Acute Pain Events Research Articles

Patient-reported pregnancy loss and maternal complications: Insights from the sickle cell disease implementation consortium.

Sickle cell disease (SCD) is associated with complications during pregnancy and can negatively influence maternal outcomes. Our study aimed to determine the prevalence and predictors of maternal morbidity among participants enrolled in an eight-site SCD Implementation Consortium (SCDIC) registry. We conducted a cross-sectional analysis of female registry participants, aged 15-45 years, with a confirmed diagnosis of SCD. Participants completed a survey of self-reported pregnancies and outcomes. Seven hundred and thirty-eight individuals had at least one pregnancy event, with 1076 live births. Twenty percent reported a pregnancy loss or fetal demise. Of the 1076 live births, 75% involved at least one complication. The most prevalent complications were pain crises (61.1%) and pregnancy requiring blood transfusion(s) (33.0%). Multiparous individuals with a prior occurrence of a complication in a previous pregnancy had higher odds of recurrence of the same complication in subsequent pregnancies (i.e., previous acute crisis was associated with subsequent acute pain events odds ratio [OR]: 3.13; 95% confidence interval [CI]: 2.06-4.76) and prior transfusion requiring another transfusion (OR: 3.22; 95% CI: 2.01-5.16). Individuals reported a high prevalence of pregnancy loss and maternal complications. Our findings underscore the importance of preconception counseling and early initiation of perinatal care in SCD.

Deep learning models for the prediction of acute postoperative pain in PACU for video‐assisted thoracoscopic surgery

BackgroundPostoperative pain is a prevalent symptom experienced by patients undergoing surgical procedures. This study aims to develop deep learning algorithms for predicting acute postoperative pain using both essential patient details and real-time vital sign data during surgery.MethodsThrough a retrospective observational approach, we utilized Graph Attention Networks (GAT) and graph Transformer Networks (GTN) deep learning algorithms to construct the DoseFormer model while incorporating an attention mechanism. This model employed patient information and intraoperative vital signs obtained during Video-assisted thoracoscopic surgery (VATS) surgery to anticipate postoperative pain. By categorizing the static and dynamic data, the DoseFormer model performed binary classification to predict the likelihood of postoperative acute pain.ResultsA total of 1758 patients were initially included, with 1552 patients after data cleaning. These patients were then divided into training set (n = 931) and testing set (n = 621). In the testing set, the DoseFormer model exhibited significantly higher AUROC (0.98) compared to classical machine learning algorithms. Furthermore, the DoseFormer model displayed a significantly higher F1 value (0.85) in comparison to other classical machine learning algorithms. Notably, the attending anesthesiologists' F1 values (attending: 0.49, fellow: 0.43, Resident: 0.16) were significantly lower than those of the DoseFormer model in predicting acute postoperative pain.ConclusionsDeep learning model can predict postoperative acute pain events based on patients' basic information and intraoperative vital signs.

Patients under Palliative Oncology Care

When very advanced or in a terminal stage, cancer causes acute painful events. Care applied to patients with active, progressive, and incurable diseases such as cancer must receive effective and broad relief of symptoms, whether physical, psychosocial or spiritual, which only increases the challenge.

The Optimal Threshold for Hemoglobin S Percent Level While Performing Regular Blood Transfusion Therapy to Prevent Severe Vaso-Occlusive Pain Events in Children with Sickle Cell Anemia: A Secondary Data Analysis of Participants in the SIT Trial

Introduction: Children with sickle cell disease (SCD) often experience frequent severe acute vaso-occlusive pain events, unresponsive to FDA-approved therapies (hydroxyurea, L-glutamine, crizanlizumab) to decrease the severe acute vaso-occlusive pain event incidence rate. The ASH guidelines for pain management recommend regular blood transfusion therapy after FDA-approved therapies have failed to decrease the high rate of severe acute vaso-occlusive pain events ( The Journal of Pediatrics, 139(6), 785-789). However, unlike regular blood transfusion therapy for primary and secondary stroke prevention, for which the goal hemoglobin S (Hb S) level is ≤ 30% , no optimal Hb S threshold has been established to attenuate the severe acute vaso-occlusive pain event incidence rate. We tested the hypothesis that among children receiving regular blood transfusion therapy with a goal to keep the mean hemoglobin S level < 30%, participants that achieved a mean Hb S level < 30% would have lower rates of severe acute vaso-occlusive pain events requiring hospitalization than children regularly transfused with mean Hb S level > 30%. Evidence to support our hypothesis would provide the first evidence-based guidelines for the optimal hemoglobin S threshold to decrease the acute vaso-occlusive pain event incidence rate in children with sickle cell anemia (HbSS). Methods: The SIT trial was a single-blind clinical trial( Blood Advances, 4(12), 2656-2701), where participants were children with sickle cell anemia randomly allocated to receive regular blood transfusion therapy (transfusion group) or standard care (observation group). Participants receiving regular blood transfusion therapy from the SIT Trial were included in the secondary analysis. Eligibility criteria include participants between 5 and 15 years of age, with no history of stroke, one or more silent cerebral infarcts on magnetic resonance imaging, and a neurologic examination showing no abnormalities. The transfusion therapy goal was to keep the maximum Hb S level < 30%. For the ancillary study, participants were included only in the transfusion arm of the trial. The primary endpoint of this ancillary study was the incidence rate of hospitalization for vaso-occlusive pain episodes among those receiving only regular blood transfusion therapy. We conducted a zero-inflated negative binomial regression analysis to determine the association between the incidence rate for severe acute vaso-occlusive pain events requiring hospitalization and independent covariates, including age at the time of random allocation, sex, and mean hemoglobin S level (< 30% and > 30%). Results: A total of 90 participants received regular blood transfusion therapy in the SIT trial. Among participants transfused, 53 and 37 individuals had a mean Hb S level of < 30% and > 30%, respectively. The median time on transfusions for the groups with Hb S levels of < 30% and > 30% was 2.9 years for both groups. Among the participants, 10.8% (4/37) who had a mean Hb S < 30% and 20.8% (11/53) of those with a mean Hb S > 30% experienced at least one hospitalization for a severe acute vaso-occlusive pain event. The mean hemoglobin S levels in the < 30% and > 30% groups were 25.4% and 37.5%, respectively. The mean hospital rates for severe acute vaso-occlusive pain events in the two groups < 30% and >30% were 9.4 (95% confidence interval 9.4 - 17.2 person-years) and 29.2 per 100 person-years (95% confidence interval, 21.0 - 39.5 person-years), respectively, P = 0.078. In the multivariable analysis, the incidence rate ratio for severe acute vaso-occlusive pain events showed that there was no statistical difference between those with a mean Hb S level in groups < 30% and > 30%, 0.65; P=0.43. Children with a higher baseline hemoglobin level were more likely to achieve a mean hemoglobin S level < 30%. Conclusion: In children with sickle cell anemia, receiving regular blood transfusion therapy with the goal of keeping the mean hemoglobin S level < 30%, achieving a mean hemoglobin S level > 30% was as effective as a mean hemoglobin S level < 30 % in decreasing the incidence rate of severe acute vaso-occlusive pain events requiring hospitalization. Further studies are warranted to identify reliable measures of the efficacy of regular blood transfusion therapy for the reduction of acute vaso-occlusive pain events.

