The Utility of Routine Electrolytes in Patients with Sickle Cell Anemia Presenting with an Acute Pain Crisis

Abstract Abstract 1651 Background: Pain crises are the most common symptom experienced by individuals with sickle cell anemia (SCA). Frequency of pain crises varies significantly and high rate is a risk factor for higher mortality in adults with SCA. The risk factors for pain crises in children and adolescents with SCA are not completely understood. To determine factors associated with frequent severe pain crises, we analyzed the cohort of children and adolescents with SCA who were enrolled in the prospective study “The Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH)”. All children were evaluated in their steady, non-crisis state. Methods: Family-reported history of number of severe pain crises in the preceding 12 months was recorded prospectively in 365 children and adolescents with SCA. Severe pain crises were defined as painful vaso-occlusive episodes requiring evaluation in Emergency Department (ED) or in-patient hospitalization. Lifetime history of red cell transfusions, echocardiography, and laboratory studies were obtained. Clinical and laboratory characteristics of study subjects who had ≥3 severe pain crises in the preceding year were compared to subjects with < 3 severe pain crises. Results: Study subject ranged in age from 3–20 years and 175 (48%) were female. Seventy two children (20 %) had ≥3 severe pain crises in the preceding year (frequent pain crisis group); 293 (80%) children had < 3 severe pain crises (infrequent pain crisis group), including 224 (61%) subjects who had no admissions/ ED visits for pain. Associated factors for frequent pain crisis included older age (odds ratio 1.2; 95% confidence interval 1.12–1.35; P <0.001) and α-thalassemia trait (odds ratio 3.22; 95% confidence interval 1.55–6.69; P =0.002) while higher steady state serum lactate dehydrogenase (LDH) was associated with infrequent pain crisis (odds ratio 0.35; 95% confidence interval 0.13–0.98; P =0.045). In a group of patients without α-thalassemia trait, older age and low LDH were linked to frequent pain crisis. Subjects in the frequent pain crisis group had higher median hemoglobin (9.0 vs. 8.5 gm/dL; p=0.003) and higher ferritin (median 455 vs. 191 ng/mL; p=0.008). Higher ferritin in the frequent pain crisis group was mirrored by the higher percentage who reported >10 lifetime transfusions (42% vs. 22%; p=0.001). Median tricuspid regurgitation jet velocity (TRV) was higher in the frequent pain crisis group (2.41 vs. 2.31; p= 0.001) but the proportion of children with TRV>2.5 was not different (19.4% vs.11.5% in infrequent crises group; p=0.09). Hydroxyurea use was not different between the groups (51% vs. 40%; p=0.08) nor was fetal hemoglobin (10% vs. 12%; p=0.2). Conclusions: The occurrence of severe pain crisis varies among children and adolescents with SCA with a large number of children experiencing no severe painful episodes. Consistent with the Cooperative Study of Sickle Cell Disease report, the risk of severe pain crisis increases with age. Individuals with α-thalassemia trait are likely to experience more frequent pain crises possibly related to higher hemoglobin concentration and viscosity. However, even after controlling for α-thalassemia trait, children and adolescents who reported more frequent severe pain crises showed evidence of less hemolysis, consistent with a hypothetical model associating the hemolytic subphenotype of SCA with less frequent vasoocclusive pain crises. Further studies are indicated to identify the molecular mechanisms of pain in sickle cell anemia. Disclosures: No relevant conflicts of interest to declare.

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Chronic Pain Is An Independent Predictor of Lower 6 Minute Walk Distance In Patients with Sickle Cell Disease: Results From Walk-PHaSST Study

Blood ◽

10.1182/blood.v116.21.2658.2658 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2658-2658

Author(s):

Lakshmanan Krishnamurti ◽

Ruchika Goel ◽

Oswaldo Castro ◽

Robyn J. Barst ◽

Erika Berman Rosenzweig ◽

...

