Treatment Of Vaso-occlusive Crisis Research Articles

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.

Outpatient Management of Sickle Cell Vaso-Occlusive Crisis As a Strategy of Decreasing Emergency Department Visits

Background: Complications of sickle cell disease (SCD), including vaso-occlusive crises (VOC), usually require emergency room visits or even hospitalization for management. Outpatient treatment programs have been developed for management of VOC, however the literature is limited as to the efficacy of these models. Previously, patients in Edmonton, Canada followed by the Hemoglobinopathy Clinic would have to present to the emergency department (ED) for assessment of and management of VOC. Since 2019, patients experiencing early VOC symptoms were able to present to the Medical Outpatient Unit (MOU), an infusion clinic shared with other benign and malignant hematology conditions, to be assessed and receive treatment. This study retrospectively evaluated the outcomes of this treatment strategy. Hypothesis: Outpatient management of VOC is an effective way to assess patients and provide appropriate treatment, thereby reducing the frequency of ED presentations for SCD patients. Methods: Patients were able to schedule their own appointments and were encouraged to present early before they developed severe symptoms. They would be assessed by a nurse, who could then release orders from their personalized pain plan, which is a standing set of orders from an SCD clinic physician. Examples of orders include intravenous fluids and pain medications. Based on the severity of symptoms, patients could also be referred to the ED or for assessment by a physician or nurse practitioner. Chart review of patients aged 18 years or older with SCD followed by the Edmonton Hemoglobinopathy Clinic and who presented to MOU from November 2019 to December 2022 for management of VOC was completed. Information gathered included if the patient was on hydroxyurea at the time, investigations ordered, treatments administered, if NP or physician assessment was required, and disposition following the encounter. Encounters within 7 days were counted as one episode and assumed to be the same VOC event. Visits to ED for this cohort were counted and compared to the number of ED visits from 2016 to 2018. Results: 26 SCD patients had at least one MOU encounter for VOC or prophylaxis resulting in a total of 136 encounters (median 2, maximum 25). These accounted for 96 separate episodes of VOC (median 2, maximum 19), with a median of 1 encounter to MOU per episode (maximum 5). Patient demographics had a mean age of 32 years as of the beginning of the study (maximum 65, minimum 16) with 14 males (54%) and 12 females (46%). Patient diagnoses included 10 with HbSS (38%), 12 with HbSC (46%), 3 with HbSD (12%), and 1 with HbSB° (4%). 21 of 26 patients (81%) were on hydroxyurea at some point during this time period. IV fluids were administered in 129 encounters (95%), and pain medications were given in 64 encounters (47%), with opioid medications being given in 24 encounters (18%). 109 encounters had assessment by a nurse only (80%), while 24 were also assessed by a nurse practitioner (18%) and only 3 required assessment by a physician (2%). Patients were discharged home in 134 of 136 encounters (99%), with only 2 encounters resulting in assessment in ED. 70 of 96 episodes of VOC treated in MOU did not have presentation to ED within 30 days (73%). Total ED visits for this cohort decreased from 59 in 2016-2018 to 38 during the time of this study. Conclusion: Treatment of VOC in an outpatient setting was effective for assessment and treatment and decreased ED visits in our cohort. While retrospective, these results suggest outpatient treatment of VOC can be completed safely and efficiently in a shared infusion unit and may be generalized to other centres with outpatient IV infusion programs.

1307. Vaso-occlusive Crisis is Associated with Subsequent Osteomyelitis in Pediatric Sickle Cell Disease

Abstract Background Children with sickle cell disease (SCD) commonly develop microvascular infarcts of bone known as vaso-occlusive crisis (VOC) and are also at high risk of osteomyelitis (OM). VOC and OM can be challenging to distinguish due to overlapping clinical features. VOC might predispose to OM, or an initial misdiagnosis of OM as VOC might lead to delayed diagnosis of OM. This study aimed to test whether VOC was associated with subsequent development of OM in children with SCD. Methods A retrospective Pediatric Health Information System (PHIS) database study (2010-2021) was performed. ICD-code data related to common diagnoses in pediatric patients with SCD were extracted. The rate of VOC within 30 and 180 days preceding episodes of OM was compared to the rate preceding acute chest syndrome (ACS), another common diagnosis in children with SCD but unlikely to be anatomically related to OM. Odds ratios (OR) were used to evaluate the association between these diagnoses. Results Of 22,818 PHIS participants with SCD, 13,699; 450; and 7,327 had ≥ 1 episode of VOC, OM and ACS, respectively. The distribution of OM diagnoses was similar across pre-specified age groups (0-4, 5-12, and 13-18 years). The odds ratio of VOC preceding a diagnosis of OM vs. ACS was 2.15 within 30 days (95% CI: 1.82-2.54; p= 3.68 x 10-18), and within 180 days was 1.39 (95% CI: 1.20-1.62; p=2.04 x 10-5). VOC Preceding Osteomyelitis vs. Acute Chest Syndrome Conclusion VOC was significantly more common in the days preceding a diagnosis of OM than of ACS. The strength of association was stronger within 30 days prior to OM than 180 days. These results suggest possible misdiagnosis of OM since VOC might delay OM diagnosis in some cases, that recurrent VOC might be misdiagnosed as OM, or that VOC can directly contribute to risk of OM in some cases. Limitations of this study include possible incomplete adjustment for unmeasured variables which could confound the analysis. More research is needed to confirm and evaluate the mechanism behind this association. Understanding the relationship could lead to improved screening and treatment of both VOC and OM. Disclosures Joshua Wolf, MBBS, PhD, Karius Inc.: Grant/Research Support|Merck Inc.: Participation in industry-sponsored research Sandra Arnold, MD, Contrafect: Grant/Research Support|Enanta: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support

A multimodal pain protocol for treatment of vaso-occlusive crisis in patients with sickle cell disease: Implementation and evaluation.

