Acute Pain Events Research Articles

Impact of a Pediatric Sickle Cell Outpatient Pain Clinic on Health Outcomes

Over a one-year period at our institution, we identified over 350 emergency department (ED) visits for acute sickle cell pain, with 100 of these acute pain events resulting in hospital admission. While the NIH SCD Management guidelines recommend rapid initiation of analgesia, achieving this metric is challenging in a busy ED setting. Our personal challenge in meeting this rapid analgesic recommendation in our ED prompted our decision to develop an outpatient pain clinic aimed to reduce the time to initial opioid administration and decrease the hospital admission rate for acute pain events. In addition to opioids, relaxation training delivered via virtual reality (VR) is a distraction technique shown to alleviate the pain and anxiety associated with acute and chronic pain. We hypothesized that children and adolescents with SCD presenting with acute pain to our outpatient pain clinic would receive quicker pain management and have a lower rate of admission. In addition, we tested the hypothesis that virtual reality delivered relaxation training would be acceptable in the acute pain setting. Methods. We compared SCD pain outcomes for patients evaluated in the outpatient pain clinic versus the ED at Children's of Alabama. We abstracted the exact times for triage, time the first dose of NSAID and opioid were ordered and time the first NSAID and opioids were administered from the electronic medical records to determine the time to first opioid from triage for all outpatient pain clinic visits and the most recent ED visit. The dose of NSAID (mg) and opioid (mg/kg) was recorded. The administration and timing of repeated opioid dosing, total time receiving care, and hospitalization were recorded. VR was offered to the patients that presented to the outpatient pain clinic but was not offered to any ED patient. We analyzed differences between all encounters in the pain clinic and ED using t-test for continuous variables and Fisher's exact for categorical outcomes. We then performed a matched-pair analysis to account for repeat patients using only the first pain clinic visit and most recent ED visit using a Wilcoxon Signed Rank test to account for possible non-normal distribution in this small study. Results. We identified 21 patients presenting to the outpatient pain clinic accounting for 27 pain clinic visits. Fifteen patients have a clinical diagnosis of HbSS, 3 with HbSB0 thalassemia, and 6 with HbSC. Only two (7%) of the 27 pain clinic visits resulted in an admission for further pain management as compared to 6 (29%) of the 21 ED visits for pain (p=0.05). Among all visits, patients seen in the pain clinic had a significantly shorter time to first dose of opioid order than patients seen in the ED (33 vs 50 minutes, p=0.05). The time from triage to discharge disposition was non-significantly shorter in the pain clinic (182 vs 232 minutes, p=0.09). In the pain clinic, oral opioids were the initial treatment in 7 of 27 encounters as compared to 1 of the 21 ED visits (p=0.06). VR was administered to 19 of the 27 outpatient pain clinic encounters. The use of VR in the outpatient clinic did not impact time to first opioid order (34 minutes with VR vs 28 minutes without VR, p=0.5). Additionally, VR did not change time to discharge disposition (180 with VR vs 187 minutes without VR, p=0.85). Using a matched pair analysis to compare the first pain clinic encounter to the most recent ED visit (within 6 months of the pain clinic visit) for 13 patients, we identified a significant reduction in total IV morphine milligram equivalents received (5.3 vs 7.8mg, p=0.007) and a non-significant shorter time to first opioid (34 vs 50 minutes, p=0.08) and time to final disposition (177 vs 299 minutes, p=0.18). Discussion: An outpatient sickle cell pain clinic was associated with a shorter time to first opioid order, lower total IV morphine milligram equivalents administered, and lower admission rate for pain events. Patients were accepting of VR relaxation training techniques and this intervention did not prolong time to first opioid order. Disclosures Howard: Novartis: Consultancy. Lebensburger:Pfizer: Research Funding; Novartis: Consultancy.

Analysis of the Eligibility of Patients with Sickle Cell Disease for Palliative Care