Exploring Factors Linked to Home-Reported Acute Pain Events and Pain Crises in Sickle Cell Disease (SCD) through Flare Tracking in the Ascend Study

Introduction: Pain is a prominent symptom in sickle cell disease (SCD) and often broadly categorized as persistent chronic pain or more intense acute pain episodes compared to regular chronic pain experiences. Many research studies focus solely on pain events requiring healthcare utilization, neglecting those experienced at home, which may cloud the understanding of an individual's daily experience in managing their symptoms. Capturing home-reported evidence is crucial for comprehending SCD's impact on patients and potential effects of medical interventions. Objective: The objective of the Ascend Study was to collect individuals' experiences with pain events in SCD, employing a flexible, home-reported outcomes data collection methodology in Folia Health's mobile and web-based platform. Methods: The Advarra IRB-approved study recruited individuals with any genotype of SCD in the U.S., aged 13 and above, and caregivers of children aged 4 to 12. E-consent and data collection occurred through the Folia platform, where participants selected and tracked relevant symptoms (including, but not limited, to pain-specific symptoms) and treatments, along with health-related quality of life, over the course of 3 months per participant. Baseline severity scores were collected on a 1 to 10 Likert scale for symptoms that were pre-selected by participants at the start of the study. Participants also directly reported potential acute pain events and pain crises experienced in monthly surveys. Detailed flare tracking was set up for four symptom types (chronic pain, acute pain, pain crises, pain and discomfort), enabling structured follow-up questions on select pain flare events. Flare tracking was activated if participants reported a 2-point increase in severity compared to self-identified baselines or opted to track a pain symptom outside of their pre-selected routine. Overall pain burden was collected by participants who routinely tracked all of these various pain experiences, comprising the Ascend Study's home-reported pain hierarchy (Figure A). Results: 89% (n=59) of tracking participants reported experiencing a potential pain crisis for at least 1 month through monthly surveys. Analysis using the flare threshold applied to all pain symptoms tracked (sensitivity 77.5%; specificity 44.9%) identified 2,660 potential pain flare events. Among participants, 86% (n=57) experienced at least one flare event based on the flare threshold. On average, each participant had 24.9 flare days. Flare events identified by the threshold included 9 pain types tracked on a 1-10 Likert scale and 26 pain types tracked as binary “yes/no.” A total of 812 potential pain flare events reported by 46 participants prompted flare tracking follow-up questions (Table 1). Increases in chronic pain were more common than new types. 74% of these participants (n=34) opted to provide additional information through flare tracking in 282 pain flare events. Real-time flare tracking was reported in 85% of flare tracking events. From follow-up responses, most common classifications of pain were stabbing(188, 30.3%), pulsing or throbbing(144, 23.2%), and dull or aching(143, 23.0%). The back (155, 15.7%) and leg (268, 27.2%) were the most prevalent pain locations, with weather (177) and seasonal change (92) identified as potential triggers. Top flare descriptors included ‘can't do normal activities’ (84, 24.4%) and ‘not getting better with home pain meds’ (78, 22.7%). Conclusion: The Ascend Study provides detailed insights into SCD acute pain experiences, showing a high percentage of real-time flare tracking. Chronic pain flares were frequently reported, back and leg pain being the most prevalent locations, and seasonal changes identified as potential triggers. While the flare threshold analysis identified many potential pain flare events, the method's sensitivity might lead to lower specificity for pain flare events and the inclusion of potentially non-flare events. Findings provide valuable insights into the acute pain experiences of individuals with SCD, emphasizing the significance of capturing home-reported evidence to improve patient care and SCD therapies.

Opioid-free anesthesia reduces the severity of acute postoperative motion-induced pain and patient-controlled epidural analgesia-related adverse events in lung surgery: randomized clinical trial.