Pain management during a vaso-occlusive crisis (VOC) for patients with sickle cell disease (SCD) remains a major challenge and strongly depends on opioids. We developed a multimodality pain protocol for rapid, opioid-sparing pain treatment of VOC and evaluated its feasibility. Patients were included for evaluation if they were ≥18 years, diagnosed with SCD and visited the emergency department (ED) because of VOC between July 2018 and December 2020. Primary evaluation outcome was the feasibility of multimodal pain analgesia (i.e., the use of at least two analgesics with different underlying mechanisms of action). A total of 131 SCD patients visited the ED because of VOC with a total of 550 ED presentations, of which 377 were eventually hospitalised. A total of 508 (92.4%) ED presentations and 374 (99.2%) hospital admissions received multimodal pain treatment. Time to first administration of an opioid was median [IQR] 34.0 [21.0-62.0] minutes. The implementation of a pain protocol using multimodal analgesia for VOC in patients with SCD appeared to be feasible and facilitated rapid administration of opioids. Controlled trials are needed to investigate the effectiveness of multimodal analgesia on pain and should focus on patient reported outcome measures.

Predicting Pain in People With Sickle Cell Disease in the Day Hospital Using the Commercial Wearable Apple Watch: Feasibility Study.

Sickle cell disease (SCD) is a genetic red blood cell disorder associated with severe complications including chronic anemia, stroke, and vaso-occlusive crises (VOCs). VOCs are unpredictable, difficult to treat, and the leading cause of hospitalization. Recent efforts have focused on the use of mobile health technology to develop algorithms to predict pain in people with sickle cell disease. Combining the data collection abilities of a consumer wearable, such as the Apple Watch, and machine learning techniques may help us better understand the pain experience and find trends to predict pain from VOCs. The aim of this study is to (1) determine the feasibility of using the Apple Watch to predict the pain scores in people with sickle cell disease admitted to the Duke University SCD Day Hospital, referred to as the Day Hospital, and (2) build and evaluate machine learning algorithms to predict the pain scores of VOCs with the Apple Watch. Following approval of the institutional review board, patients with sickle cell disease, older than 18 years, and admitted to Day Hospital for a VOC between July 2021 and September 2021 were approached to participate in the study. Participants were provided with an Apple Watch Series 3, which is to be worn for the duration of their visit. Data collected from the Apple Watch included heart rate, heart rate variability (calculated), and calories. Pain scores and vital signs were collected from the electronic medical record. Data were analyzed using 3 different machine learning models: multinomial logistic regression, gradient boosting, and random forest, and 2 null models, to assess the accuracy of pain scores. The evaluation metrics considered were accuracy (F1-score), area under the receiving operating characteristic curve, and root-mean-square error (RMSE). We enrolled 20 patients with sickle cell disease, all of whom identified as Black or African American and consisted of 12 (60%) females and 8 (40%) males. There were 14 individuals diagnosed with hemoglobin type SS (70%). The median age of the population was 35.5 (IQR 30-41) years. The median time each individual spent wearing the Apple Watch was 2 hours and 17 minutes and a total of 15,683 data points were collected across the population. All models outperformed the null models, and the best-performing model was the random forest model, which was able to predict the pain scores with an accuracy of 84.5%, and a RMSE of 0.84. The strong performance of the model in all metrics validates feasibility and the ability to use data collected from a noninvasive device, the Apple Watch, to predict the pain scores during VOCs. It is a novel and feasible approach and presents a low-cost method that could benefit clinicians and individuals with sickle cell disease in the treatment of VOCs.

Crovalimab. Anti-C5 monoclonal antibody, Treatment of paroxysmal nocturnal hemoglobinuria, Treatment of atypical hemolytic uremic syndrome, Treatment of vaso-occlusive crisis in sickle cell disease

Crovalimab. Anti-C5 monoclonal antibody, Treatment of paroxysmal nocturnal hemoglobinuria, Treatment of atypical hemolytic uremic syndrome, Treatment of vaso-occlusive crisis in sickle cell disease

Knowledge, Attitude, and Practice Among Physicians Regarding Pain Management in Patients with SCD