Background: Palliative care (PC) is an approach that improves the quality of life of patients facing problems associated with any disease that leads to multiple or hard to manage symptoms, through the prevention and relief of suffering by early identification and impeccable assessment of physical, psychosocial and spiritual problems. Sickle cell diseases (SCD) consist of a group of congenital diseases characterized by the presence of the sickle hemoglobin (HbS), which can polymerize and predispose to hemolytic and ischemic events. In addition to the acute pain events, sometimes recurrent and hard to control, lesions in target organs commonly occur, leading to multiple comorbidities and serious decrease in quality of life. Aims: To evaluate clinical and demographic factors that could influence physical, psychosocial and spiritual symptom burden and confer eligibility criteria to PC in a group of SCD patients. Methods: Clinical and demographic data of SCD patients were collected by interviews using a standardized questionnaire: diagnosis, time from diagnosis, number of comorbidities and of medical specialties on regular follow up, infectious episodes, need for seeking the emergency and for hospitalization during the last 12 months, delirium events, wounds, dysphagia, recurrent falls, adverse events to medication, quality of communication with the medical team, fears regarding the disease and its complications, religious support, age, gender, monthly household income (MI), level of schooling (SCH) and profession. Specific PC scores were also applied: Edmonton Symptom Assessment Scale (ESAS) and Palliative Performance Scale (PPS). Statistical univariate and multivariate analysis were performed. P value <0.05 was considered statistically significant. This research was approved by the Institutional and National Review Board; written informed consent was obtained from all subjects. Results: Fifty-one patients were evaluated (SS, n=34; SC, n=11; SB+, n=3; SB0, n=3), with a median of age of 40 years (18-69). SB0 patients were considered in the SS subgroup for statistical analysis. According to ESAS, pain scores were worse for patients with a higher age (p=0.0039), higher number of children (p=0.0228), for individuals that had completed only primary school versus patients who received more education (p=0.0293), and for the subjects on follow up with three or more medical specialties (p=0.0411). ESAS evaluation for tiredness revealed worse scores for the patients that had no formal occupation versus those who actively work (p=0.0275). ESAS assessment for depression was worse in patients that had a lower MI (p=0.0080), lower SCH (p=0.0585) and for those who had been to emergency services three or more times during the last year (p=0.0290). ESAS for appetite scored worse for older patients (p=0.0165), for those with a lower MI (p=0.0105) and for the individuals with a higher number of comorbidities (p=0.0018). Regarding shortness of breath, ESAS was poorer for older patients (p=0.0330), for those with a lower MI (p=0.0009), for the subjects in follow up with three or more medical specialties (p=0.0064) and for the patients with lower SCH (p=0.0413). ESAS for best wellbeing was worse for the patients with a lower MI (p=0.0425) and for those with lower SCH (p=0.0314). Due to the low incidence of the following symptoms, no differences were observed between groups for ESAS evaluation of nausea, anxiety and drowsiness. PPS score was significantly better for married individuals (p=0.0490) and for those with higher MI (p=0.0121). Finally, patients with no formal occupation showed a significant higher risk of going to the emergency within twelve months (OR=14.286, CI 95% 1.475-142.857, p=0.0217). Conclusions: This study strongly indicated that SCD patients live with chronic limiting symptoms that significantly impair their quality of life, which make them a group eligible for PC. The results showed that age and a higher number of comorbidities significantly impact symptom burden. Importantly, social and economic factors, in particular a lower monthly household income and a worse level of schooling have a major adverse impact on palliative scores. These data reinforce the negative impact of social inequality in this underprivileged group of patients and the need of facing this problem when seeking global patient care. Disclosures No relevant conflicts of interest to declare.

Barriers to the Use of Endari™ in an Urban Adult Sickle Cell Center

Background In 2017, the US Food and Drug Administration (FDA) approved Endari (L-glutamine oral powder) for patients age five years and older with sickle cell disease (SCD) to reduce sickle cell-related acute pain events and hospitalizations1. This was applauded as the first medication approval for SCD in almost 20 years, following Hydroxyurea (HU) in 1998. We report our experience with barriers to accessibility to a new medication such as Endari, and patients' adherence in adults with SCD in an urban adult sickle cell center. Methods After prospectively establishing internal guidelines for the use of Endari, adult patients with SCD seen in clinic at a large urban adult SCD center were prescribed Endari via a local specialty pharmacy, over a 14 month period. Upon return to clinic, patients were asked about barriers to obtaining the medication and adherence to the twice a day dosing. Adherence was also evaluated by calculating the mean possession ratio (MPR) utilizing pharmacy records. Results 111 patients with SCD (57% females) were prescribed Endari over a 14 month period (Table 1): 83% with severe disease genotypes (Hb SS/Sβ0), 17% with "milder" genotypes (Hb SC/Sβ+). Mean age was 36 years old. 74% of patients were on concomitant HU and 1% on chronic transfusions (>6 months). At the end of the 14 month period, 21 patients (19%) were actively taking Endari, 47 (42%) had discontinued it, 39 (35%) never filled the prescription, and 4 (4%) had received but never initiated therapy. Of the 39 who never filled the initial prescription, barriers included denial of prior authorizations (38% of patients), high deductibles (21%), and inability of pharmacy to contact patient after approval was obtained (23%) (Table 2). Reasons for discontinuing Endari included poor adherence (36%), as defined by patients who did not refill after the initial/subsequent prescriptions (mean refill 1.79 times) and/or missed follow up appointments, side effects (13%), no perceived benefit (4%), and pregnancy/breastfeeding (4%) (Table 3). Average MPR for the 21 patients that are still taking Endari is 0.73, similar to the adherence reported in the landmark phase III trial (77.4%)1. Discussion This is the first study that addresses both acceptance of a new medication by the sickle cell population and the barriers to obtaining it. We identified significant barriers to the initiation of Endari in our urban adult SCD patient population and a high rate of self-discontinuation. Patients who discontinued Endari, did so after a median of 47 days after the initial prescription. The most common reasons for not initiating therapy, present in ~ 70% of the cases, were insurance-related issues, such as prior authorization denial or high deductible/co-pays. In 30% of the cases patients were not reachable or had other issues for not filling it, despite obtaining prior authorization, which may indicate a lack of interest on their part. A small number of patients (6) reported discontinuing due to side effects. After 14 months, only 21/111, ~20% of the original cohort of patients prescribed Endari, reported taking it. The MPR of the patients that were taking the medication was 0.73, similar to the adherence in the Endari study (77.4%)1. Prospective studies are needed to confirm if this pattern is reproducible in other patients' populations across the country and to investigate whether the introduction of a new drug affects adherence to HU. As experienced with HU, several years elapsed from initial FDA approval to its being more accepted and widely used, and adherence remains sub-optimal. From our report, it is critical to evaluate and mitigate barriers to initiation and adherence to Endari, to ensure it is available to and accepted by the patient population it gained approval and was intended for. 1. N Engl J Med.2018 Jul 19;379(3):226-235 Disclosures Ogu: Vertex Pharmaceuticals: Consultancy. Minniti:Doris Duke Foundation: Research Funding.

