Vaso occlusive crisis (VOC) is the most common reason for hospital admissions and emergency room visits in sickle cell disease (SCD). Education of patients, caregivers, and the healthcare team are a key factor in reducing readmission rates following hospitalization for children with VOC. There is a paucity of data on parental understanding of pain medications on hospital discharge, a confusing and intense time for families. This quality improvement (QI) project addresses provider and patient/parent knowledge gaps by incorporating a sickle cell pain action plan (SPAP) into the discharge process.
Methods: The key drivers comprised of pharmacy, nursing, pediatric residents, patient representatives and pediatric hematologists. The SPAP was modeled on the success of the asthma action plan and helps distinguish patients degree of pain, with specific medical instructions for treatment. PDSA cycles included implementation of the SPAP with medication teaching at bedside, nursing teaching with SPAP during admission and pharmacy consults. The QI leader performed monthly educational modules to the house staff, pharmacists and nursing, and sent weekly email reminders to leaders of the inpatient team. Monthly run charts were created to assess 7 and 30- day readmissions. There are 14 months of data reported to capture both 7 and 30-day readmissions in the total study period. Readmissions were compared monthly to the year prior to implementation of the SPAP. Process measures were the number of documented pharmacy consults, documented SPAPs in the chart and surveys (5 point Likert scale) on patients understanding of their medications post discharge.
Results: There were 230 admissions for VOC the 12 months prior to implementation of the SPAP and 293 VOC admissions during the study period. Thirty-day readmission rates from April-July 2016 had a 36% reduction compared to 2015 data. The rise in readmissions during August, November and December of 2016 prompted implementation of new team champions and reeducation of staff, and subsequent months had reduction in readmissions. The cumulative decrease at completion of the project was an 18% reduction in thirty-day readmission rates and 13% reduction in 7-day readmission rates, whether or not there was a documented SPAP. Patients that had a documented SPAP in their chart (n=33) had a 65% reduction in thirty-day readmissions and 22% reduction in seven-day readmissions. Of the patients/parents surveyed (n=20 pre-implementation, n=34 post implementation) 91% and 74% strongly agreed they knew which pain medications to administer and how to escalate care compared to 56% and 47% prior to the project. Ninety percent of the surveyed families agreed that the SPAP: helped them understand their pain medications, remember medication names, was easy to understand and would be used again in the future. Pareto charts showed the following barriers to implementation of the QI intervention: pharmacy consults not performed due to lack of adequate staffing, SPAP documentation lacking despite a pharmacy consult being requested, and difficulties of staff adjusting to a new electronic medical record.
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A total of 67 patients with SCD and 14 unaffected siblings of the patients enrolled on to the study for determining baseline AHR (ClinicalTrials.gov Identifier: NCT00448370). Chief eligibility criteria included a diagnosis of SCD (HbSS, HbSC or HbS b-thalassemia) confirmed by hemoglobin electrophoresis or gene sequencing, ages 5.5 years to 30 years who were able to complete pulmonary function testing and were at baseline/steady state (no acute sickle events 3 weeks prior or acute chest syndrome (ACS) 4 weeks prior). Excluded were patients taking anti-leukotriene medications within 30 days prior, although patients with SCD who had a known history of asthma but not on leukotriene inhibitors were eligible. Patients with chronic transfusions, congenital lung or heart condition, or other medical condition that could affect the pulmonary function testing were also ineligible. Unaffected siblings of the 67 enrolled SCD patients living in the same household were offered enrollment for MCT and those consenting were enrolled.