Introduction Pain from vaso-occlusive crises (VOC) is the most common symptom experienced by patients with sickle cell disease (SCD). It is also the most common cause for emergency department (ED) visits and hospital admissions. Nevertheless, clinical studies of appropriateness of treatment provided during these episodes are sparse, and there are concerns that care for these patients is both inadequate and doesn't meet guidelines. Therefore, studies assessing the healthcare practitioners' knowledge and practice in pain management in SCD patients are an integral component in the process of improving the care provided to this vulnerable population. The goal of our study is to assess adherence of physicians caring for SCD patients to the published guidelines in pain management (published by National Heart, Lung, and Blood Institute, and American Pain Society), and to identify risk factors for self-reported non-adherence. Thus this study should provide an opportunity for focused strategies to improve patients' care. Moreover, this study is particularly important for The State of Qatar, as the burden of SCD in it is among the highest in the entire world. Materials and Methods This is a cross-sectional convenience sample survey study of physicians in Internal Medicine, Hematology and Emergency departments in two hospitals under Hamad Medical Corporation, the main health care provider in The State of Qatar. It is conducted using a validated written survey consisting of 34 items to assess provider attitudes and practices with SCD patients. Excel program and SPSS version 29 were used for data analysis. Continuous data was analyzed descriptively using median (IQR). Mann Whitney test and Kruskal-Wallis test were used to compare average between groups at alpha level = 0.05). Results: We have 130 eligible participants with an 85% complete response rate (111 completed surveys). Most physicians self-report adherence to using parenteral opioids (81%) and acetaminophen (77.5%). Self-reported adherence is lower for other recommendations including redosing opioids within 30 minutes if analgesia is inadequate (21%), use of patient-controlled analgesia (18%), sparing non-steroidal anti-inflammatory drugs (66%) and using hypotonic fluids for euvolemic patients (5%). Factors that are associated with significant differences in analgesic practices in our study include age and race. For example, male physicians are more likely to use acetaminophen, and physicians who identified as "Others" under the category of race versus Whites, Blacks and Asians are more likely to administer morphine (P value = 0.015) during VOC. Other factors such as age, level of practice, and department are not associated with significant differences in analgesic practices. Furthermore, analgesic practices are affected by physicians' attitudes. Interestingly, high scores on both the positive and negative attitudes scales (thought to reflect opposing perceptions of individuals with SCD) are both associated with more frequent use of acetaminophen. Unexpectedly, and as shown in the table below, high scores on negative attitudes scale are associated with more frequent use of morphine, while high scores on positive attitudes scale are associated with less frequent use of it. Discussion and conclusion A large number of SCD patients will have at least one VOC annually. There's an association between the number and severity of these crises and mortality rate. Also, these crises affect patients' quality of life, economic contribution, and overall satisfaction. The cornerstones of managing VOC are parenteral opioids and frequent reassessments. Our data show that the majority of surveyed physicians report that they adhere to guidelines about the use of opioids and acetaminophen for the treatment of VOC, while other recommendations have less penetration. Positive and negative attitudes toward SCD patients are not associated with lower adherence to guidelines. Our data indicate that penetration of many of these recommendations into practice is poor. A policy statement from respective professional societies may help expert recommendations to penetrate the providers' practice. Furthermore, interventions to improve attitudes towards SCD patients should be undertaken, since these attitudes can exert some effects on patients' care. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intravenous Fluid Administration and the Risk of Adverse Outcomes in Sickle Cell Disease Patients Hospitalized for Vaso-Occlusive Crisis.

Vaso-occlusive crisis (VOC) is the leading cause of hospitalization in sickle cell disease (SCD). Intravenous fluid (IVF) administration is the usual practice during VOC episodes to slow the sickling process. In the absence of an evidence-based, clear-cut consensus on the optimal choice, route, and rate of fluid administration, there has been a wide variability in the practice of IVF administration in the treatment of VOC. However, there are growing concerns about the safety of this practice. This systematic review summarized the current evidence on the risk of negative outcomes in SCD patients treated for VOC with IVFs. A database search of Medline/PubMed, EMBASE, Scopus, Web of Science, CINAHL, Wiley Cochrane Library, Clinicaltrials.gov, and conference proceedings of the European Hematology Association (EHA) and American Society of Hematology (ASH) were performed. The results were presented using narrative analysis of quantitative data. Of the 2,821 identified records, a total of three eligible retrospective cohort studies with a total demographic population of 549 SCD patients were included in this review. Normal saline, a frequently used IVF for VOC may be associated with adverse outcomes such as poor pain control and volume overload. Volume overload, new oxygen requirement, acute chest syndrome, and acute kidney injury are potential adverse outcomes of inappropriate IVF use in VOC. There is limited evidence supporting the current practice of IVF use in VOC. Randomized controlled trials are required to fully clarify the place and safety of IVF in the management of VOC.

Opioid Use in Vaso-Occlusive Crisis During Intravenous Opioid Drug Shortage.

Introduction: In October 2017, the Food and Drug Administration announced a shortage of intravenous (IV) opioid medications. Patients with sickle cell disease (SCD) are particularly vulnerable, as high amounts of IV opioid medications are standard therapy during vaso-occlusive crises (VOC). Our institution responded to the crises by implementing IV to oral (PO) conversions of opioid therapies and encouraging multimodal pain management with non-opioid medications. Objectives: The primary objective was the assessment of IV opioid medication utilization before and during the shortage. Secondary objectives included total opioid consumption, length of stay, and prescribing of non-opioid analgesics. Methods: This single-institution retrospective study included patients >18 years of age admitted to adult medicine teams with VOC during February 2017 or February 2018. The amount of opioid medication administered to patients during both periods was assessed, and quantities were then converted to PO morphine milligram equivalents and compared between years. The number of patients receiving scheduled non-opioid medications were also compared. Length of stay and readmissions were compared between years. Results: Between 2017 and 2018, IV opioid use for VOC decreased by 52% on inpatient services, and there was a 34% reduction in overall opioid use. Oral opioid use more than doubled during the period (10.2% in 2017 vs 39.1% in 2018, P < .01). LOS between 2017 and 2018 (6 vs 6 days, P = .4774) and total number of ED visits (27 vs 8, P = .276) were similar. There were significantly fewer 30-day readmissions in 2018 versus 2017 (15 vs 28, P = .025). Conclusion: The implementation of IV opioid restrictions resulted in a decrease in IV opioid use in treatment of VOC in patients with SCD without causing increases in length of stay or readmissions. Oral opioids should be considered an option for VOC management in patients with SCD.

Examining Experiences of Acute and Chronic Pain Among Individuals with Sickle Cell Disease (SCD) in Jamaica and Cameroon