Chronic pain persists in adults with sickle cell disease despite regular red cell transfusions

BackgroundPain affects over 50% of adults with sickle cell disease (SCD), and this pain is largely managed outside of the hospital. While chronic transfusion therapy is used to decrease the rate of acute pain events in patients with SCD, less is known about its impact on the day-to-day experience of pain. To address this knowledge gap, we provided pain diaries to patients with SCD receiving chronic transfusion. Patients and MethodsA convenience sample of chronically-transfused adults with SCD successfully completed a diary over the course of at least 2 transfusion events. Patients receiving simple transfusions and red cell exchanges were included. Pain was rated on a scale of 0 to 10 each day, and patient laboratory values, co-morbidities, and hospital utilization were also obtained using the electronic medical record. The mean pain scores pre- and post-transfusion were evaluated using both a random effects-expectation maximization regression tree analysis and a generalized linear mixed regression model. ResultsTen subjects (63%) in this cohort were defined as having chronic pain, while the remaining four (27%) subjects had episodic pain. Despite chronic transfusion and a suppressed HbS% (22.5% (16.5-25.9)), 10 patients (63%) continued to report nearly daily pain, and on almost 70% of diary days, the pain was significant (≥5/10). When the relationship between HbS% and reported pain intensity was examined, no association was found. DiscussionThese results suggest that, even with regular transfusions and a low HbS%, daily pain persists in many adults with SCD.

Children and adolescents with sickle cell disease have worse cold and mechanical hypersensitivity during acute painful events.

Sickle cell disease (SCD) pain associates with cold temperature and touch. Patients and murine models with SCD have baseline thermal and mechanical pain. In SCD mice, the baseline hypersensitivity is exacerbated by experimental vaso-occlusive crises. We hypothesized that patients with SCD will similarly experience increased hypersensitivity to thermal and mechanical stimuli during acute painful events compared with baseline health. We conducted a prospective study of 24 patients with SCD aged 7 to 19 years. Patients underwent quantitative sensory testing to thermal (cold/heat) and mechanical stimuli on the thenar eminence of the nondominant hand (glabrous skin) and the lateral dorsum of the foot (hairy skin) during baseline health and within 48 hours of hospitalization for acute pain. Primary outcomes were changes in: (1) cold pain threshold (°C), (2) heat pain threshold (°C), and (3) mechanical pain threshold (g). Median age was 10.5 (interquartile range [IQR] 9-14.8) years, 67% were females, and 92% were on hydroxyurea. Patients with SCD had increased cold pain sensitivity in the hand during hospitalization compared with baseline (25.2°C [IQR 18.4-27.5°C] vs 21.3°C [IQR 4.9-26.2°C]; P = 0.011) and increased mechanical pain sensitivity in the foot during hospitalization (0.32 g [IQR 0.09-1.1 g] vs 1.7 g [IQR 0.4-8.3 g]; P = 0.003). There were no differences in heat pain sensitivity. The increased cold (P = 0.02) and mechanical (P = 0.0016) pain sensitivity during hospitalization persisted after adjusting for age, sex, hydroxyurea use, opioid consumption, and numeric pain score. Thus, cold and mechanical pain is significantly worse during an acute SCD painful event as compared to baseline health in patients with SCD.

Sickle cell disease.

Sickle cell disease (SCD) is a group of inherited disorders caused by mutations in HBB, which encodes haemoglobin subunit β. The incidence is estimated to be between 300,000 and 400,000 neonates globally each year, the majority in sub-Saharan Africa. Haemoglobin molecules that include mutant sickle β-globin subunits can polymerize; erythrocytes that contain mostly haemoglobin polymers assume a sickled form and are prone to haemolysis. Other pathophysiological mechanisms that contribute to the SCD phenotype are vaso-occlusion and activation of the immune system. SCD is characterized by a remarkable phenotypic complexity. Common acute complications are acute pain events, acute chest syndrome and stroke; chronic complications (including chronic kidney disease) can damage all organs. Hydroxycarbamide, blood transfusions and haematopoietic stem cell transplantation can reduce the severity of the disease. Early diagnosis is crucial to improve survival, and universal newborn screening programmes have been implemented in some countries but are challenging in low-income, high-burden settings.

The determinants of meaning of pain following an acute traumatic injury.

Meaning is an integral aspect of life that drives behaviours, actions and emotions. Perception of pain is believed to be affected by the meaning of pain. Our primary aim was to investigate and discuss the determinants of meaning in acute pain following a traumatic injury. Using the Interpretive Description approach, a method of qualitative inquiry, 13 adults hospitalised due to their accidental injuries were recruited. Semi-structured interviews that were digitally recorded were used to collect the data. Ethical approval was received by our local Health Research Ethics Board, and all relevant ethical standards were followed as outlined in the approved ethics proposal. The three primary determinants of meaning during an acute pain event, or the experience of acute pain include permanence of injuries, incongruence of care quality, and personal responses to the injury and care received. Although the permanence of an injury is lasting, we did not find any emotional response to this fact while the participants were hospitalised. The emotion characterising the personal response to the perceived poor quality of hospital care received was anxiety. Both the technical and personal components of healthcare quality have the potential to increase the perception of pain. Meanings in an acute pain event are primarily related to the determinants of incongruent care and the personal response to that determinant: anxiety.

Topical analgesics for acute and chronic pain in adults - an overview of Cochrane Reviews.