Results: 64 SCD patients and 14 siblings underwent a MCT; 3 of 67 SCD patients had FEV1<70% of predicted at baseline, and therefore, for safety reasons, were not subjected to MCT. The degree of AHR was defined by the provocative concentration of methacholine that resulted in a 20% decline in FEV1 (PC20): no AHR=PC20 >16mg/mL; borderline AHR=PC20 4-16mg/mL; mild AHR=PC20 1-3mg/mL and moderate-severe AHR=PC20 <1mg/mL. All subjects were given a dose of albuterol after completion of MCT. MCT was safe in all subjects, and no AHR or acute sickle events occurred in any subject for three weeks after the MCT. Overall, 25 of 67 (37%) SCD patients had no AHR, 8 of 67 (12%) had borderline AHR (PC20 9±1.4mg/ml), 10 of 67 (15%) had mild AHR (PC20 1.72 ±0.16) and 24 of 67 (36%) had moderate-severe AHR (PC20 0.6 ±0.06). Of unaffected siblings, 10 of 14 (71%) had no AHR, 2 of 14 (14%) had borderline AHR (PC20 10±0.4) and 2 of 14 (14%) had mild AHR (PC20 1.7±0.4). Moderate to severe AHR was only seen in SCD patients and not sibling controls. Severe AHR prevalence was highest in the HbSS group. We analyzed the clinical characteristics of the SCD subjects, including acute sickle episodes, defined as admission for one of the following: pain crises, fever with or without a known source of infection, cough/wheezing/chest pain, impending acute chest syndrome, enlarged and splenic sequestration or priapism. SCD patients with AHR had significantly higher (P<0.05) admissions from acute sickle episodes (2.7±0.1) and acute chest syndrome (1.5±0.15). We next assessed PlGF and leukotriene levels in SCD subjects. PlGF levels were not quantifiable due to presence of hemolysis, which confounds PlGF ELISA. However, we found a trend towards higher (1.3-2 fold) expression of PlGF-induced target genes (VEGF, IL-1β, IL-8, CCL2) in the mononuclear cells of patients with severe AHR; Also, circulating cysteinyl leukotriene D4 levels in their plasma were significantly higher.
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The impact of racial and socioeconomic status (SES) on access to hematopoietic cell transplantation (HCT) are well known. Even when controlled for SES, racial minorities have lower access to HCT than the racial majority groups. Since the majority of patients with sickle cell disease (SCD) in the US are of African descent, HCT for SCD provides a unique opportunity to study the impact of SES on access to HCT in a relatively uniform racial population. The objectives of this study were to explore whether insurance status and SES are associated with the HCT for SCD.
Methods: The clinical database from the SCD program at Children’s Healthcare of Atlanta (CHOA), which contains over 3,100 patients, was used to identify SCD patients who have undergone HCT between January 1, 2012 and December 31, 2016 at CHOA. We then identified non-transplanted SCD patients matched for age at transplant, gender, and SCD genotype. Three matched controls were randomly selected for each case except for one older patient who only had two controls. Non-Georgia residents during the year of transplant were excluded; one sickle cell patient who had BMT due to acute lymphoblastic leukemia was also excluded. Among both the transplanted patients and their controls, insurance status was assessed as well as socioeconomic status was estimated based on block-level census data, specifically household income, home value, percent single parent households, percent unemployment, and education level. Conditional logistic regression analysis using backwards elimation was performed to determine the odds of receiving HCT.
Results: Of 34 patients with SCD who underwent HCT at CHOA during this time period, 27 (66.7% females and 33.3% males) were Georgia residents. Twenty-five of the 27 patients received a matched-sibling donor transplant and two had matched-unrelated donor transplant. Among the HCT patients, the median age at transplant was 8 ± 4.7 years (range 1-20 yr). Of the 27 HCT patients, 59.3% had Medicaid and 40.7% had Private insurance at the time of transplant. Among the controls, 81.3% were covered by Medicaid insurance, 17.5% with Private insurance, and 1.3% self-pay. Using a conditional logistic regression model, we found insurance status to be a statistically significant factor in predicting whether a patient undergoes HCT. The model showed that those with Private Insurance are 2.96 (95% Confidence Interval: 1.02, 8.54) times more likely to undergo HCT compared to patients with Medicaid and self-pay. No other socioeconomic status variables were associated with receiving HCT.
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Sickle cell anaemia (SCA) has been associated with cognitive dysfunction. Increasing evidence suggests that some complications of SCA, such as kidney disease and venous thromboembolism, also affect those with sickle cell trait (SCT). Thus, SCT may not be a benign condition. Based on these findings, we hypothesized that SCT is a risk factor for cognitive function in African-Americans. We previously reported no association of SCT with cognitive impairment evaluated by a global screening test. Here we studied specific cognitive function measures.