Introduction: Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy that causes red blood cell sickling and blockage of blood vessels that result in painful debilitating vaso-occlusive crises (VOC). Yet, individuals with SCD face negative stereotyping and stigmatization when accessing healthcare that contribute not only to feelings of shame, anger and distrust towards providers, but also to serious complications and poor outcomes. Comparison of individuals' experiences, assessment and management of VOC across different cultural landscapes may identify intervenable targets that could improve overall care and outcomes of SCD.Methods: This is a transnational qualitative research study that examined the perceptions, treatments and socio-economic impacts of pain in participants living with SCD in Jamaica (n= 31) and Cameroon (n=50). Participants completed semi-structured interviews that were collectively examined for themes and differences in experiences with acute and chronic pain. Analysis was completed using NVivo 12.Results: Both Jamaican and Cameroonian participants reported diverse psychosocial, physical and health causes of their VOC including, strenuous physical activity, intense emotionality, unhealthy lifestyle behaviors, other health conditions and extreme weather conditions. Similarly, both had challenges communicating the severity and type of VOC pain to providers when accessing healthcare for themselves and their children. Furthermore, both reported providers' reliance on non-validated forms of pain assessment (Cameroon > Jamaica) such as behavioral cues rather than standardized numerical or visual scales that participants believed were easy-to-use and capable of improving the assessment and treatment of VOC. Jamaican participants also experienced more positive, less-discriminatory practices treating their VOC in specialized vs. unspecialized SCD public and private clinical settings. At least half of all participants reported satisfaction with overall provider treatment of VOC. Both Jamaican and Cameroonian participants primarily used non-opioid pain analgesics, daily folic acid and distraction rather than hydroxyurea to manage their acute and chronic VOC pain and thereby, presented late for treatment of unbearable pain. Participants also reported using both traditional medicine and lifestyle changes to maintain a positive mindset and decrease the occurrences of VOC. Lifestyle changes included eating a healthy diet, engaging in relaxation activities and mindfulness techniques (massages, breathing exercises, listening to music and resting). All participants were interested in learning about alternative methods of managing their VOC pain.Conclusion: The use of validated numerical and visual pain scales as well as the implementation of specialized SCD facilities in the public and private clinic settings may help eliminate communication barriers and discriminatory practices to improve overall satisfaction and treatment of VOC in SCD. DisclosuresAsnani: Aruvant Sciences: Research Funding; Avicanna Ltd.: Research Funding.

Numb Chin Syndrome in Sickle Cell Disease: A Systematic Review

Introduction: Numb Chin Syndrome (NCS) is a rare sensory neuropathy characterized by inferior alveolar or mental nerve damage. It manifests as hypoesthesia, paraesthesia, or pain in the chin and lower lip. Few case reports have been published on NCS secondary to sickle cell disease (SCD). As a result, information about causes, disease course and treatment are lacking. Our objective was to synthesize all currently available relevant literature on this rare condition.Methods: A systematic review was performed following the PRISMA guidelines. The following databases were searched: Medline, EMBASE and CINAHL Complete. The search strategy was designed by a librarian and utilized text words and relevant indexing terms to identify studies about NCS in patients with SCD. Conference abstracts of relevant scientific meetings were manually searched. No language limits were applied. Reviews, notes, editorials or comments were excluded. Patient demographics (including age, sex, country, SCD genotype), clinical presentation, investigations, treatment and outcomes were extracted by two independent reviewers.Results: The systematic search revealed 73 publications (Figure). Only 11 publications from the databases and 3 from a manual search met the inclusion/exclusion criteria. Together, these case reports and series described 33 unique SCD patients. They originated from different regions (India, Turkey, Jamaica, USA, France, England). They were published between 1972 and 2021. Reports described between 1 and 13 patients each. Mean age was 28.3 years (standard deviation 11.7) and ranged from 11 to 60 years (Table). Sixteen were female. Genotype distribution was as follows: SS in 13 (39%), SC in 5 (15%), Sbeta-thalassemia in 3 (9%), not reported in 12 (36%). All but one case (97%) were associated with a vaso-occlusive crisis (VOC) and/or acute chest syndrome (ACS). One patient also developed multiorgan failure. One case occurred post dental surgery which led to a VOC. One case was associated with mandibular osteomyelitis and four others with infections. One patient presented with avascular osteonecrosis of the mandible. Comorbid medical conditions were reported as follows: rheumatoid arthritis treated with prednisone (1), pregnancy (1), type II diabetes (1) metastatic breast cancer treated by chemotherapy (1), membranoproliferative glomerulonephritis (1), asthma (1), retinal detachment (1) and splenectomy (1).X-Rays were the most utilized imaging modality (10 [30%]), followed by CT-scan (7 [21%]), magnetic resonance imaging (MRI) (6 [18%]) and bone scan (2 [6%]). Two X-Rays revealed subtle radiolucencies suggestive of bone infarction, 1 X-Ray changes consistent with avascular necrosis and 1 X-Ray lytic lesions typical of osteomyelitis. One patient had a normal X-ray, but a CT-scan showed loss of cortical condensation around the mental canal which corresponded on a bone scan to a region of slightly increased tracer uptake suggestive of infarction. The MRI for one patient with bilateral NCS showed increased T2 signal in both mandibular rami with associated small subperiosteal fluid collections. One patient had a lumbar puncture that was normal.Management of the neuropathy was mostly directed towards the underlying cause: treatment of VOC and SCD acute complications, antibiotics for infection, and tooth extraction for infectious control. Two patients received transfusions during their acute medical condition. The duration of symptoms ranged from a few hours to 14 years. Eleven patients (33%) were reported to have a complete resolution of NCS.Conclusion: We provide a systematic review of the clinical manifestations, investigations and management of NCS in patients with SCD. NCS occurred most often in the context of VOC/ACS. Radiological evidence of mandibular infarction was reported for some. Together, this suggests that vaso-occlusion and bone infarction could be pathophysiological mechanisms of NCS. Careful evaluation is warranted to rule out differential causes including local infection, avascular necrosis, primary neoplasm or metastatic disease. Publication bias, a small sample size, and author-dependant lexical variability used to describe NCS are some limitations to our review. Through this largest report of NCS in SCD, we draw attention to a rare and potentially underrecognized neurological complication that deserves further investigation to optimize management. [Display omitted] DisclosuresSoulieres: Novartis: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Forte: Novartis: Honoraria; Canadian Hematology Society: Research Funding; Pfizer: Research Funding.