Opioids have been used as pain relievers for thousands of years. However, they may also cause undesirable side effects. We therefore performed this study to compare the effect of opioid-free anesthesia (OFA) versus opioid-sparing anesthesia (OSA) on postoperative pain and patient-controlled epidural analgesia (PCEA)-related events. This is a single center randomized clinical trial that was recruited patients aged from 18 to 70 years who received video-assisted lung surgery between October 2021 and February 2022. Participants were 1:1 randomly assigned to OFA or OSA. Patients in the OFA group received propofol, rocuronium, esmolol, lidocaine, and magnesium sulfate intravenously with epidural ropivacaine. Patients in the OSA group received propofol, rocuronium, remifentanil, and sufentanil intravenously with epidural hydromorphone and ropivacaine. A total number of 124 patients were randomly allocated to the OFA or OSA group. In the OFA group, the severity of pain during coughs on the first postoperative days (PODs; VAS score 1.88 ± 0.88 vs. 2.16 ± 1.1, p = 0.044) was significantly lower than that in the OSA group. The total ratio of PCEA-related adverse events in the OFA group [11 (19.6%) vs. 26 (47.3%), p = 0.003] was significantly lower than in the OSA group. OFA in patients who received video-assisted lung surgery led to lower severity of acute postoperative motion-induced pain and fewer PCEA-related adverse events on the first POD than in the patients in the OSA group. clinicaltrials.gov, identifier (NCT05063396).

In Phase 2 and Phase 3 Trials, Broadening the Definition of Acute Vaso-Occlusive Pain to Include at Least One Episode of Pain Requiring Nsaids, Opioids, or Both Treatments at Home within 30 Days of a Physician Visit

Introduction:Despite the high incidence of acute painful events in children and adults with SCD, there is a lack of consensus on the acute pain definition in controlled clinical trials. To address this limitation, we elected to have three definitions of acute vaso-occlusive pain based on the setting for the pain location: inpatient, outpatient, ED, or at home. Based on the results of the SPRING Trial, the primary stroke prevention trial in children with SCD conducted in Nigeria (The Lancet Haematol. 2022 Jan 1;9(1):e26-37), and the PISCES study (Annals of internal medicine. 2008 Jan 15;148(2):94-101), most acute pain events in low-middle and high-income countries occur at home. We tested the hypothesis that the majority of negative phase 2 and phase 3-controlled trials for SCD failed to consider acute pain events in all four settings. Methods: To identify the relevant Phase II and III trials with acute pain as an outcome, we conducted a literature review using the website clinicaltrials.gov with the following key terms: “Sickle Cell Disease,” and “Vaso-occlusive.”. Studies that were not Phase II or Phase III were excluded from our search. We identified Phase 2 or 3 SCD pain trials published between 2015 and 2023. Inclusion criteria: definitions in the clinicaltrials.gov trial page, protocol, or method section. An inclusive, consensus definition for vaso-occlusive pain was chosen from the SPRING Trial. This definition was compared to the acute vaso-occlusive pain definitions of both SCD Phase 2 and 3 trials, with vaso-occlusive pain as a primary or secondary outcome. Based on the SPRING Trial and the results of the PISCES study, we elected to have three definitions of acute vaso-occlusive pain: 1. inpatient uncomplicated pain that excludes a concomitant diagnosis of acute chest syndrome; 2. Pain that required either an inpatient or outpatient visit and opioid treatment; and 3. An acute pain event at home requiring NSAIDs, opioids, or both. Only uncomplicated pain events were included to avoid double counting participants who developed acute chest syndrome or strokes that may have preceded the vaso-occlusive pain event. Results: We identified 35 articles based on our criteria. Our study sample included 3 clinical trials that led to the FDA approval for therapy to prevent acute vaso-occlusive pain events (FDA-approved therapy trials). Among these 35 trials, 32 clinical trials did not provide any evidence of the therapeutic benefits of the experimental agent (negative controlled trials). The three randomized controlled trials that led to FDA approval for therapy to prevent acute pain were: Hydroxyurea, L-Glutamine, and Crizanlizumab. Hospitalization for pain was included in all three FDA-approved therapy trials and 34.4% (11/32) of negative controlled trials. The ED visits in the pain definition were included in all 3 FDA-approved therapy trials and 28.1% (9/32) of negative controlled trials. Outpatient visits in the pain definition were included in all 3 FDA-approved therapy trials and 21.9% (7/32) of negative controlled trials. Home pain episodes were included in none of the FDA-approved therapy trials and 9.4% (3/32) of negative controlled trials. Finally, 43.8% (14/32) negative controlled trials were excluded as they failed to define vaso-occlusive pain in their methods or definition section and 15.6% (5/32) negative controlled trials did not have a publication. Conclusion: Most controlled trials designed to evaluate the efficacy of new treatment did not include the setting where pain occurs most frequently, at home. For future therapeutic trials designed to address whether a new therapy decreases the incidence rate of acute pain, we recommend an assessment of pain in all 4 four settings (Hospitalization, ED, Outpatient, and Home).