Methods: We studied African-American adults aged 45 and older from a national prospective cohort study of 30,239 white and black Americans; the REGARDS study. Participants were enrolled in 2003-7 and followed for up to 10 years. We collected extensive baseline risk factor data, and administered a cognitive battery every 2 years including tests of learning and memory (Word List Learning (WLL), Word List Recall (WLR)), semantic fluency by the Animal Naming test, and phonemic fluency by the Letter F test. WLL is the sum of words learned over 3 trials of immediate recall of 10 words (score ranges 0-30 words). WLR is the sum of words recalled after intervening questions (range 0-10 words). The Animal Naming score is the number of animals a participant can name within 1-minute and the Letter F score is the number of words beginning with the letter F that a participant can say within 1-minute. Participants included in this analysis were African-Americans without SCA or prebaseline stroke, who had SCT genotyping. Participants with baseline cognitive impairment by a global screening test were excluded. Mixed models were employed to assess the association of SCT with repeated measures of each test, adjusted for risk factors. Censoring occurred at the time of a stroke, death or withdrawal from the study.
Results: There were 7,078 participants with at least 1 assessment of WLL and WLR who met inclusion criteria; their mean age was 63.4 years, 64% were women, and 517 had SCT. Those with SCT were more likely than those without to have hypertension (65% vs 60%; p=0.04), no alcohol use (75% vs 70%, p=0.03), and lower estimated glomerular filtration rate (eGFR) (86 vs 90 ml/min/1.73m2; p<0.0001). They were similar on other factors. The top panel of the figure shows that WLL and WLR changed little over time and there was no difference in scores by SCT status (adjusted p values shown). There were 7,296 participants included in the Animal Naming analysis and 5,946 for Letter F (differences due to delays in processing scores). The lower panel of the figure shows that performance on both tests worsened over time, with no difference by SCT status (adjusted p values shown).
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Sickle cell disease (SCD) is the most common inherited disease worldwide. Because favoring the risk of vaso-occlusive crises (VOC), SCD patients are banned from strenuous exercise. We hypothesized that a well-controlled moderate-intensity endurance exercise training (EET) program could improve SCD patients without provoking VOC.
Patients and Methods: We conducted a prospective, multicenter, controlled study with individually tailored Blood lactate-guided (BL) endurance training on a cycloergometer for 8 weeks in adult SCD patients. The primary end point was the submaximal incremental cardio-pulmonary exercise testing (CPET) at a BL concentration of 4 mmol.L-1. Secondary endpoints were: CPET at a BL 2.5 mmol/L and at the first lactic threshold (LT1), BL levels at given workload level (Female: 40W and Male: 60W), safety (pain, VOC and acute chest syndrome), biological and echocardiography parameters, pulmonary function test (PFT), 6-minute walk test (6MWT), quality of life (QoL) and muscle properties and vascularization (biopsy of vastus lateralis muscle).
Results: Forty homozygous SCD patients (33±10 years, 23 male) were included. Four patients (3 EET and 1 control) were lost to follow-up. Data of 33 patients (15 EET and 18 controls) were analyzed. EET and control patients were comparable at baseline with regard to CPET, clinical, biological, and resting cardiorespiratory parameters. EET patients presented a significant increase of CPET workload at BL4 (p=0.031), BL2.5 (p=0.003) and LT1 (p<0.0001) compared to the control group that remained unchanged. BL levels at a given level decreased significantly by 18% in the EET group compared to control group (p=0.01). Among the 40 randomized patients, 5 MAE occurred in the control group and 2 in the EET group. Quality of life improved for vitality (p=0.04) and physical activity (p=0.03) in the EET group compared to control group. Thigh biopsy showed in the EET group a significant increase of the proportion of oxidative type I fibers and of COX activity, paralleled by a significant increase in capillary density. No significant alterations were found in the control group. No change was found according to biological and echocardiography parameters, 6MWT and pulmonary function test.