The Effect of Individualized Pain Plans for Patients with Sickle Cell Disease on Emergency Provider Satisfaction: A Win for the Patient Can be a Win for the Provider

BackgroundSickle cell disease (SCD) is an inherited hematologic disorder that affects approximately 100,000 Americans and results in over 200,000 emergency departments visits annually, largely due to pain (Lanzkron et al). Delay in treatment in emergency room has been a significant barrier to patients with SCD, particularly adults. The objective of this study is to determine the effects of utilizing individualized pain plans for the treatment of vaso-occlusive crisis (VOC) on the satisfaction of healthcare providers in the emergency department (ED).MethodsThe Ohio State University has a comprehensive sickle cell center which creates individualized pain plans for patients who present to the ED with pain related to VOC. In January 2015, these pain plans were implemented into the electronic medical record listed in the overview of the problem sickle cell disease in each chart. In addition to creating pain plans, an interdisciplinary team was formed consisting of hematologists, pharmacists, and ED providers with the goal of education regarding SCD and the new implementation of pain plans. Surveys, using the secure web application, RedCAP, were distributed to the emergency department providers at the OSU ED. Questions included responders' role in the ED, prior experience with treating pain crisis, time to make treatment management decisions for VOC, satisfaction with treatment decision, and the providers view of their relationship with patients. Wilcoxon signed-rank test and Fisher's exact test were applied to evaluate the differences between pre and post survey numeric and categorical responses.ResultsSurveys were sent electronically to 170 ED providers. Sixty-nine responses, making up 40.5% of those surveyed, were obtained from 30 attending physicians, 2 fellows, 22 nurse practitioners or physician assistants, 1 registered nurse, and 14 residents. Of those who answered the survey, 14 had experience with treating pain crisis prior to the implementation of individualized pain plans. Implementation of individualized pain plans led to a reduction in median time to make treatment decisions from 5.5 to 2.5 minutes with a p-value of 0.0161. Provider satisfaction with treatment decisions improved as well (p = 0.0029) (Figure 2). In addition, ED providers felt more satisfied with their relationship with patients (p = 0.0078) (Figure 3). The majority of responders (91.2%) also rated their satisfaction with the treatment decision as either satisfied or very satisfied (Figure 1). Seventy eight percent of those answering the survey rated with relationship with patients as being good or very good (Figure 1). In terms of the ease of finding the pain plan in the electronic medical record, 91.3% of providers found them to be either very easy or easy to locate with 94.12% responding that implementing the plan was either easy or very easy (Figure 4). Regarding efficacy of the pain plans, 89.85% found the pain plans to be either effective or very effective (Figure 5). Finally, of the 36 providers who worked elsewhere, about half of the institutions from which they came did not have pain plans.DiscussionThe results of this study show the importance of utilizing individualized pain plans in the treatment of VOC in the ED. As shown in our prior studies, the implementation of individualized pain plans for patients with SCD resulted in a 48% decrease in time to first opioid in the ED, thereby signifying more prompt treatment (Della-Moretta et al). Not only does the data support an improvement in time to make treatment decisions, which benefit the patients, but providers also appear to view their use as an advantage. Pain plan utilization also leads to an increase in provider confidence in their treatment plans as well as a perceived improvement in patient-provider relationships. This is particularly significant as historically the relationship between emergency room staff and sickle cell patients has been seen as challenging by both patients as well emergency room providers (Haywood et al). Making patient centered individualized pain plans readily available, easily accessible, and simple to enact, can further enhance the relationship between the patient, emergency room, and the hematology team. Ongoing communication and education between all parties is beneficial. With the combination of patient and provider data, we show that a win for the patient can also be a win for the provider. [Display omitted] DisclosuresDesai: Pfizer: Other: Publication Fee, Research Funding; Novartis: Research Funding, Speakers Bureau; Global Blood Therapeutics: Honoraria, Research Funding; Foundation for Sickle Cell Research: Honoraria; Forma: Consultancy.

Fluid overload due to intravenous fluid therapy for vaso-occlusive crisis in sickle cell disease: incidence and risk factors.

SummaryIntravenous fluid therapy (IV‐FT) is routinely used in the treatment of vaso‐occlusive crises (VOCs), as dehydration possibly promotes and sustains erythrocyte sickling. Patients with sickle cell disease (SCD) are at risk of developing diastolic dysfunction and fluid overload due to IV‐FT. However, data on the adverse effects of IV‐FT for VOC is sparse. We aimed to evaluate the incidence and risk factors of fluid overload due to IV‐FT in patients with SCD. Consecutive hospitalisations for VOC treated with IV‐FT between September 2016 and September 2018 were retrospectively analysed. The median (interquartile range) age was 25·0 (18·3–33·8) years and 65% had a severe genotype (HbSS/HbSβ0‐thal). Fluid overload occurred in 21% of 100 patients. Hospital stay was longer in patients with fluid overload (6·0 vs. 4·0 days, P = 0·037). A positive history of fluid overload (P = 0·017), lactate dehydrogenase level (P = 0·011), and top‐up transfusion during admission (P = 0·005) were independently associated with fluid overload occurrence. IV‐FT was not reduced in 86% of patients despite a previous history of fluid overload. Fluid overload is frequently encountered during IV‐FT for VOC. IV‐FT is often not adjusted despite a positive history of fluid overload or when top‐up transfusion is indicated, emphasising the need for more awareness of this complication and a personalised approach.

Treatment of Acute Pain in Adults With Sickle Cell Disease in an Infusion Center Versus the Emergency Department : A Multicenter Prospective Cohort Study.