Topical analgesics for acute and chronic pain in adults - an overview of Cochrane Reviews.

A New Phase II Agent Holds Promise for First FDA Approved Therapy for Treatment of Acute Vaso-Occlusive Pain Events in SCD

A New Phase II Agent Holds Promise for First FDA Approved Therapy for Treatment of Acute Vaso-Occlusive Pain Events in SCD

Management of Severe Chronic Pain with Methadone in Pediatric Patients with Sickle Cell Disease

IntroductionPatients with sickle cell disease (SCD) experience acute painful events; some patients develop chronic pain requiring daily short acting opioids, and frequent emergency department (ED) visits, and inpatient hospitalization. From the Cooperative Study of Sickle Disease (Platt, NEJM 1991), only 1% of patients with SCD experience more than 6 pain events per year. Methadone is a synthetic opioid used in chronic pain, but there is a paucity of data on its use and effectiveness in the pediatric SCD population. We hypothesized that methadone can be used safely in pediatric patients with SCD with severe chronic pain and would reduce ED visits and hospitalizations.MethodsWe conducted a retrospective cohort study (IRB approved) of 16 pediatric patients with SCD who received methadone for chronic pain management, indicating having more than 5 pain events per year. These patients were among 1100 total patients with SCD at our center. Primary SCD providers escalated doses to maximal effect and when clinically stable, doses were weaned. Follow-up started at time of methadone initiation and ended when a patient was weaned or transitioned to adult care; the 1 year period before treatment initiation was defined as the baseline period. We calculated descriptive statistics to characterize the study population. We compared clinical outcomes (ED visits or hospitalization for pain) for the baseline period and 1 year post methadone initiation using paired T test. To evaluate methadone dosing and dependency, we identified the mean dose, percentage of time at highest dose, and wean of methadone. We assessed withdrawal and safety by reviewing outpatient encounters, EKG screening for QTc > 450, eGFR by cystatin C to determine either a decrease in eGFR by 20% or an eGFR <80, and microalbumin/creatinine urinary excretion.ResultsAmong the 16 participants, 10 (62.5%) were male and the genotypes of each patient were: 14 SS, 1 S/β0-thalassemia, 1 SC. The mean age was 15.5 (±2.8) years at time of methadone initiation and there was a medium follow-up of 2.1 years. Clinically, 13 (81.3%) had previous cholecystectomy, 6 (37.5%) had previous splenectomy, 7 (43.8%) had radiographic evidence of infarction of a long bone within the year prior to initiation of methadone, 10 (62.5%) were receiving chronic transfusion during methadone, and 10 (62.5%) received psychosocial counseling for depression and/or anxiety. The average number of ED visits per month was 0.31 (±0.27) in the baseline period and were 0.28 (±0.28, p=0.658) and 0.31 (±0.25, p=0.921) in the 1 year post and entire follow-up periods. The rate of hospitalizations per month decreased from 0.35 (±0.19) in the baseline period to 0.19 (±0.17, p=0.016) and 0.22 (±0.21, p=0.05) in the 1 year post and entire follow-up periods. The average initial starting dose was 12.5 mg and the mean highest dose was 26.6 mg. In 14 (87.5%) patients the final dose was less than the highest dose and 4 (25.0%) patients were weaned completely off of methadone. For the entire cohort, each patient spent a median of 183 days at their highest dose, a mean of 34% of the total time treated with methadone. No patients experienced signs consistent with opioid withdrawal during the follow-up period. The most common subjective complaints were sedation (12%), nausea and/or vomiting (24%) and constipation (6%). We found no documented new abnormal QTc intervals, changes in eGFR, or new onset proteinuria during the follow up period.ConclusionMethadone use in pediatric patients with SCD is well-tolerated and may lead to improved pain control as evidence by significant reduction in hospitalizations. Additionally, when followed closely, methadone can be used safely without concern for physiologic dependency; this is supported by our ability to wean patients off methadone entirely or weaning to a lower dose than their highest dose in the majority of the cohort. Hematologists should consider methadone as a part of chronic pain management in patients with SCD and severe chronic pain. DisclosuresLebensburger:ASH: Research Funding; NHLBI K23: Research Funding.

Impact of emergency department care on outcomes of acute pain events in children with sickle cell disease.

The impact of emergency department (ED) treatment on outcomes of sickle cell disease (SCD) acute pain hospitalizations is not well described. We investigated whether length of stay (LOS) and change in health-related quality of life (HRQL) are affected by initial opioid dose and time to administration. We conducted secondary analyses of data from the randomized-controlled Magnesium for children in Crisis (MAGiC) trial. The primary outcome was LOS. Secondary outcome was change in HRQL, assessed using PedsQL SCD Pain and Hurt and Pain Impact Domains measured in ED and at discharge. Independent variables were (1) time to first IV opioid, (2) total initial opioid dose (mg/kg/hr of morphine equivalents administered between ED and first study drug), and (3) Time to first oral opioid. Spearman correlations determined the associations with LOS. Using two-sample t-tests, we compared mean change in HRQL scores between IV opioid initiated within 60 and >60 min, opioid doses in the highest and lowest tertiles, and oral opioid initiated within 24 and >24 hr. Two hundred and four patients participated at 8 sites. Mean (SD) age was 13.6 (4.7) years. Earlier initiation of oral opioids was strongly correlated with shorter LOS (r = 0.61, P < 0.01). Higher initial opioid dose was weakly correlated with longer LOS (r = 0.34, P < 0.01). Higher initial opioid doses (6 vs -2.2; P = 0.01) and oral opioids initiated within 24 hr (5.7 vs -1.7, P = 0.04) were associated with larger mean change in HRQL at discharge. Prospective trials evaluating the impact of ED care on outcomes of pain hospitalizations could improve SCD pain treatment. Am. J. Hematol. 91:1175-1180, 2016. © 2016 Wiley Periodicals, Inc.