Keyword(s):

Chronic Pain ◽

Exercise Capacity ◽

Sickle Cell ◽

Acute Pain ◽

Research Funding ◽

History Of ◽

Pain Crisis ◽

The Mean ◽

Minute Walk Distance ◽

Minute Walk

Abstract Abstract 2658 Introduction: Six minute walk distance (6MWD), is a measure of exercise capacity commonly used as an endpoint in pulmonary hypertension (PH) clinical trials. Many patients with sickle cell disease (SCD) have acute pain crises or chronic pain syndromes that impair their quality of life. While patients with SCD who are undergoing screening for PH are generally screened in steady state, i.e., when they have not had a recent pain crisis, the impact of chronic pain on exercise capacity in this group of patients has not been previously evaluated. Methods: walk-PHaSST was a multi-center screening study designed to identify subjects with SCD at increased risk for symptomatic PH, defined by a tricuspid regurgitant velocity (TRV) ≥ 2.7 m/sec and 6MWD between 150–500 meters, for enrollment in a double-blind placebo controlled trial of sildenafil. The primary endpoint was the change in 6MWD after 16 weeks of treatment. We examined the relationship between subjects' self-reported acute and chronic pain and baseline 6MWD in the screened SCD patients in walk-PHaSST. Results: For 90% of subjects, the information about pain was reported by the patient or parent/family member. Documentation of pain management and utilization of services was verified from medical records in 10% of subjects. Ninety four percent of all subjects reported having a history of acute sickle cell pain crises; 6% reported never having had an acute pain crisis. For the subjects who reported a history of acute pain crises, the ‘typical’ acute pain rating on a scale of 0 to 10 was ≥ 7 (maximum 10) for 77% of this subset of subjects. A total of 342 (50%) subjects reported not having had any pain crises in the preceding week. Of 720 subjects screened medical history and 6 MWD was available in 673 patients. Of these 633 (94%) subjects did not report having had a pain crisis requiring an emergency department visit or hospitalization in the preceding week. A total of 39% of subjects reported chronic sickle cell related pain; no rating was reported for chronic pain. 88% of patients reported using medications for pain control while 15% reported using non-drug therapy including physical therapy in 3%, alternative therapy in 2%, acupuncture in 2% and hypnosis in < 1% of patients. The mean 6MWD for the screened population was 439 meters (median 438 m, range 123–713 m). A total of 171/673 (26%) subjects had a 6MWD >500 meters, which was above the screening cut-off for enrollment in the main interventional trial. By univariate analysis, subjects reporting chronic pain had a significant lower odds ratio for walking > 500 meters (OR 0.637, 95% C.I 0.44–0.99); a similar observation was seen with those subjects with a history of acute pain crises (OR 0.47, 95% C.I 0.24–0.91). Multivariable logistic regression analysis revealed a significant inverse relationship between chronic pain but not acute pain and 6MWD after adjusting for age, TRV, gender, hematocrit and smoking history (See Table 1). The mean 6MWD decreased by 27 meters with self reported chronic pain after adjusting for TRV, age, gender, hematocrit and 6MWD. Conclusions: TRV is a known predictor of 6MWD. However, these data suggest that patient self reported sickle cell related chronic pain is also an independent predictor of 6MWD. This relationship raises interesting questions about the potentially confounding effects of pain on exercise capacity as assessed by the 6MW test. Further study is warranted to investigate an association between chronic pain and exercise capacity in SCD as well as exploration of appropriate endpoints for future clinical trials in patients with SCD and suspected symptomatic PH. Disclosures: Barst: Pfizer: Consultancy, Research Funding. Rosenzweig:Pfizer: Research Funding. Badesch:Pfizer: Honoraria, Research Funding. Hassell:Novartis: Research Funding.

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Health Care Utilization for Painful Events Is Associated with Early Mortality in a Contemporary Population of Adults with Sickle Cell Anemia

Blood ◽

10.1182/blood.v118.21.2115.2115 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2115-2115

Author(s):