Patients with sickle cell disease (SCD) have vaso-occlusive crises (VOCs). Infusion centers (ICs) are alternatives to emergency department (ED) care and may improve patient outcomes. To assess whether care in ICs or EDs leads to better outcomes for the treatment of uncomplicated VOCs. Prospective cohort. (ClinicalTrials.gov: NCT02411396). 4 U.S. sites, with recruitment between April 2015 and December 2016. Adults with SCD living within 60 miles of a study site. Participants were followed for 18 months after enrollment. Outcomes of interest were time to first dose of parenteral pain medication, whether pain reassessment was completed within 30 minutes after the first dose, and patient disposition on discharge from the acute care visit. Treatment effects for ICs versus EDs were estimated using a time-varying propensity score adjustment. Researchers enrolled 483 participants; the 269 who had acute care visits on weekdays are included in this report. With inverse probability of treatment-weighted adjustment, the mean time to first dose was 62 minutes in ICs and 132 minutes in EDs; the difference was 70 minutes (95% CI, 54 to 98 minutes; E-value, 2.8). The probability of pain reassessment within 30 minutes of the first dose of parenteral pain medication was 3.8 times greater (CI, 2.63 to 5.64 times greater; E-value, 4.7) in the IC than the ED. The probability that a participant's visit would end in admission to the hospital was smaller by a factor of 4 (0.25 [CI, 0.18 to 0.33]) with treatment in an IC versus an ED. The study was restricted to participants with uncomplicated VOCs. In adults with SCD having a VOC, treatment in an IC is associated with substantially better outcomes than treatment in an ED. Patient-Centered Outcomes Research Institute.

Utilization of a Pediatric Sickle Cell Day Hospital By Patients with Sickle Cell Disease and Pain Events Is Associated with a Lower Rate of Inpatient Hospital Admission Compared to Utilization of the Pediatric Emergency Department

Introduction:Vaso-occlusive crisis (VOC) is a leading cause of morbidity in children with sickle cell disease (SCD) and is the most common reason for hospitalization. Frequent and prolonged hospitalization is a risk factor for development of acute chest syndrome and increased mortality, and also leads to decreases in school attendance and quality of life measures. Furthermore, inpatient care accounts for a large proportion of total disease-related costs.A sickle cell day hospital (DH) is an outpatient facility with several beds, staffed by hematology/oncology trained attending physicians, fellows, nurse practitioners and bedside nurses, all with expertise in caring for patients with SCD. The concept of the DH as an alternative to the emergency department (ED) for treatment of VOC has been explored in adults, with evidence for reduced hospitalization rate, superior pain relief and significant cost-savings. In pediatrics, there is limited data on the utility of a DH for VOC management.We hypothesize that pediatric patients with SCD presenting to our institution with acute VOC who are managed in the DH will have a lower rate of inpatient admission than those managed in the ED.Methods:We performed a retrospective chart review of children aged 4 to 21 years with HbSS, HbSC, HbSβ0- or β+- thalassemia who received initial treatment for uncomplicated VOC with IV opioids in the DH or ED at the Children's Hospital at Montefiore during three consecutive calendar years. Patients were excluded if they had any of the following at the time of presentation: pain score < 7, temperature > 38.0°C, decrease in oxygen saturation >2% below baseline or <92% on room air, new chest x-ray infiltrate, headache or other neurological symptoms, or evidence of splenic sequestration. Patients selected for the ED cohort were limited to those who presented during the hours when the DH was open. Additionally, patients transferred from the DH to the ED or vice versa at any time during the visit were excluded. We abstracted data from the charts of 60 unique patients for each site to allow for assessment of our primary outcome of need for inpatient admission at the time of initial visit, as well as secondary outcomes including time to initial and rescue doses of opioid analgesic. The study was approved by the Institutional Review Board at Montefiore Medical Center.Results:Data from 56 DH and 55 ED patients have been analyzed to date. In general, the cohorts had similar demographics, sickle cell disease status, and pain scores (Table 1), except for younger age in the DH cohort (median 12 years vs 13 years, p = 0.012). Patients who presented to the DH were significantly less likely to be admitted than patients who presented to the ED, with admission rates of 41.1% and 67.3%, respectively (p= 0.008) (Fig 1A). Admitted patients from each setting were further stratified by pain score at presentation (Fig 1B) and by hydroxyurea (HU) status as a surrogate marker of disease severity (Fig 1C). In patients with an initial pain score of 10, there was no significant difference in admission rate based on treatment location (DH 56% vs ED 72.7%, p= 0.362). In contrast, patients with an initial pain score of 7-9 were significantly less likely to be admitted from the DH than from the ED (29% vs 63.6%, p= 0.007). DH-managed patients were significantly less likely to be admitted regardless of HU status compared to ED-managed patients (on HU: 44.8% vs 77.8%, p= 0.036; not on HU: 37% vs 78.4%, p= 0.002).Secondary analyses showed a significant difference between the DH and ED in the median time to initial (Fig 2A) and rescue (Fig 2C) opioid doses (initial: 65 mins vs 76 mins, p= 0.044; rescue: 45 mins vs 123 mins, p < 0.001). This comparison was further stratified based on pain score at presentation, and demonstrated significantly longer median time to initial dose of opioid in the ED for those patients with initial pain score of 7-9 (78 mins vs 93 mins, p= 0.032 - Fig 2B), but no significant difference for those with initial pain score of 10. Time to rescue dose of opioid was significantly longer for patients seen in the ED, regardless of pain score (pain 7-9: median 43 mins vs 125 mins, p < 0.001; pain 10: median 65 mins vs 120 mins p= 0.006 - Fig 2D).Conclusions:A dedicated pediatric sickle cell day hospital is an effective setting for the management of uncomplicated acute VOC. Treatment in this setting is associated with decreased rates of inpatient admission and faster administration of appropriate analgesics. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Tolerance of Vascular Electrical Stimulation Therapy in the Management of Vaso-Occlusive Crises in Patients with Sickle Cell Disease: A Phase II Single-Centre Randomized Study in Ivory Coast.