Long-Term Retrospective Analysis of Gene Therapy with Alipogene Tiparvovec and Its Effect on Lipoprotein Lipase Deficiency-Induced Pancreatitis.

Alipogene tiparvovec (Glybera) is a gene therapy product approved in Europe under the "exceptional circumstances" pathway as a treatment for lipoprotein lipase deficiency (LPLD), a rare genetic disease resulting in chylomicronemia and a concomitantly increased risk of acute and recurrent pancreatitis, with potentially lethal outcome. This retrospective study analyzed the frequency and severity of pancreatitis in 19 patients with LPLD up to 6 years after a single treatment with alipogene tiparvovec. An independent adjudication board of three pancreas experts, blinded to patient identification and to pre- or post-gene therapy period, performed a retrospective review of data extracted from the patients' medical records and categorized LPLD-related acute abdominal pain events requiring hospital visits and/or hospitalizations based on the adapted 2012 Atlanta diagnostic criteria for pancreatitis. Both entire disease time period data and data from an equal time period before and after gene therapy were analyzed. Events with available medical record information meeting the Atlanta diagnostic criteria were categorized as definite pancreatitis; events treated as pancreatitis but with variable levels of laboratory and imaging data were categorized as probable pancreatitis or acute abdominal pain events. A reduction of approximately 50% was observed in all three categories of the adjudicated post-gene therapy events. Notably, no severe pancreatitis and only one intensive care unit admission was observed in the post-alipogene tiparvovec period. However, important inter- and intraindividual variations in the pre- and post-gene therapy incidence of events were observed. There was no relationship between the posttreatment incidence of events and the number of LPL gene copies injected, the administration of immunosuppressive regimen or the percent triglyceride decrease achieved at 12 weeks (primary end point in the prospective clinical studies). Although a causal relationship cannot be established and despite the limited number of individuals evaluated, results from this long-term analysis suggest that alipogene tiparvovec was associated with a lower frequency and severity of pancreatitis events, and a consequent overall reduction in health care resource use up to 6 years posttreatment.

Does Attendance at a Sickle Cell Educational Conference Improve Clinician Knowledge and Attitude Toward Patients with Sickle Cell Disease?

Sickle cell disease (SCD) is a genetic disease associated with both chronic pain and acute painful events referred to as vaso-occlusive crises. Individuals with SCD suffer from a multitude of medical complications in addition to pain. Patients often are stigmatized as “drug-seeking” and receive inadequate pain management. The purpose of this study was to compare clinicians' SCD knowledge and attitudes toward patients with SCD before attending a 2-day conference on SCD (T1) with knowledge and attitudes immediately postconference (T2) and 2 months postconference (T3). A prospective, descriptive survey design was used. The authors administered surveys to assess SCD knowledge and clinicians' attitudes toward patients with SCD at three time points: T1 (N = 59), T2 (N = 38), and T3 (N = 30). SCD knowledge was measured using a 20-item survey, and clinicians’ attitudes toward patients with SCD were measured with the General Perceptions About Sickle Cell Patients Scale, which included items on four independent subscales: positive attitudes, negative attitudes, concern-raising behaviors, and red-flag behaviors. The authors compared changes in knowledge and attitude scores between T1-T2 and T1-T3. Overall, knowledge scores were significantly improved (p < .001) and significantly increased between T1-T2 (p < .0001) and T1-T3 (p = .01). Negative attitudes trended lower over the three time points (p = .07), but a significant decrease in the negative attitudes score was only noted for T1-T3 (Z = −2.16.17, p = .03). Attendance at an educational SCD conference was an effective means to improve knowledge and decrease negative attitudes among clinicians. These differences were maintained at 2 months postconference.

Higher Dose of Opioids in the Emergency Department and Earlier Initiation of Oral Opioids after Hospitalization Are Associated with Shorter Length of Stay in Children with Sickle Cell Disease Treated for Acute Pain