Effects of Air Pollution on Respiratory Events and Pain Crises Among Children with Sickle Cell Disease in New York City

Introduction: Sickle cell disease (SCD) has the highest U.S. disease burden among Black and Hispanic populations, who more commonly live in urban areas with poor ambient air quality. The effect of air pollution exposure and social environmental factors on health outcomes in SCD have not been extensively studied, especially among children, and may further contribute to health disparities. Objectives: This study aims to examine the associations between air pollution exposure and acute respiratory and pain events and to determine whether neighborhood-level social disadvantage would modify their associations. Methods: We collected retrospective data on unscheduled outpatient visits, emergency department (ED) visits, and hospital admissions for respiratory events (i.e., respiratory tract infections, asthma exacerbation, acute chest syndrome) and vaso-occlusive pain crises requiring hospitalization (VOCs) for children with SCD in a tertiary care center in New York City (NYC) from 2015-2018. A total of 114 children with SCD (Table 1) were included in this study and had between 1-4 annual repeated measures of annual average air pollutants (i.e., black carbon (BC), fine particulate matter (PM 2.5), and nitrogen dioxide (NO 2)) with a total of 425 visits. Using home addresses, modeled data from the NYC Community Air Survey data were used to estimate street-level, annual average exposure to air pollution. The area deprivation index (ADI), a composite index of neighborhood-level social disadvantage, was dichotomized at the upper tertile (higher vs lower). Multivariable Poisson regression in generalized estimating equation (GEE) models were used to estimate relative risks (RR), after adjusting for potential covariates. Results: Overall, there were no significant associations between air pollution levels and acute respiratory and pain events among children with SCD. When stratified by ADI, increased exposure to PM 2.5 and NO 2, but not BC, was significantly associated with more frequent respiratory outpatient and ED visits among children residing in higher ADI neighborhoods (RR (95%CI)= 1.13 (1.00, 1.28) and 1.43 (1.01, 2.02) for PM 2.5 and NO 2, respectively, p<0.05 for all), but not among those in lower ADI neighborhoods (P-value for interaction=0.2 and 0.02 for PM 2.5 and NO 2, respectively) (Figure 1). Associations of air pollution with hospital admissions and VOCs were not observed for neither high ADI nor low ADI neighborhoods (p-value>0.05). Conclusions: Exposure to air pollutants increased respiratory complications among children living in deprived neighborhoods.

Impact of Vaso-Occlusive Crises on the Transcriptomes of Patients with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is an inherited, multisystem blood disorder that affects millions of people worldwide and is particularly common among those of African descent. Vaso-occlusive crises (VOCs) or acute pain events involving complex interactions among sickled erythrocytes, endothelial cells, leukocytes, and activated platelets are hallmark symptoms of SCD. Over time, episodic bouts of acute VOC may develop into chronic pain, defined as pain most days for 6 months. At present, there are no biomarkers that distinguish between acute and chronic pain. Here, we explore differences in gene expression during VOC events in a cohort of pediatric patients with SCD. The objective of this study was to examine transcriptome alterations in CD45+ cells of individuals with SCD during a VOC event compared with steady state (SS) in patients with or without chronic pain. Methods: Patients were aged <21 years, with HbSS or HbSβ 0 genotypes. Informed consent was obtained for all patients. CD45+ cell (lymphohematopoietic lineage) samples were collected from 158 patients with SCD under SS conditions (at the maximum tolerated dose of hydroxyurea; some patients were also on metformin) during a VOC event, and at a follow-up visit after a VOC. RNA sequencing (RNA-Seq) was performed using a 101-base pair, paired-end protocol run on the NovaSeq 6000 system. We applied supervised normalization of microarrays to adjust the normalized gene expression values for the effect of multiple covariates. ToppGene Suite was used for over-representation analysis (ORA; Chen et al. Nucleic Acid Res 2009). Analysis of differentially expressed genes was performed using limma software and gene set enrichment analysis using the Molecular Signature Database. Results: A summary of the study cohort is presented (Table). Most patients (98.7%) were on hydroxyurea. We collected RNA-Seq data from unpaired and paired samples at SS and during a VOC. After adjusting for age, sex, chronic pain status, and metformin status, analyses of RNA-Seq data showed upregulated genes linked to TNFα signaling via NFΚB, IL-6/JAK/STAT3 signaling, complement activation, and coagulation were enriched in CD45+ cells during VOCs compared with SS (Figure). Differentially expressed genes were also compared with whole blood transcriptome samples collected at baseline and during a VOC event as reported by Creary et al (Sci Rep 2020). Approximately 290 upregulated and 33 downregulated genes were shared in both studies. ORA analysis of the shared genes revealed upregulation of pathways such as neutrophil degranulation and complement activation during a VOC event. Analysis of samples from patients without chronic pain at SS indicated similar immune-related pathways, such as complement activation and interferon α response, were upregulated during a VOC event. In contrast, analysis of samples from patients reporting chronic pain revealed no significant differences in gene expression between a VOC event and SS. Conclusions: Samples collected during a VOC event showed significant changes in the transcriptome of CD45+ cells compared with SS in pediatric patients who had the most severe disease, or sickle cell anemia characterized by HbSS and HBSβ 0/+ genotypes, without a diagnosis of chronic pain, with multiple pathways altered by VOC. However, when VOC transcriptomes in patients with chronic pain were compared with SS, these pathways were not significantly altered. Our pediatric patient population had low rates of chronic pain; therefore, our sample size was limited. Additional analyses of SS and VOC transcriptomes, particularly in patients with chronic pain, will expand our understanding of the impact of VOC events on transcriptomes in individuals with and without chronic pain. This may lead to identification of quantitative biomarkers for a VOC, facilitating testing of new therapies for the treatment of pain in people with SCD.

Gastrointestinal symptoms, diagnostic evaluations, and abdominal pathology in children with sickle cell disease.