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Acute vaso-occlusive pain episodes are the primary reason for hospitalization in sickle cell disease (SCD) and predict mortality in adults. Women with SCD have higher pain rates than men, particularly during their reproductive years. Studies of the temporal relationship between the onset of menstruation and acute vaso-occlusive pain have reached conflicting conclusions. Healthcare providers often do not recognize the temporal relationship between the onset of menstruation and acute vaso-occlusive pain, with the common perception that acute vaso-occlusive pain is synonymous with dysmenorrhea. In sequentially independent cross-sectional studies involving discovery and confirmatory cohorts, we tested the hypothesis that acute vaso-occlusive pain is associated with the onset of menstruation in women with SCD and is distinct from dysmenorrhea. Evidence to support our hypothesis was based on identifying four distinct groups: 1) women with dysmenorrhea without acute vaso-occlusive pain associated with menstruation, 2) women with acute vaso-occlusive pain associated with menstruation without dysmenorrhea, 3) women with both, and 4) women with neither.
Methods: Discovery cohort: In an initial cross-sectional study, we interviewed women in the outpatient and inpatient settings at Vanderbilt University and Wayne State University (Figure 1). After obtaining informed consent, we conducted self-administered surveys which included a validated questionnaire to define acute vaso-occlusive pain associated with menstruation and dysmenorrhea (Behav Res Ther 1975, 13(4):237-44). Acute vaso-occlusive pain associated with menstruation and dysmenorrhea were defined by temporal and frequency criteria so that participants could meet either or both criteria (Table 1). Associations of clinical and demographic variables with acute vaso-occlusive pain triggered by menstruation and dysmenorrhea were evaluated by the chi-square test and t-test, and then in a multivariable regression model. The proportions of women who met criteria for acute vaso-occlusive pain associated with menstruation and dysmenorrhea were determined. A p-value of 0.05 was considered significant for all analyses. Confirmatory cohort: In a subsequent cross-sectional study, we conducted an identical online questionnaire using select websites to validate our initial findings. Statistical analyses were identical to the discovery cohort.
Results: Discovery cohort: A total of 95 women were surveyed using face-to-face questionnaires. Baseline characteristics are summarized in Table 2. Twenty-eight women (29.5%) met defined criteria for acute vaso-occlusive pain associated with menstruation. Age (p=0.211) and genotype (p=0.343) were not associated with acute vaso-occlusive pain triggered by menstruation. Sixty-two women (65.3%) met criteria for dysmenorrhea. Importantly, among the 95 participants in the discovery cohort, 3% met criteria for acute vaso-occlusive pain associated with menstruation alone, in the absence of dysmenorrhea, while 26% met criteria for both acute vaso-occlusive pain associated with menstruation and dysmenorrhea.
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Pain is the most common symptom of sickle cell disease (SCD). Hematopoietic stem cell transplant (HSCT) is currently the only curative therapy for SCD; however, some patients continue to report pain requiring opioid treatment despite hematologic cure following successful HSCT. Knowledge of factors associated with continued pain and opioid use may help reduce post-HSCT pain-related morbidity. We analyzed data from a cohort of SCD patients who have been successfully treated by nonmyeloablative HLA-matched sibling allogeneic HSCT. Our goal was to investigate pre-HSCT factors that are associated with continued pain and opioid use at 12 months after a successful HSCT.
Methods: Detailed data on the clinical course, pain, opioid use, and laboratory values were collected from medical records at 3 months pre-HSCT and 12 months post-HSCT (n=35). Patient Reported Outcomes Measurement Information System (PROMIS) measures were available in a subgroup of these patients (n=20), also collected at the same time points. Patients with pre-HSCT pain were classified using Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks-American Pain Society Pain Taxonomy (AAPT) guidelines into one of three pain categories: 1. Chronic pain without contributory SCD complication; 2. Chronic pain explained by contributory SCD complication, eg. avascular necrosis; 3. Chronic pain with a mixed pain phenotype (eg. some pain explained by a contributory SCD complication but also pain occurring in unrelated sites). Patients who only experienced acute episodic pain were grouped separately (Episodic pain only).