Deepika S. Darbari ◽

Mariana Hildeshem ◽

Caterina Minniti ◽

Gregory J. Kato ◽

James G. Taylor

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Severe Pain ◽

Early Mortality ◽

Care Utilization ◽

Cell Disease ◽

History Of ◽

Pain Crisis ◽

Ed Visits ◽

Painful Events

Abstract Abstract 2115 Background: Painful vaso-occlusive crises are the most common symptom associated with sickle cell anemia (SCA) and show a large inter-patient variability in the frequency and severity. Historically a high rate of admissions for pain is associated with early mortality in SCA adults. Modern day management of SCA includes screening for life threatening complications such as pulmonary hypertension and disease modifying therapies such as hydroxyurea and chronic blood transfusions. It has also become clear that all acute painful events including some self reported crisis do not lead to ED visit/ hospitalization therefore use of healthcare utilization may underestimate the actual frequency of painful vaso-occlusive crises. The present study determined if ED visit/ hospitalizations for painful vaso-occlusive crises remain a marker of early mortality in the modern era. Methods: To determine the relative contribution of pain and other established risk factors for death in a contemporary adult cohort with sickle cell anemia, we analyzed data of SCA individuals who were evaluated at NIH between February 2001 and June 2007 for screening of the IRB approved protocol to study pulmonary hypertension in sickle cell disease. Self reported history of vaso-occlusive painful events requiring visit to an emergency department (ED) or in-patient hospitalization in 12 months preceding the enrollment was used to stratify study subjects into no-ED visit/ hospitalization or ED visit/hospitalization group. Characteristics between the groups were compared. Doppler echocardiography was used to estimate systolic pulmonary artery pressure through measurement of the tricuspid regurgitation velocity (TRV). Study subjects were followed prospectively and age at death was recorded. Results: One hundred and four (40%) SCA subjects reported no ED visit/ hospitalization while 160 (60%) reported at least one ED visit/ hospitalization in 12 months preceding the enrollment. Although not statistically significant, a higher proportion of study participants in the ED visit/ hospitalization group were on hydroxyurea (38 vs. 69%; P=0.4), and more likely to have received > 10 red cell transfusions (37 vs. 48%; P= 0.09). The no-ED/ hospitalization group and ED/ hospitalization groups were not different in median age (33 vs. 31; P=0.1) or fetal hemoglobin concentration (7.7 vs. 6.9%; P=0.3). Overall forty (15.1%) individuals died during the median follow-up period of 5 years. Cox proportional hazards analysis was performed to determine if severe pain crisis requiring ED visits/hospitalizations were associated with early mortality after adjusting for other known risk factors for mortality (Table 1). Risk for mortality was significantly associated with a history of severe pain crisis requiring ED visit/hospitalization in preceding year (RR 2.81, 95% CI: 1.2–6.4, P= 0.04), elevated TRV ≥ 3 m/s (RR 4.07, 95% CI: 1.3–12.8, P= 0.02) and elevated ferritin (RR 2.31, 95% CI: 1.0–5.0, P= 0.04). Conclusions: Severe painful episodes requiring health care utilization are associated with premature mortality and despite likely underestimation of actual frequency of pain, remain a marker of disease severity. Elevated TRV a marker of elevated pulmonary arterial pressure and early mortality has a cumulative effect with pain on reduced survival. Consistent with Cooperative Study of Sickle Cell Disease (CSSCD) report, higher hemoglobin (and lower LDH) was associated with reports of ED visit/ hospitalization likely related to increased viscosity. We conclude that as a group, SCA patients reporting severe pain requiring ED visits /hospitalization and elevated TRV are at the highest risk for shortened survival. Disclosures: No relevant conflicts of interest to declare.

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2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia

Blood ◽

10.1182/blood.v96.7.2379.h8002379_2379_2384 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2379-2384

Author(s):

Mabel Koshy ◽

Louise Dorn ◽

Linda Bressler ◽

Robert Molokie ◽

Donald Lavelle ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Complete Blood Count ◽

Fetal Hemoglobin ◽

Therapeutic Benefit ◽

Additional Treatment ◽

Acute Chest Syndrome ◽

F Cells ◽

Pain Crisis ◽

Globin Synthesis

Augmentation of the fetal hemoglobin (HbF) levels is of therapeutic benefit in patients with sickle cell anemia. Hydroxyurea (HU), by increasing HbF, lowers rates of pain crisis, episodes of acute chest syndrome, and requirements for blood transfusions. For patients with no HbF elevation after HU treatment, augmentation of HbF levels by 5-aza-2′-deoxycytidine (5-aza-CdR, decitabine) could serve as an alternate mode of treatment. Eight adult patients participated in a dose-escalating phase I/II study with 5-aza-CdR at doses ranging from 0.15 to 0.30 mg/kg given 5 days a week for 2 weeks. HbF, F cell, F/F cell, γ-globin synthesis ratio, complete blood count, and chemistry were measured. The average γ-globin synthesis relative to non-α-globin synthesis prior to therapy was 3.19% ± 1.43% and increased to 13.66% ± 4.35% after treatment. HbF increased from 3.55% ± 2.47% to 13.45% ± 3.69%. F cells increased from 21% ± 14.8% to 55% ± 13.5% and HbF/F cell increased from 17% to 24%. In the HU nonresponders HbF levels increased from 2.28% ± 1.61% to 2.6% ± 2.15% on HU, whereas on 5-aza-CdR HbF increased to 12.70% ± 1.81%. Total hemoglobin increased by 1 g/dL in 6 of 8 patients with only minor reversible toxicities, and all patients tolerated the drug. Maximum HbF was attained within 4 weeks of treatment and persisted for 2 weeks before falling below 90% of the maximum. Therefore 5-aza-CdR could be effective in increasing HbF in patients with sickle cell anemia who failed to increase HbF with HU. Demonstration of sustained F levels with additional treatment cycles without toxicity is currently being performed.