There is currently no standardized approach to emergency department (ED) and inpatient treatment of an acute pain event for patients with sickle cell disease (SCD). In addition, how the initial treatment of a pain event influences the outcome of that pain event is not well described. In surgical patients, aggressive pre-operative and peri-operative pain management is associated with improved pain outcomes post-operatively. Furthermore, in post-operative patients, using oral opioids alone or in combination with intravenous (IV) opioids is shown to provide better pain control, decreased IV opioid consumption, less side effects and higher patient satisfaction. In SCD, it is not known whether more aggressive opioid treatment at presentation to ED care or earlier initiation of oral opioids after hospitalization is associated with improved outcomes. Thus, we sought to determine the impact of the following treatment-related aspects of acute pain events on length of hospital stay: 1) total opioid dose at presentation, 2) time to initiation of first IV opioid at presentation, and 3) time to initiation of first oral opioid after hospitalization. We hypothesized that increased total initial dose of opioids, more rapid initiation of IV opioids in the ED, and earlier initiation of oral opioids after hospitalization would be associated with shorter length of hospital stay.We conducted a secondary analysis of data from the randomized controlled Magnesium for children in Crisis (MAGiC) trial. The MAGiC trial was a double-blind randomized controlled trial of IV magnesium versus saline placebo added to standard treatment for pediatric pain events. All patients had HbSS or HbSβ0 thalassemia to be eligible. The primary outcome, length of stay, was a composite endpoint of actual discharge or 12 hours after administration of last IV opioid, whichever came first. Patients were defined as having severe disease if a history of acute chest syndrome and/or 3 or more pain hospitalizations in the prior 3 years existed. A priori, all pain events were considered severe as the need for hospitalization indicated failure of outpatient therapy. Our primary variables of interest were: 1) Total initial opioid dose: total mg/kg/hr of morphine equivalents administered between first opioid in ED through start of study drug, 2) Time to first IV opioid: total hours between ED arrival and first IV opioid, 3) Time to first oral opioid: total hours between ED arrival and start of first oral opioid after hospitalization. Spearman correlations were used to determine the association between the above variables and length of stay and between length of stay and rehospitalization within 7 days to determine the consequence of earlier discharge.A total of 204 patients were enrolled at 8 sites. Mean (SD) age was 13.6 (4.7) years, 51.5% were female, 88.2% had severe disease and 60.3% were taking hydroxyurea. The primary MAGiC trial analysis found IV magnesium had no impact on length of stay. The mean total initial dose of opioid was 0.043 (0.029) mg/kg/hr that was administered over a median of 8.5 (IQR 6.4-13.1) hours. Higher total initial opioid dose was correlated with shorter length of stay (r=0.34, p<0.01). The median time to first IV opioid was 1.02 (IQR 0.65-1.33) hours. There was no association between the time to first IV opioid and length of stay (r=0.006, p=0.93). The median time to time to first oral opioid was 28.3 (IQR 12.2-61.1) hours. Earlier initiation of oral opioids was strongly associated with shorter length of stay (r=0.61, p<0.01). Neither shorter length of stay (r=-0.08, p=0.28) nor earlier initiation of oral opioids (r=-0.02, p=0.82) was associated with rehospitalization within 7 days.Earlier initiation of oral opioids was strongly associated with shorter length of stay without associated increased rehospitalizations. Higher doses of opioids during the initial management of a pain event also contributed to shorter length of stay, however, more rapid initiation of IV opioids did not alter length of stay. These data suggest that higher initial doses of opioids in the ED and earlier introduction of oral opioids after hospitalization may improve outcomes of pain events. Prospective trials designed to evaluate the impact of initial ED care on outcomes of hospitalizations for pain events and trials aimed at standardizing inpatient treatment for pain events are needed and could ultimately lead to improved outcomes for pain in children with SCD. DisclosuresBrandow:NIH, ASH: Research Funding. Panepinto:NKT Therapeutics, Inc: Consultancy; HRSA, NIH: Research Funding. Brousseau:NIH: Research Funding.

The Neuropeptide Substance P Is Elevated in Patients with Sickle Cell Disease

Patients with sickle cell disease (SCD) experience increased pain to thermal (cold, heat) stimuli compared to healthy controls suggesting peripheral and/or central sensitization. However, the underlying etiology of this thermal hypersensitivity is unknown. Substance P (SP), a primary pain neurotransmitter, is a potent mediator of neurogenic inflammation where inflammatory cell activation, vasodilation, and edema occur after the stimulation of sensory nerve fibers. Chronic elevation of SP can sensitize peripheral nociceptors resulting in thermal hypersensitivity and chronic neuropathic pain as shown in mice and humans without SCD and in SCD mice. Little is known about SP levels in patients with SCD in baseline health compared to healthy African American controls. Furthermore, little is known about changes in SP levels during acute SCD pain. The objective of this study was to evaluate plasma SP levels in SCD patients and controls in baseline health and in SCD patients during acute pain. We hypothesized that SCD patients, in baseline health, will have significantly higher SP levels compared to controls suggesting chronic pain sensitization and that SP levels will significantly increase during acute pain.Patients with SCD in baseline health and during admission for acute pain and healthy African American controls were recruited. Our primary outcome was plasma SP level measured in 3 independent cohorts: healthy African American controls, SCD patients in baseline heath, and SCD patients during acute pain. Plasma samples were assayed in duplicate for SP levels using competitive enzyme-linked immunosorbent assay (Cayman Chemical). Independent samples student's t-test was used to compare SP levels between: 1) SCD patients in baseline health and controls and 2) SCD patients in baseline health and those in acute pain. Multivariable linear regression analysis was used to determine the impact of age and gender on SP levels in the 3 independent groups.Thirty-five African American controls, 25 SCD patients in baseline health, and 12 SCD patients during acute pain completed the study. Controls were older than SCD patients in baseline health (mean (SD) age 21.5 (12.5) vs. 11.8 (3.8) yrs, p=0.0004) and there was no difference in the mean age of SCD patients in baseline health compared to those in acute pain (11.8 (3.8) vs. 12.1 (3.5) yrs, p=0.81). Gender did not differ between the same comparison groups. Genotypes of SCD groups were: 1) baseline: 68% SS, 24% SC, 8% Sβ+thal and 2) acute pain: 67% SS, 25% SC, 8% SOArab. The mean (SD) SP level of SCD patients in baseline health was significantly higher than controls (32.4 (11.6) vs. 22.9 (7.6) pg/mL, p=0.0009) (Figure 1). When controls were restricted to patients less than 19 years of age (n=21) to better match SCD patients in baseline health, the significant elevation of SP levels in SCD patients persisted (32.4 (11.5) vs. 21 (7.1) pg/mL, p<0.0001). Mean SP levels were even higher during acute SCD pain compared to SP levels of SCD patients at baseline (78.1 (43.4) vs. 32.4 (11.6) pg/mL, p=0.004) (Figure 1). Age and gender were not associated with differences in SP levels in controls or in SCD patients at baseline or during acute pain.The elevated SP levels in SCD patients during baseline health compared to controls suggests that SP may be a mediator of or marker for chronic pain sensitization. SP levels further increase during acute pain suggesting that SP may also play a role in mediating or marking an acute pain event. The downstream effects of chronically increased levels of SP on the development and propagation of pain in patients with SCD warrant further investigation. Ultimately, SP could differentiate those at risk for development of chronic pain and could be used as a novel biomarker for acute pain and resolution of a painful event. Eventually, compounds aimed at decreasing SP levels or blocking the SP receptor could be a target for novel treatments for SCD pain. [Display omitted] DisclosuresBrandow:NIH, ASH: Research Funding. Hillery:NIH: Research Funding. Panepinto:NKT Therapeutics, Inc: Consultancy; HRSA, NIH: Research Funding.

