average length of stay of 4:18 hours. Conclusions: Expedited care and treatment with a focus on improving quality and improving access resulted in increased volume of patients treated and decreased rate of admission to the hospital. Allocating resources to a dedicated sickle acute care observation unit can significantly decrease inpatient hospitalizations. Table. Disclosures No relevant conflicts of interest to declare.

Evaluation of a Non-Parenteral Opioid Analgesia Protocol for Acute Sickle Cell Pain Episodes in Children.

We evaluated a protocol comprising intranasal diamorphine (IND) combined with oral short and modified-release morphine for children at the emergency department (ED) with acute painful episodes of sickle cell disease (SCD). In a retrospective audit of 83 episodes in 38 children, the mean time between arrival in the treatment area and the administration of IND was 10 min (range <5 min to 1.39 h). IND was administered in <5 min in 43 (51.6%), and in <20 min in 75 (90.4%) episodes. Persisting pain, requiring background analgesia with modified-release oral morphine, was required in 25 (30.1%) episodes. Inadequate control of pain requiring a switch to intravenous morphine PCA was required in eight episodes in four patients. Acute chest syndrome (ACS) developed in four of 83 episodes (4.8%, 95% CI 0.2–9.4%) and in four of 38 children (10.5%, 95% CI 0.7–20.5%). In conclusion, this protocol enabled the rapid administration of strong opioid analgesia in an ED setting, and may reduce the short and long-term adverse effects associated with parenteral opioids in children. There was no evidence of an increased incidence of ACS associated with use of oral morphine.

Valsartan impedes epinephrine-induced ICAM-4 activation on normal, sickle cell trait and sickle cell disease red blood cells.

Abnormal red blood cell (RBC) adhesion to endothelial αvβ3 plays a crucial role in triggering vaso-occlusive episodes in sickle cell disease (SCD). It is known that epinephrine, a β-adrenergic receptor (β-AR) stimulator, increases the RBC surface density of active intercellular adhesion molecule-4 (ICAM-4) which binds to the endothelial αvβ3. It has also been demonstrated that in human embryonic kidney 293 cells, mouse cardiomyocytes, and COS-7 cell lines, the β-adrenergic and renin-angiotensin systems are interrelated and that there is a direct interaction and cross-regulation between β-AR and angiotensin II type 1 receptor (AT1R). Selective blockade of AT1R reciprocally inhibits the downstream signaling of β-ARs, similar to the inhibition observed in the presence of a β-AR-blocker. However, it is not known if this mechanism is active in human RBCs. Here, we studied the effect of valsartan, an AT1R blocker, on the surface density of active ICAM-4 receptors in normal, sickle cell trait, and homozygous sickle RBCs. We applied single molecule force spectroscopy to detect active ICAM-4 receptors on the RBC plasma membrane with and without the presence of valsartan and epinephrine. We found that epinephrine significantly increased whereas valsartan decreased their surface density. Importantly, we found that pretreatment of RBCs with valsartan significantly impeded the activation of ICAM-4 receptors induced by epinephrine. The observed reduced expression of active ICAM-4 receptors on the RBC plasma membrane leads us to conjecture that valsartan may be used as a supporting remedy for the prevention and treatment of vaso-occlusive crisis in SCD.

Comparing Individualized vs. Weight Based Protocols to Treat VOE in SCD Occlusive Episodes in Sickle Cell Disease

Comparing Individualized vs. Weight Based Protocols to Treat VOE in SCD Occlusive Episodes in Sickle Cell Disease

Case report: a rare case of concomitant haemophilia a and sickle cell disease

Co-existing haemophilia A and sickle cell disease is rarely reported in the medical literature.1 Haemophilia A, an X-linked recessive bleeding disorder due to reduced factor VIII levels, has a reported incidence of 1:10,000 males globally.1 Sickle cell disease (SCD), an autosomal recessive disorder with abnormal haemoglobin production (HbS), affects 20–25 million people globally.1 This case presentation describes a rare presentation of haemophilia A and SCD in a 4-year-old male recently immigrated from Uganda, who presented with a four day history of a painful right knee and background of easy bruising and bleeding. Clinical examination was consistent with haemarthrosis. Initial screening bloods demonstrated Hb 85 g/L, MCV 88 fL, WCC 19×109/L and Plt 518×109/L. Peripheral blood film examination demonstrated numerous sickle cells and target cells. Haemoglobin variant studies performed by HPLC demonstrated an elevated HbA2 (4.5%), elevated HbF (14.2%) and HbS (80%) consistent with SCD. Given clinical history and haemarthrosis, coagulation screening was performed which demonstrated an INR 1.2 and APTT 89 s. Factor VIII levels were greatly reduced at 1% (reference range 50–165%), consistent with haemophilia A. This case highlights the need for clinical correlation when interpreting laboratory findings as not all pain episodes in SCD are consistent with vaso-occlusive crisis.

Acute Vaso-Occlusive Pain is Temporally Associated with the Onset of Menstruation in Women with Sickle Cell Disease.

Acute vaso-occlusive pain episodes in sickle cell disease (SCD) are associated with increased rates of hospitalization and early mortality. Despite the observation that women have higher rates of acute vaso-occlusive pain episodes than men, sex-specific risk factors for acute vaso-occlusive pain have not been identified. We tested the hypothesis that acute vaso-occlusive pain is temporally associated with the onset of menstruation in women with SCD. Initially, using a cross-sectional study design, we administered questionnaires, including validated measures of SCD pain frequency and severity within the last 30 days, as well as menstrual symptoms in a discovery group (n = 103). We then confirmed our findings by administering the same questionnaires online in a replication group (n = 118). A validated questionnaire was used to define dysmenorrhea. In the initial discovery group, 28% (29 of 103) reported acute vaso-occlusive pain episodes temporally associated with menstruation, and 72% (74 of 103) did not. Of the 29 reporting acute vaso-occlusive pain associated with menstruation, 90% (26) and 10% (3) did and did not meet criteria for dysmenorrhea, respectively. In the replication group, 36% (43 of 118) reported acute vaso-occlusive pain temporally associated with menstruation. Of the 43 reporting acute vaso-occlusive pain associated with menstruation, 60% (26) and 40% (17) did and did not meet criteria for dysmenorrhea, respectively. In both the discovery and replication groups, we demonstrate that acute vaso-occlusive pain is temporally associated with the onset of menstruation that women with SCD can distinguish from dysmenorrhea.