Children with sickle cell disease (SCD) frequently present with acute pain. The abdomen, a common site of acute SCD-related pain, may be present in a variety of gastrointestinal (GI) pathologies. Limited data exist on prevalence and workup of abdominal pain in patients with SCD during acute pain events. Determine prevalence of GI symptoms, GI-specific evaluation and risks of hospitalization in children with SCD presenting to the emergency department (ED) or hospitalized with abdominal pain. Retrospective study of children less than 21years presenting to the ED or hospitalized with pain in our center over 2years. Descriptive statistics were used to report clinical characteristics, frequency of GI symptoms, workup by age (<5 vs. ≥5years), and genotype (sickle cell anemia [SCA] vs. non-SCA). Logistic regression models were used to identify risks associated with hospitalization. A total of 1279 encounters in 378 patients were analyzed; 23% (n=291) encounters were associated with abdominal pain. More abdominal pain-associated hospitalizations occurred in older children, SCA, children with lower mean hemoglobin (8.7±1.9 vs. 9.6±1.6g/dL, p<.001) and higher mean white blood cell (WBC) count (14.9±6.6 vs. 13.2±5.3×103 /μL, p=.02). We identified that less than 50% of patients presenting to the ED with abdominal pain received a GI-specific evaluation. Children with SCD frequently present with abdominal pain and other GI symptoms, with limited GI evaluations performed. GI-specific evaluation may increase diagnosis of GI pathologies, rule out GI pathologies, and contribute to the limited knowledge of the abdomen as a primary site of SCD pain.

Pain "chronification": what is the problem with this model?

There appears to be an unwarranted focus on all chronic pain being a "chronification" of acute pain. Despite a plethora of studies on mechanisms to prevent this "chronification" following surgery, the positive effects have been minimal. An alternate model to explain chronic pain is presented. Research in PUBMED and accessing data from the HUNTpain examination study. Data from the HUNT pain examination study reveal that less than 25% of individuals with chronic pain in a general population can relate the onset to an acute event. Another theory explaining the origin of chronic pain is that of priming and the accumulation of events that can be predictors along a continuum before chronic pain is apparent. This theory is presented to refocus for better prevention and treatment of chronic pain. "Chronification" cannot explain all cases of chronic/persistent pain. The plastic changes in the pain processing system can be seen as a continuum where at some point where an acute pain event is only one of several possible tipping points on this continuum that changes potential pain to perceived pain.

Newborn Screening for Sickle Cell Disease Among Tribal Populations in the States of Gujarat and Madhya Pradesh in India: Evaluation and Outcome Over 6 Years.

Sickle cell disease (SCD) poses considerable public health problems in India. This study was undertaken to understand the clinical course of SCD among children identified during newborn screening programmes in Gujarat and Madhya Pradesh where the frequency of the HbS gene is high. A total of 8,916 newborn babies 8,411 from Gujarat and 505 from Madhya Pradesh were screened over 6 years (2010–2016) using HPLC and the diagnosis was confirmed by molecular analysis in a subset. A total of 128 babies (122 Gujarat, 6 Madhya Pradesh) were identified with sickle cell disease, of whom 87 (69 HbSS, 18 HbS-β thalassemia) from Gujarat were followed for 0.5–6.6 years. Acute painful events, severe anemia and fever with infections were the major complications and 23 babies required hospitalization. Severe to moderate clinical presentation was found in 13.8% babies with SCD whereas, 86.2% babies had a milder presentation. Presence of ameliorating factors (α-thalassemia and Xmn 1 polymorphism) did not have a discernible effect on the clinical severity. Parents of babies with SCD were educated and counseled for home care. Distribution of mobile phones to 44 families having babies with SCD was beneficial as it allowed regular contact with patients and their families. Genetic counseling to the affected families has increased the awareness and acceptance for prenatal diagnosis and 18 couples opted for prenatal diagnosis in subsequent pregnancies. SCD is not always mild among tribal groups in India. Therefore, facilities for early diagnosis and prophylactic treatment in the tertiary care centers should be made available. The difficulties in regular follow up of the babies in remote rural areas have also been highlighted.

Vitamin D Levels: Associations with Acute Pain Events and Self-Reported Pain in Children with Sickle Cell Disease