The importance of open emergency surgery in the treatment of acute mesenteric ischemia.

ObjectiveAcute mesenteric ischemia (AMI) is a complex disease with a high mortality rate. A patient’s chance of survival depends on early diagnosis and rapid revascularization to prevent progression of intestinal gangrene. We reviewed our experience with open surgery treatment in 54 cases of AMI.MethodsA monocentric retrospective study was conducted between 01/01/2001 and 04/30/2014; 54 AMI patients with a mean age of 56.6 years underwent surgery (26 women and 28 men). Retrospectively, the risk factors, management until diagnosis, vascular therapy and follow-up were evaluated.ResultsThe symptom upon admission was an acute abdominal pain event. The delay time from admission to surgery was, on average, 13.9 h (n = 34). The therapeutic procedures were open surgical operations. The complication rate was (53.7 %) (n = 29). The 30-day mortality was 29.6 % (n = 16). The late mortality rate was 24.1 % (n = 13), and the cumulative survival risk was 44.6 %. Survival was, on average, 60.54 months; however, in the over 70-year-old patient subgroup, the survival rate was 9.5 months (p = 0.035). The mortality rate was 27 % (n = 22) in the <12 h delay group, 20 % (n = 5) in the 12–24 h delay group, and 50 % (n = 7) in the > 24 h delay group.ConclusionsThe form of therapy depends on the intraoperative findings and the type of occlusion. Although the mortality rate has decreased in the last decade, in patients over 70 years of age, a significantly worse prognosis was seen.

Efficacy and safety of perioperative parecoxib for acute postoperative pain treatment in children: a meta-analysis.

Perioperative parecoxib administration reduces postoperative pain, opioid consumption, and adverse events in adult patients. However, the efficacy and safety of parecoxib in children remain unclear. This metaanalysis included related published studies to address this concern. Eight databases in the literature until February 2015 were systematically explored to identify randomized controlled trials (RCTs) comparing perioperative parecoxib administration and placebo/standard treatments for acute postoperative pain in children. Primary outcomes were postoperative pain scores and adverse events. The Face, Legs, Activity, Crying, Consolability scale was used to score pain in children younger than 6 years, whereas the Visual Analog Scale was used in children older than 6 years. Secondary outcomes were sedation scores (measured using the Ramsay scale), agitation scores (measured using the Sedation-Agitation Scale), and opioid consumption. The methodological quality of RCTs was independently assessed in accordance with the "Risk of bias" of Cochrane Collaboration. Data were analyzed using Review Manager 5.2. Twelve RCTs involving 994 patients met the inclusion criteria. Compared with children who received placebo treatment, those who received parecoxib demonstrated lower early (2 h) and later (12 h) postoperative pain scores; lower incidence rates of postoperative nausea, vomiting, and agitation; higher early (1 h) postoperative sedation scores; and lower agitation scores. Similarly, children who received parecoxib had lower early (2 h) and later (12 h) postoperative pain scores, lower incidence rates of postoperative nausea and vomiting, and lower early (1 h) postoperative sedation scores compared with those who received standard treatments; however, these children showed no significant difference in agitation scores. Unfortunately, data on the effect of parecoxib on opioid consumption were insufficient. Overall, these results suggested that perioperative parecoxib administration was associated with less acute postoperative pain and fewer adverse events compared with placebo or standard treatments. Parecoxib administration also resulted in less emergence agitation compared with placebo treatment and less excessive sedation concern compared with standard treatments. However, the long-term effects, effects on opioid consumption, and patient satisfaction of parecoxib administration warrant further investigation.

Alipogene tiparvovec: a review of its use in adults with familial lipoprotein lipase deficiency.