Background Vaso-occlusive crisis (VOC) is the primary cause of hospitalization in patients with sickle cell disease. Treatment mainly consists of intravenous morphine or nonsteroidal anti-inflammatory drugs (NSAIDs), which have many dose-related side effects. The question arises as to whether vascular electrical stimulation therapy (VEST) could be effective or not on VOCs. Objective To measure the effectiveness and safety of VEST in reducing the median time spent in severe VOC. Methods We conducted a phase II, single blinded, randomized, controlled, triple-arm, comparative trial. We included thirty (30) adult patients with severe vaso-occlusive crisis. The study arms were divided as follows: our control group (group 0) constituted of 10 patients followed with conventional therapy (Analgesics + Hydration + NSAIDs), while 20 patients were divided equally into two interventional arms—10 patients followed with VEST + Analgesics + Hydration (group 1) and the other 10 patients followed with VEST + Analgesics + Hydration + NSAIDs (group 2). The primary efficacy endpoint was median time to severe crisis elimination. The secondary end points were median time to end-of-crisis, median tramadol consumption, progress of the haemoglobin level over 3 days, side effects, and treatment failure. Results The age ranged from 14 to 37 years, including 23 women. We noted a beneficial influence of the VEST on the median time to severe crisis (VAS greater than 2) elimination; 17 hours (group 1) against 3.5 hours (group 2) p=0.0166 and 4 hours (group 3) with p value = 0.0448. Similar significant results were obtained on the diminution of total duration of the crisis (VAS over 0) and median tramadol consumption in patients in the interventional arms. Conclusion These statistically significant results in the interventional arms suggest that VEST could be an alternative treatment of VOC in sickle cell patients.

Outcomes in Vaso-Occlusive Crisis Treatment in the Emergency Department Vs. Acute Care Observation Center

I NTRODUCTION: Acute painful vaso-occlusive crises (VOC) are the leading cause of emergency department (ED) encounters and hospital admissions for those with sickle cell disease (SCD). For SCD patients, the goal of the sickle cell acute care observation unit (ACOU) at University of Illinois Health (UIH) is to improve patient outcomes by providing immediate care for an uncomplicated VOC. At our urban hospital which cares for more than 500 adult SCD patients, a considerable portion of SCD patients, despite having access to the ACOU, continue to present to the ED for treatment of an uncomplicated VOC. In order to help improve our current system, this study investigated outcomes in SCD patients who receive care for an uncomplicated VOC in the ACOU versus the ED at UIH. METHODS: By querying the electronic medical record, a retrospective study was conducted to analyze outcomes of encounters from the ACOU and ED at UIH between October 2019 and December 2019, specifically including SCD patients ≥18 years old who received morphine for treatment of an uncomplicated VOC. Encounters for complicated VOCs such as acute chest syndrome and stroke were excluded. Endpoints collected include time to first dose of morphine, total milligrams (mg) of IV morphine equivalents given, number of total morphine doses, admission rates, subsequent hospital length of stay, and 30-day inpatient admission rates. Time to the first dose (log transformed) and total dose in mg were analyzed by linear mixed effects models. The number of doses and hospitalization days were analyzed by negative binomial mixed effects model. Admissions and 30-day admissions were analyzed by logistic mixed effects models. These models adjusted for age, gender, and severe Hb genotype (HbSS or HbS beta0-thalassemia) and treated patient identity as random effect. P values were obtained from Wald- test. RESULTS: The ACOU data set contains 394 patient encounters for 79 patients with a median age of 33 years (interquartile range [IQR], 28-40), 71% female, and 73% with severe sickle genotypes. The ED data set contains 391 patient encounters for 128 patients with a median age of 30 years (IQR, 26-41), 53% female, and 74% with severe sickle genotypes. In the ACOU, the median time to first dose of morphine was 49 minutes (IQR, 39-60) compared to 107 minutes (IQR, 71-194) in the ED. The time to first dose was significantly longer in the ED compared to the ACOU (eβ=2.5, p &amp;lt;2×10-16). There was no significant difference in the total number of morphine doses received nor the total mg of morphine received between the two locations. Admission rate from ACOU was 6.6% compared to 53% from ED (OR=0.019, p=2x10-16). Of those admitted, the median number of hospitalization days from the ACOU was 4 days (IQR, 2.3-5.8) and 4 days (IQR, 2.0-6.5) from the ED. There was no significant difference in hospitalization days (p=0.6). The 30-day admission rate was 55% from the ACOU compared to 58% from the ED. 30-day admission rate however had strong intra-patient correlation (i.e., a patient was likely re-admitted multiple times): 44% of patients from the ACOU had admissions within 30 days of their ACOU visit compared to 32% from the ED. Controlling for the intra-patient correlation, ACOU visits had a higher 30-day admission rate than ED visit (OR=2.8, p=0.0015). DISCUSSION: SCD patients treated for an uncomplicated VOC at the sickle ACOU at UIH had a significantly shorter time to initial dose of IV pain medication. The wait time in the ED before first dose of IV pain medication received was more than double than those treated in the ACOU. Patients treated for an uncomplicated VOC in ACOU and ED had similar hospitalization days without a statistically significant difference. The 30-day admission rate to the inpatient setting was comparable for those treated in the ED versus the ACOU. However, given that only 6.6% of patients from the ACOU were admitted during the study period, this suggests that most patients who use both the ED and ACOU tend to be subsequently admitted from the ED. SCD patients may be presenting to the ED for treatment of VOC if capacity in the ACOU is exceeded or are presenting outside of hours of operation (currently 2 shifts Monday through Saturday). Therefore, improving access to our ACOU by increasing capacity and hours of operation may subsequently also lead to a decrease in time to first dose of medication and decrease in the overall 30-day admission rate. Disclosures Gordeuk: Imara: Research Funding; CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Ironwood: Research Funding.