Background/Aims: Individuals with sickle cell disease (SCD) are at high risk for vitamin D deficiency due to dark skin color, limited physical activity, poor nutrition, and renal dysfunction. In smaller retrospective studies, vitamin D deficiency in SCD was associated with increased frequency of acute pain events and higher opioid use, however the impact of vitamin D deficiency on pain related patient reported outcomes has not been described . Supplementation with high dose vitamin D is shown to be associated with fewer pain days per week and higher physical activity scores in patients with chronic pain. Thus, the objective of our study was to evaluate relationship between vitamin D levels, acute health care utilization and self-reported pain among children with SCD. We hypothesized that vitamin D deficiency is associated with increase health care utilization for pain and patient-reported outcomes for pain.Methods: Patients with SCD (1 to 18 years of age), enrolled in Sickle Cell Clinical Research and Intervention Program (SCCRIP), at St. Jude Children's Research Hospital were included in the study (Hankins et.al., Pediatric Blood and Cancer, 2018). Demographic, clinical and laboratory data were extracted from SCCRIP database. Prospective pain event leading to a hospital visit was analyzed. We analyzed pain-related hospitalizations in two ways: the number of pain-related hospitalizations within 2 years prior to and after vitamin D measurement in a cross-sectional design and longitudinally. Generalized linear regression model was used to examine associations between vitamin D and cross-sectional pain events with adjusting for hydroxyurea use. Generalized linear mixed effect model was used to assess the associations between vitamin D and longitudinal pain events, with adjusting for SCD genotype, sex, age, hydroxyurea use and interaction between age and hydroxyurea use.Pediatric Quality of Life Inventory™ Sickle Cell Disease Module (PedsQL™ SCD) was used to measure pain and pain interference using 1) Pain and Hurt and 2) Pain Impact scales. PedsQL™ SCD assessments include a Likert response scale. Items are reverse -scored and transformed to a 0-100 scale where higher scores indicate better health related quality of life in that scale. Two sample t-test or Wilcoxon rank sum test was used to compare mean scores between the two groups.Results: A total of 799 patients (females, n=398; males, n=401) were included in the study. Mean age (Standard Deviation [SD]), range at time of first vitamin D measurement for entire cohort was 8.7 (4.7), (0.8-18 years). Mean (SD) initial vitamin D level for entire cohort was 19.0 (9.4) ng/dl. Mean (SD) number of pain-related hospitalizations within two years of first vitamin D measurement was higher in the vitamin D deficient group as compared to non deficient group [0.81(1.97) vs 0.66 (1.2), (p=0.0034)]. Longitudinal data analyses showed vitamin D deficiency was associated with increased number of pain related hospitalizations (p=0.0091), after adjusting for covariates listed above (Figure 1a).Mean (SD) scores for Pain and Hurt in vitamin D deficient versus non deficient group were [74.5.7(18.2) versus 83.5(15.6), p < 0.001]. Mean (SD) scores for Pain Impact in vitamin D deficient group as compared to non deficient group were [(66.7 (22.7) versus 75.5 (22.3), p <0.001] (Figure 1b)Conclusion: Results indicated that low vitamin D levels predicted higher frequency of painful events leading to a hospital visit and were associated with higher prevalence of self-reported pain and pain interference. Further studies evaluating mechanisms by which vitamin D influences sickle cell pain are warranted and larger controlled trials can help evaluate the therapeutic efficacy of vitamin D for sickle cell pain. [Display omitted] DisclosuresHankins: UpToDate: Consultancy; Bluebird Bio: Consultancy; Vindico Medical Education: Consultancy; Global Blood Therapeutics: Consultancy.

The association of gender and persistent opioid use following an acute pain event: A retrospective population based study of renal colic

This study aims to explore gender-related differences in persistent opioid use following an acute pain episode and evaluate potential explanatory variables. This retrospective population-based study using administrative databases included all opioid-naïve patients in Ontario with renal colic between 2013 and 2017. The primary outcome was to assess any association between persistent opioid use at 3-6 months by gender. Key confounding covariates and explanatory variables examined included both care- and patient-related factors, specifically past evidence of mental health diagnoses. The dataset of 64,240 males and 37,656 females demonstrated that 8.7% of males and 9.6% of females had evidence of persistent opioid use 3-6 months after presentation (OR 1.11, 95% CI 1.05, 1.17). Females had a higher incidence of mental health services utilization [44.5% vs 29.6% (p<0.001)] and were more likely to be on a provincial disability program [5.1% vs 3.8% (p<0.001)]. Age, income quintile, mental health diagnoses and dose of opioid prescribed were associated with the primary outcome in both genders. On adjusted analysis for multiple confounding and explanatory variables, females were still more likely than males to demonstrate persistent opioid use (OR 1.07, 95% CI 1.01, 1.13) with even more pronounced associations at 1-2 years. After controlling for key covariates, females are at slightly higher risk of demonstrating long term opioid use following an episode of renal colic. Evidence of prior mental health service utilization and acute colic care did not appear to significantly explain these observations.

EDITORIAL COMMENT

When the COVID-19 fog settled on our country the Opioid Epidemic was slowly responding to several public health measures: physicians had demonstrably slowed opioid prescribing for acute pain events, regulations on prescribing buprenorphine had eased, and many states had rightly begun to tout their successes. Then the virus changed everything.

Autonomous nervous system regulation of pain in children with cerebral palsy

ABSTRACT Aim: Children with cerebral palsy (CP) have increased pain sensitivity and recurrent pain episodes; however, pain is underreported in children with intellectual impairment. Cardiac autonomic regulation is imbalanced in chronic pain conditions and neurological disorders. This study aims at exploring the autonomous nervous system regulation of pain in children with CP compared with typically developing peers (TDP).Method: Heart rate variability (HRV) was recorded during 24 hours in 26 children with CP and 26 TDP, and examined offline at baseline (sleeping, seated rest) and during spontaneous pain events. Pain and fatigue, HRV indices (linear indices on time – IBI, SDNN, RMSSD – and frequency domains – high, low, and very low frequency – and non-linear indices – Hurst coefficient and multiscale entropy) were computed.Results: Children with CP showed comparable HRV during daily conditions and similar reductions after pain events than their TDP, regardless of their level of intellectual impairment. Interpretation: Children with CP have an intact autonomic regulation in acute pain events. HRV could be an accurate pain biomarker in children with CP and intellectual disability. What this paper adds: Autonomic regulation in acute pain is efficient in children with cerebral palsy. Heart rate variability indices can be reliable pain biomarkers in intellectual impairment.