Results: The median age of the cohort was 30.5 years (range: 16-65 years) and 21 (60%) patients were male. Pre-HSCT, all patients experienced intermittent episodes of pain. Forty-six% of the patients experienced acute episodic pain only, 26% also had chronic pain with a contributory SCD complication and 28% also had chronic pain without contributory SCD complication or a mixed pain phenotype. Post-HSCT, median pain-related admissions decreased significantly (from 3 admissions/year (range 0-24) pre-HSCT to 0 (range 0-3) post-HSCT; (p<0.001)). There were significant reductions in the prescription of both short- and long-acting opioids pre- vs post-HSCT (91% to 40% for short acting and 40% to 14% for long acting opioids; p<0.001). While 14 out of 35 (40%) reported pain at 12 months post-HSCT, examination of continued opioid use patterns across the AAPT groups showed that in the group of chronic pain patients without contributory SCD complications, 90% continued to use opioids to manage their pain whereas none of the patients in the episodic pain only group received opioids post-HSCT and for the group of patients with chronic pain related to a SCD complication, 50% stopped using opioids post-transplant. Analysis of PROMIS data, showed significant improvement in the subscales of Pain Intensity (p=0.03), Pain Impact (p=0.007), Satisfaction with Social Role (p= 0.03), and Physical Function (p= 0.004) following HSCT but no significant changes were seen for Fatigue (p=0.09), Anxiety, Depression or Sleep Disturbance (which may be explained by the small sample size not having enough variance). However, when comparing patients with persistent pain and opioid use without related SCD complications (n=6) versus those with resolved pain post-HSCT (n=9), pre-HSCT Anxiety ratings were significantly higher in the group with unexplainable, persistent pain (p=0.05). For those same groups, additional pre-HSCT factors that were associated with unexplainable, persistent pain post-HSCT were higher burden of pain as defined by higher median pain admissions/year (2 (0-10) vs. 5.5 (3-9); p=0.04); higher overall numerical pain rating on a 0-10 scale (2 (0-5) vs. 6 (5-7); p=0.02) and treatment with long acting opioids (0% vs. 86%; p<0.001).
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A Phase 3, double-blind, randomized, placebo-controlled trial of L-glutamine in 230 patients (ages 5-58) over 48 weeks was conducted at 31 centers in the United States. Twice daily oral administration of L-glutamine or placebo was based on body weight approximating 0.3 g/kg/dose. The primary endpoint was the number of sickle cell crises (SCCs) during 48 weeks of follow-up. The treatment effect measured was the difference of two median numbers of SCCs between two arms by week 48. The SCCs required treatment with I.V. narcotics/ketorolac at an emergency department or during hospitalization in patients with a history of ≥ 2 crisis from the previous year. Splenic sequestration, acute chest syndrome and priapism were also considered to be SCCs. Patients stabilized on hydroxyurea (HU) treatment for at least 3 months prior to study screening (66% in both arms of the study) remained on HU for the duration of the study. The primary analysis via a Cochran-Mantel-Haenszel (CMH) test statistic showed a highly significant treatment effect (p=0.005). There was a median of 3 crises for the L-glutamine treatment arm and 4 for the placebo arm (25% difference). There were no concerning adverse events from the treatment compared with the placebo arm. In this abstract, we reported the results from additional analyses of times to first and second crisis as well as cumulative recurrent events, which further demonstrated the clinically meaningful treatment effect of L-glutamine.
Methods: The Kaplan-Meier estimates are constructed with the data from the times to the first and second SCC for both arms. The corresponding estimates of the hazard ratios with confidence intervals and p-values are obtained to evaluate the relative merit of two groups. The 50% quartile (median) of the curve and the 95% confidence interval were reported by treatment. Furthermore, recurrent event time analysis was also performed using the Andersen-Gill procedure as well as the robust method by Lin, Wei, Yang and Ying to estimate the intensity rates.
Results: L-glutamine therapy significantly prolonged the time to first and the time to second SCCs. The median time to first crisis was delayed by 30 days (84 days vs. placebo 54 days; p=0.0152) and the median time to second crisis was delayed by 79 days (212 days vs. placebo 133 days; p=0.0260). Hazard ratios for the time to first and second crisis were similar (0.69 and 0.68 respectively), suggesting an approximately 30% hazard reduction from the treatment (Figures 1 and 2). Both cumulative recurrent event analyses models for SCCs yielded an intensity rate ratio of 0.75 with 95% confidence intervals based on the Andersen-Gill of (0.62, 0.90) and Lin, Wei, Yang and Ying of (0.55, 1.01), respectively (Figure 3). This suggested that the average cumulative crisis count was reduced by approximately 25% over the entire 48-week period. Cumulative event curve separation was clear by day 30 of treatment and was maintained over the 48-week study period.
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