Alipogene tiparvovec (Glybera®; AMT-011, AAV1-LPL(S447X)) is an adeno-associated virus serotype 1-based gene therapy for adult patients with familial lipoprotein lipase (LPL) deficiency (LPLD) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. It is administered as a one-time series of intramuscular injections in the legs. LPLD, a rare autosomal recessive disorder, results in hyperchylomicronaemia and severe hypertriglyceridaemia, which in turn, are associated with an increased risk of clinical complications, the most debilitating of which is recurrent severe and potentially life-threatening pancreatitis. In clinical studies (n = 27 patients), one-time administration of alipogene tiparvovec was associated with significant reductions in plasma triglyceride levels during the 12 or 14 week study period post administration. Although triglyceride levels returned to pre-treatment levels within 16-26 weeks after administration, patients had sustained improvements in postprandial chylomicron metabolism, with sustained expression of functional copies of the LPL (S477X) gene and of biologically active LPL in skeletal muscle. Moreover, after up to 6 years' follow-up post administration, there were clinically relevant reductions in the incidence of documented pancreatitis and acute abdominal pain events consistent with pancreatitis. Alipogene tiparvovec was generally well tolerated, with most adverse events being localized, transient, mild to moderate injection-site reactions. This article reviews the pharmacology of alipogene tiparvovec and its efficacy and safety in adults with LPLD.

Effect of Induced Epidural Anesthesia before Surgical Incision on Acute Pain and Postoperative Pulmonary Events: Results from a Population with Lung Resection by Thoracotomy

Introduction: Our study evaluated the effect on postoperative pain and pulmonary complications of a lidocaine injection in thoracic epidural anesthesia before surgical incision in patients with suspected lung cancer resected by thoracotomy. Patients and methods: Between November 2012 and November 2013, we prospectively recruited patients requiring thoracotomy for suspected non-small cell lung cancer (NSCLC). All patients had a posterior lateral or lateral thoracotomy, and all had preoperative epidurals. Thoracic epidural catheter was removed 4 or 5 days after surgery. We studied NRS score on days 1 and 6 after surgery. Significant pain was defined as NRS>3. We recorded all pulmonary complications such as pneumonia, atelectasis requiring bronchoscopy, bronchopleural fistula, reintubation and tracheostomy. Results: 128 patients were included; 91 patients were male and 37 were female (ratio M/F: 2.46). The median (IQR) NRS score at D1 and D6 post-surgery were 0 (0–3) and 2 (0–3) respectively. The prevalence of pain was 12.5% (95% CI 7.3–19.5) at D1, and 21.9% (95% CI 15.1–30.1) at D6. Postoperative pulmonary events arose in 24.2% of cases (n=31), including pneumonia in14.8% of cases (n=19), and atelectasis in 11.7% (n=15). No relationship was found between acute pain and pulmonary complications. There were no significant differences between groups of patients with and without pain related to the extent of lung resection or surgical technique. The D1 NRS score was correlated with the NRS score at D6 (r=0.24, P=0.006). Conclusion: With our peroperative anesthetic management, postoperative acute pain is very low. Nevertheless, good care did not lead to a decrease in pulmonary complications. We conclude that thoracic epidural anesthesia should be induced before incision, to decrease acute post-thoracotomy pain.

Detection of Pulmonary Platelet Thrombi in Acute Chest Syndrome in Sickle Cell Disease: Novel Findings in an Autopsy Case Series

Introduction: Acute chest syndrome (ACS) is one of the leading causes of death in patients with sickle cell disease (SCD). The pulmonary manifestations of ACS often appear suddenly and can progress rapidly to fatality. There are multiple identified etiologies associated with the development of ACS including infection, fat or pulmonary embolism, and opiate intoxication. The cause cannot be attributed to a single agent in most cases and if so, is likely determined authoritatively only at autopsy. One potential commonality, however, is that an acute pain event usually precedes the onset of ACS. Although, clearly there remains much to be learned, acute pain events are one of the better characterized aspects of SCD. In most cases, there is an increase in inflammatory markers and indicators of endothelial dysfunction. Platelet activation increases during pain events, as do platelet-derived markers of inflammation. In fact, platelets are emerging as potentially pivotal contributors to the overall inflammatory state of patients. Although patients at steady state typically have high platelet counts, platelet count decrease during pain events. Overt thrombocytopenia has been noted in ACS and is usually attributed to platelet sequestration in the vasculature. Thus, we considered the platelet to be a potential contributor to pulmonary pathology in cases of ACS. To lend support to our hypothesis, we performed an autopsy study of pulmonary histology in patients with SCD and ACS.Objective: To interrogate whether platelet thrombi were significant findings in lungs of patients who died concurrent with ACS.Methods: We performed an autopsy case series. Ten autopsies and corresponding medical records from patients with SCD were selected from those conducted at Georgia Regents Medical Center from 1997-2013. From the medical record or autopsy report, all cases had ACS listed concurrent with or as the primary cause of death. No pediatric cases were included in the series (age range 18-45 years old). Paraffin-embedded lung samples were obtained from all cases. Standard immunohistochemical techniques were used to detect platelet thrombi. A comprehensive perimortem medical record was available for 8 patients. A genotype of either SS or S/β0-Thalassemia was acceptable. Two cases were recorded with an S/β0-Thalassemia genotype, the rest were listed as SS.Results: Profound arterial platelet thrombi were detected in 3 out of the 10 cases. In these 3 positive cases, arterial vessels of all size (large arterial vessels to arterioles) were completely occluded by platelets. All platelet positive cases had a genotype of SS. In 2 of the 3 platelet thrombi positive cases, none of the established causes of ACS were noted in the medical record or autopsy report. In 1 platelet positive case, lipid-laden macrophages and ascites were noted at autopsy. Extensive pulmonary artery remodeling was noted in all 10 cases regardless of age or medical history.Conclusions: This case series illustrates that platelet- rich arterial thrombi are present in potentially up to 33 percent of fatal cases of ACS. These data are thus suggestive of a novel pathological role for platelets in ACS. DisclosuresKutlar:NIH/NIMHD: Research Funding.