Healthcare Utilization Among Children and Adolescents with Sickle Cell Disease during the COVID-19 Pandemic

BackgroundEarly experience with the COVID-19 pandemic showed disproportionately high morbidity and mortality among individuals with certain chronic medical conditions. Individuals with sickle cell disease (SCD) are at high risk for pulmonary and other complications including acute chest syndrome (ACS) and have high rates of hospitalization from other viral respiratory infections, raising concern that COVID-19 would be associated with higher morbidity, mortality and health care utilization among those with SCD. Public health interventions such as social distancing, avoidance of large group activities, and widespread use of masks have been shown to reduce the transmission of COVID-19 in the general population but have been inconsistently implemented. In Georgia, COVID-19 restrictions, including school closures, were implemented in mid-March, and on-site school instruction was replaced by virtual instruction for the remainder of the school year. At our institution, most routine, non-urgent outpatient clinic visits were cancelled or postponed from mid-March through May in order to minimize COVID-19 exposure risk. Efforts to initiate the use of telemedicine as an alternative to in-person office visits were rapidly instituted. We hypothesized that adherence to public health restrictions, especially sheltering in place, would be high among patients and families with SCD, and sought to measure the impact of COVID pandemic on healthcare utilization in children and adolescents with SCD in the Atlanta area.MethodsThe SCD Program at Children's Healthcare of Atlanta (CHOA) provides comprehensive outpatient, emergency and inpatient services at 3 locations in metropolitan Atlanta. CHOA's Sickle Cell Clinical Database (SCCD) contains prospectively collected demographic, diagnostic, treatment and other clinical information on all patients with SCD beginning in 2010, including all outpatient clinic, emergency department (ED) and inpatient hospital utilization. To assess the impact of COVID-19 on healthcare utilization, we tracked clinic, ED and inpatient utilization for the 4-month period (March through June) 2020 compared with the same 4-month period in 2018 and 2019.ResultsThe figure shows utilization patterns for each four-month period from 2018-2020. As expected, face to face outpatient clinic visits fell dramatically from February to April 2020 (-25% in March, -64% in April) and then returned to pre-COVID levels by June. The addition of telemedicine visits raised total outpatient visits in June 2020 to above pre-COVID levels. Total utilization during the 4-month period in 2020 were compared to the mean for the same periods in 2018 and 2019. Face to face clinic visits decreased from 2971.5 to 2023 (-32%), ED visits from 1,217 to 687 (-44%), and total inpatient admissions from 699 to 410 (-41%). Admissions with a primary discharge diagnosis of pain decreased from a mean of 407 in 2018-2019 to 173 (-57%), fever/infection from 67.5 to 40 (-41%), and ACS from 101 to 75 (-26%). Patients with chronic pain and/or history of high utilization (>5 admissions in a given year) showed decreases in utilization similar to all other patients.SummaryThese data describe the significant changes in utilization among pediatric patients with SCD during the COVID-19 pandemic. Face to face outpatient clinic visits decreased during March and April but returned to pre-COVID levels in June. Unexpectedly, ED and inpatient hospital utilization for acute illness decreased dramatically through April and remained low through June. In March there was a significant decrease in the clinic setting due to a large number of cancelled or rescheduled outpatient visits, despite many being rescheduled as telemedicine visits. However, the largest unexpected decrease was seen in emergency department visits and hospitalizations for acute events, specifically fever and pain events. It is also important to note the decreased utilization of patients with chronic pain who are typically high utilizers. During clinic encounters, families mentioned that less stress from school, reduced respiratory infections, and better medication adherence with parents at home, were possible contributors to reduced sickle cell symptoms while sheltering in place. These observations will guide the development of a patient survey with the goal of obtaining qualitative data to explain the reasons for decreased utilization during the pandemic.FigureDisclosuresLane:FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Hydroxyurea to Reduce Stroke Risk in Tanzanian Children with Sickle Cell Anemia