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Sevuparin for the treatment of acute pain crisis in patients with sickle cell disease: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

The Lancet Haematology ◽

10.1016/s2352-3026(21)00053-3 ◽

2021 ◽

Vol 8 (5) ◽

pp. e334-e343

Author(s):

Bart J Biemond ◽

Anil Tombak ◽

Yurdanur Kilinc ◽

Murtadha Al-Khabori ◽

Miguel Abboud ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Acute Pain ◽

Phase 2 ◽

Cell Disease ◽

Double Blind ◽

Double Blind Placebo ◽

Phase 2 Trial ◽

Pain Crisis

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Hematological Changes from Baseline in Children with Sickle Cell Disease Admitted for Acute Chest Syndrome Compared to Acute Pain Crisis

Blood ◽

10.1182/blood-2018-99-118977 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4909-4909

Author(s):

Timothy Klouda ◽

Nataly Apollonsky ◽

Deepti Raybagkar ◽

Bruce Bernstein

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Acute Pain ◽

Neutrophil Count ◽

Laboratory Data ◽

Acute Chest Syndrome ◽

Cell Disease ◽

History Of ◽

Pain Crisis ◽

Hematological Changes

Abstract Title: Hematological Changes from Baseline in Children with Sickle Cell Disease Admitted for Acute Chest Syndrome Compared to Acute Pain Crisis Authors: Timothy Klouda1, Deepti. Raybagkar2, Bruce Bernstein1, Nataly Apollonsky2, Institutes:1Pediatrics, St Christopher's Hospital for Children, Philadelphia, PA, United States, 2Hematology, St Christopher's Hospital for Children, Philadelphia, PA, United States, Introduction: Children with Sickle Cell Disease suffer from multiple complications including acute pain crisis (VOC) and acute chest syndrome (ACS). Nearly 30% of children with SCD have had one episode of ACS, with the incidence higher in early childhood. The proposed pathophysiology of ACS is thought to be multi-factorial, with pulmonary fat embolism or infectious etiology being identified in a large number of patients. Increased sickling due to hypoxemia or pain has been shown to place patients at risk for ACS development., Studies have shown an increase in inflammatory markers including leukocytes and neutrophils, along with a decreased hemoglobin in SCD children who developed ACS, but no studies to date have compared laboratory changes during the acute illness to their baseline values. We hypothesized that children with SCD who are admitted for ACS will have a larger decrease in hemoglobin from baseline and a higher increase in white blood cell count from baseline when compared to those admitted for an acute pain crisis. Methods: Through retrospective chart review of patients with SCD admitted to St.Christopher's Hospital for Children we identified 45 patients with ACS. Laboratory data collected on admission from chart review included SCD genotype, age, BMI, hemoglobin, white blood cell count, absolute neutrophil count, absolute eosinophil count, platelets, reticulocyte count, hemoglobin F, vital signs and medication history. All 45 children had laboratory data collected from an acute pain crisis that occurred during a different admission for comparison. Collected data was compared to baseline laboratory data, collected during routine visit at sickle cell clinic within 1 year of admission. Changes in laboratory data from baseline during admission for ACS were compared to changes during admission for uncomplicated VOC. Results: Children with SCD who were admitted or developed ACS during admission had a larger increase in leukocyte count (6.99 vs 4.18, p=0.027) and neutrophil count (6.3 vs 3.74, p=0.04) from baseline compared to those admitted for VOC alone. Patients with ACS development also had a larger decrease in platelets (-124.74 vs -56.21, p=.047) from baseline when compared to VOC admissions. There was no statistically significant change from baseline labs when comparing hemoglobin (p=0.10), eosinophil count (p=.382), reticulocyte count (p=0.754), AST (p=0.061) and ALT (p=0.082) in the ACS and VOC groups. Children with a history of 2 or more lifetime ACS were more likely to have OSA (p=0.021), 3 or more VOCs in the past year (p=0.002), and a history of splenectomy, but it was not found to be statistically significant (p=0.155) Conclusion: Children with SCD who developed or were admitted with ACS had a significant increase in leukocyte and neutrophil count from baseline, and a decrease in platelets when compared to VOC admissions. There was no significant change from baseline in hemoglobin, reticulocyte and eosinophils detected. Future larger and multi-center prospective studies need to be performed to confirm the various changes identified in hematological markers seen in ACS vs VOC. Disclosures No relevant conflicts of interest to declare.