Microvascular Stasis Inhibition By Hemopexin in the Townes Mouse Model of Sickle Cell Disease

Polymerization of hemoglobin-S (HbS) in the deoxy conformation shortens the lifespan of sickle red blood cells and promotes intravascular and extravascular hemolysis. When sickle red blood cells are lysed intravascularly, HbS is released into the vascular space where it can consume nitric oxide and be oxidized to higher oxidative forms. During these reactions, ferric (Fe3+) HbS is formed, which readily releases heme. The released heme can activate the innate immune pattern recognition receptor toll-like receptor 4 (TLR4) on endothelium, leading to P-selectin expression, NF-ĸB activation, and microvascular stasis in sickle cell disease (SCD) mice with implanted dorsal skin-fold chambers (DSFCs). Heme-induced TLR4 signalling and stasis are blocked by administering hemopexin with the heme. Plasma hemopexin has the highest binding affinity for free heme, rendering it relatively nonreactive and delivering it safely to the liver for endocytosis and degradation by heme oxygenase-1 (HO-1). Due to chronic hemolysis, hemopexin levels are depleted in SCD patients and mice. We previously reported that intravenous hemopexin induces hepatic HO-1 activity and inhibits ongoing, spontaneous stasis in the venules of SCD mice for up to 48 hours. Inhibition of HO-1 activity with tin protoporphyrin (SnPP) and the administration of carbon monoxide (CO) to SnPP-treated mice demonstrated that HO-1 and its reaction product CO play important roles in the protection against stasis. In the current studies, we asked the question how much of the hemopexin-mediated protection is due to preventing heme activation of TLR4 signalling versus induction of HO-1 and CO production. We wondered if hemopexin complexed with heme would be as effective as hemopexin alone in treating a vaso-occlusive crisis (VOC) induced with hemoglobin heme. First, in a stasis prevention model, we intravenously administered different doses of hemopexin in Townes SCD mice with a DSFC one hour prior to a hemoglobin challenge. Briefly, anesthetized mice were placed on an intravital microscopy stage, and 20-24 flowing subcutaneous venules were selected and mapped. After baseline selection of flowing venules and one hour after administration of different doses of hemopexin (0 - 160 mg/kg body weight), microvascular stasis was triggered by infusing hemoglobin (1 µmol/kg). The same vessels were re-examined for stasis (no flow) and percent stasis was calculated. Our results show that hemopexin effectively reduced stasis in a dose responsive manner when delivered one hour prior to the hemoglobin challenge (Figure 1A). Second, we evaluated hemopexin in a VOC acute treatment model by infusing various doses of hemopexin 30 minutes after the intravenous hemoglobin challenge. We found a dose-dependent effect of hemopexin to reduce and resolve microvascular stasis during an acute VOC one hour after hemopexin infusion (Figure 1B). We obtained similar results after inducing stasis with lipopolysaccharide (LPS) or hypoxia-reoxygenation in place of hemoglobin challenge. Third, we evaluated equimolar hemopexin-heme complexes in a VOC acute treatment model by infusing the same doses of hemopexin-heme 40 minutes after the intravenous hemoglobin challenge (1 µmol/kg) to further elucidate the effects of heme scavenging versus HO-1 induction. Our results showed a striking, dose-dependent reduction in stasis, albeit to a detectably lower degree than hemopexin free of heme (Figure 1C). In summary, hemopexin has a dose-dependent effect to prevent and treat vaso-occlusion induced in a mouse model of SCD by hemoglobin, LPS, and hypoxia-reoxygenation. This effect is partially replicated by hemopexin pre-complexed with heme, suggesting that the beneficial effect is not limited to clearance of circulating heme and prevention of TLR4 signalling. The partial effectiveness of hemopexin-heme complex is consistent with our prior published data implicating CO generation by HO-1 as playing a role in the relief of vaso-occlusion by hemopexin. We conclude that hemopexin shows promise for the treatment of VOC. Additional experiments are needed to clarify the activity of hemopexin in clearance-dependent and -independent mechanisms of resolution of vaso-occlusion. Clinical trials of hemopexin are warranted to evaluate its safety, tolerability and potential efficacy in relieving vaso-occlusive pain crisis in patients with SCD. Disclosures Gentinetta: CSL Behring: Current Employment. Vercellotti:CSL Behring: Research Funding. Kato:CSL Behring AG: Current Employment. Brinkman:CSL Behring: Current Employment. Zuercher:CSL Behring AG: Current Employment. Belcher:Mitobridge-Astellas: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Hillhurst Biopharmaceuticals: Consultancy.

Randomized phase 2 trial of Intravenous Gamma Globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: Lessons learned from the midpoint analysis

Sickle Cell Disease (SCD) is a chronic hemolytic disorder associated with frequent pain episodes, end organ damage and a shortened lifespan. Currently there exist no disease specific targeted therapies for the treatment of acute vaso-occlusive crisis (VOC) and management with analgesics and hydration is purely supportive. Improvement in understanding of disease pathophysiology has resulted in a great interest in disease modifying novel therapies and many are being evaluated in clinical trials. Here we report the results from the pre-specified mid-point analysis of the Phase 2 study of Intravenous Gamma Globulin (IVIG) for the treatment of acute VOC in patients with SCD and lessons learned.

The vaso-occlusive pain crisis in sickle cell disease: Definition, pathophysiology, and management.

Early diagnosis, treatment, and prevention of a vaso-occlusive crisis (VOC) are critical to the management of patients with sickle cell disease. It is essential to differentiate between VOC-associated pain and chronic pain, hyperalgesia, neuropathy, and neuropathic pain. The pathophysiology of VOCs includes polymerization of abnormal sickle hemoglobin, inflammation, and adhesion. Hydroxyurea, L-glutamine, crizanlizumab, and voxelotor have been approved by the US Food and Drug Administration for reducing the frequency of VOCs; the European Medicines Agency has approved only hydroxyurea. Other novel treatments are in late-stage clinical development in both the United States and the European Union. The development of agents for prevention and treatment of VOCs should be driven by our understanding of its pathophysiology.