Introduction: Sickle cell anemia (SCA) is highly prevalent in sub-Saharan Africa with &amp;gt;300,000 annual births, and substantial morbidity and mortality due to limited resources. The burden of stroke in this population is of particular concern, given the devastating clinical and neurocognitive sequelae of these events. Hydroxyurea, a potent disease modifying therapy for SCA, is safe and feasible for low-resource and malarial endemic countries within sub-Saharan Africa and when used at maximum tolerated dose (MTD), decreases the incidence of acute painful vaso-occlusive events, infections, malaria, transfusions, hospitalizations, and death. Whether hydroxyurea can prevent primary stroke in SCA within Africa has not yet been determined, due in part to lack of stroke screening programs using transcranial Doppler (TCD) ultrasonography. If effective, hydroxyurea would have even more therapeutic benefits for children with SCA, particularly in settings where blood is not available, affordable, or safe. We designed the Stroke Prevention with Hydroxyurea Enabled through Research and Education (SPHERE) trial to determine the stroke risk among Tanzanian children using TCD screening and to investigate the effects of hydroxyurea to reduce that risk. Methods: The SPHERE trial (NCT03948867) is a single center prospective phase 2 open-label screening and treatment pilot study at Bugando Medical Centre, a teaching and referral hospital in Mwanza, Tanzania. Children 2-16 years old with SCA consented to TCD screening by locally trained and certified examiners; recent febrile illness, red cell transfusion, or hospitalization were temporary exclusions. Study participants with maximum Time-Averaged Mean Velocity (TAMV) on TCD exam categorized as conditional (170-199 cm/sec) or abnormal (≥200 cm/sec) are offered hydroxyurea with escalation to MTD, while those with normal TCD screening exams will be rescreened annually. Hydroxyurea is initiated at ~20 mg/kg/day using 500 mg capsules and a weekly dosing calculator, then escalated every 8 weeks by 5 mg/kg/day up to 35 mg/kg/day. Children on hydroxyurea are seen monthly during dose escalation and every 3 months after reaching MTD. The primary endpoint is change in TCD velocity after 12 months of hydroxyurea therapy. Secondary endpoints include changes in splenic volume and filtrative function; change in renal function; incidence of infection, especially malaria; hydroxyurea pharmacokinetics; and genetic modifiers of disease including pharmacogenomics. Results: From April 2019 to April 2020, a total of 202 children underwent TCD screening, exceeding the projected enrollment pace and goal (Figure). The average age (mean ± SD) at enrollment was 6.8 ± 3.5 years, and 53% were female. A majority had previous dactylitis (75%), painful vaso-occlusive episode (93%), blood transfusion (68%), and malaria (89%). Recurrent hospitalization was common with 30% having &amp;gt;5 previous hospitalizations. Only 4% had previously used hydroxyurea. Baseline labs included hemoglobin = 7.8 ± 1.3 g/dL, HbF = 9.3 ± 5.4 %, and ANC = 5.5 ± 2.4 x 109/L. Baseline assessment revealed a palpable spleen in 46 children (23%), and most of these (29) were ≥5 cm below the costal margin. Abdominal ultrasonography documented splenic tissue in 91% of children with an average volume of 101 ± 123 mL (range 8-1045). TCD examinations were performed in all children at enrollment with average TAMV of 148 ± 27 cm/sec [median 144, IQR 130-169 cm/sec] with 76% normal, 21% conditional, 2% abnormal, and 1% inadequate exams. Of 47 children eligible for hydroxyurea for elevated TCD velocities, 45 successfully initiated treatment, while 1 lived too far away for regular visits, and 1 had low blood counts from acute splenic sequestration and died before initiating study treatment. Conclusion: Children with SCA in Tanzania have a high risk for primary stroke. Identification of elevated TCD velocities through screening by local trained certified examiners, coupled with initiation of hydroxyurea treatment with dose escalation to MTD, offers a feasible and affordable means by which to lower TCD velocities and reduce primary stroke risk. Now fully enrolled, SPHERE has built local clinical capacity, research infrastructure and high-quality TCD screening, and will prospectively determine the benefits of hydroxyurea for stroke prevention, as a prelude for expanding hydroxyurea access for children with SCA in Tanzania. Figure Disclosures No relevant conflicts of interest to declare.

Outpatient pain clinic and intranasal fentanyl to improve sickle cell disease outcomes.

Acute pain events are a leading complication for sickle cell patients. In an attempt to improve pain outcomes, we developed an outpatient pain clinic, and included intranasal fentanyl in the opioid emergency department (ED) pain order set. We evaluated admission rates and opioid administration for patients that attended both the outpatient pain clinic and ED within a 3-month period. We recorded the admission rate, IV morphine equivalents, and time from triage for each opioid order and administration from both an outpatient pain clinic and ED visit within a 3-month period for an individual pediatric patient with sickle cell disease. Thirty patients received acute pain management in both settings. We identified a significant reduction in hospital admission when patients received care in the pain clinic as compared to the ED (17% vs 43%, P=.02). Additionally, outpatient pain clinic patients received significantly less IV morphine equivalents than patients received in the ED (5.6 vs 10.6 IV morphine equivalents, P<.0001). In the ED, intranasal fentanyl was administered in a significantly shorter time than patients ordered intravenous opioid (43 vs 75min, P=.02). The mean time to receiving an opioid in the outpatient pain clinic was 57min. The use of an outpatient pain clinic can reduce admission rates as compared to the ED. The use of intranasal fentanyl reduced the time to first opioid administration in the ED. Patient-centered research or quality improvement projects should continue to focus on novel approaches to acute pain event management.

Short-term safety and beneficial effects of hydroxyurea therapy in children with sickle cell disease

Introduction: Worldwide, sickle cell disease (SCD) is the most common hemoglobinopathy among which SS pattern is more common. Although hydroxyurea (HU) is approved by the Food and Drug Administration for the treatment of recurrent moderate-to-severe painful crises in pediatric sickle cell anemia, there is a fear of toxicities. Objectives: The objectives of the study were to evaluate the short-term safety and beneficial effects of low-dose HU therapy in SCD (SS pattern) children. Materials and Methods: This prospective cohort study enrolled 40 cases of severe SCD and started HU in a fixed dose of 10 mg/kg/day. During follow-up, cases were evaluated for compliance of HU, its toxic effects and adverse events from their histories, clinical examinations, and laboratory parameters. Furthermore, beneficial effects of HU therapy were evaluated by assessing blood transfusion rate, frequency of painful events, strokes, acute chest syndrome, avascular necrosis of femur, and estimation of hemoglobin F (HbF) level after 2 years of therapy. HU was discontinued temporarily if any toxicity or minor adverse drug events occurred during therapy and was restarted at the same dose after normalization of deranged laboratory parameters. Results: The clinical adverse drug events seen were nausea (8.33%), diarrhea (2.78%), and hematuria (2.78%). The most common hematological toxicity was anemia and thrombocytopenia. Renal and hepatic toxicities were transient in nature. The mean acute painful events and blood transfusion rate reduced significantly on HU therapy. It increased Hb and HbF level significantly in SCD children. Conclusion: HU is a safe drug without significant toxicity or adverse events in a dose of 10 mg/kg/day for short duration and it is beneficial in SCD (SS pattern) children in reducing acute painful events and decrease blood transfusion rate.