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A Pilot Study of a Functional Pain Assessment for Adult Patients Admitted with Sickle Cell Pain Crisis

Blood ◽

10.1182/blood-2019-124847 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4693-4693

Author(s):

Marquita Nelson ◽

Monica Peek ◽

Kenneth Cohen ◽

Danielle Bowsman ◽

Nabil Abou-Baker

Keyword(s):

Sickle Cell ◽

Acute Pain ◽

Pain Assessment ◽

Assessment Tool ◽

Adult Patients ◽

Free Response ◽

Response Options ◽

Pain Scores ◽

Functional Pain ◽

Pain Crisis

Introduction Acute vaso-occlusive pain crises are the most common complications of sickle cell disease (SCD). Pain is a subjective sensation and is often difficult to describe and for practitioners to understand. The complexity and multidimensional nature of pain requires additional evaluation beyond pain intensity. Pain assessment is also influenced by implicit and explicit biases related to race and ethnicity which can negatively influence treatment (Wandner et al J Pain 2012). In this pilot quality improvement study, we studied resident perceptions to a functional assessment tool in adult patients hospitalized with sickle cell vaso-occlusive crises. We used the Youth Acute Pain Functional Ability Questionnaire (YAPFAQ), a validated questionnaire of physical function in youth experiencing acute pain (Zempsky et al J Pain 2014) (Figure 1). Resident responses to using the YAPFAQ were measured as an initial step to implementation of functional pain assessment in hospitalized adults with SCD pain crises. Methods We piloted this study on internal medicine residents. First, residents completed the Resident Acute SCD Pain Assessment Survey regarding their current management of acute pain in SCD (Figure 2). This was done to determine their baseline demographic information, methods of pain assessment, satisfaction with the numerical pain score system, and to understand barriers in assessing acute pain. This survey included a combination of multiple choice, free response, and binary response options. The residents then trialed the YAPFAQ with a patient admitted with vaso-occlusive pain crisis then the residents completed The Post YAPFAQ Evaluation Survey in response to this assessment tool (Figure 3). This survey included a combination of multiple choice, free response, and binary response options. The goal of this survey was to assess resident satisfaction with YAPFAQ, perceived patient receptiveness to YAPFAQ, and feasibility of using this tool during daily assessments. Patients were not surveyed during this pilot study. We performed descriptive statistics to describe the survey results. Results Sixteen residents completed the Acute SCD Pain Management survey prior to using the YAPFAQ. Sixty-nine percent of residents reported dissatisfaction with using numerical pain scores. Reported barriers to assessing pain included: subjectivity of pain scores, concern for malingering, and the ceiling effect of the numeric scale. Seven residents completed the post YAPFAQ evaluation survey. A majority of residents (86%) were extremely satisfied or satisfied with using the YAPFAQ. Fifty seven percent of residents felt that patients were extremely receptive or receptive to using this tool. The majority of residents (85%) felt that the YAPFAQ improved their understanding of patients' pain. All YAPFAQs were completed with patients in 10 minutes or less. Most residents (57%) reported that the tool would be feasible for implementation on rounds. Conclusions Similar to previous studies, our residents felt that numerical pain score systems inadequately describe pain. Residents had generally positive responses to the YAPFAQ. One resident stated that the questionnaire was "structured and easy to compare day to day." Functional pain assessment allows providers to better understand how pain limits daily activities and can provide useful functional targets for safe hospital discharge. Future directions of this project include performing a larger study of patients hospitalized with vaso-occlusive pain crises to validate the YAPFAQ in adult patients, survey patients regarding experiences with the YAPFAQ, and to create tailored pain management plans based on functional pain assessments. Disclosures No relevant conflicts of interest to declare.

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