Severe Painful Crises Research Articles

Phytomedicines (medicines derived from plants) for sickle cell disease.

Sickle cell disease, a common recessively inherited haemoglobin disorder, affects people from sub-Saharan Africa, the Middle East, Mediterranean basin, Indian subcontinent, Caribbean and South America. It is associated with complications and a reduced life expectancy. Phytomedicines (medicine derived from plants in their original state) encompass many of the plant remedies from traditional healers which the populations most affected would encounter. There has been little systematic appraisal of their benefits. This is an update of a Cochrane Review first published in 2010 and updated in 2013. To assess the benefits and risks of phytomedicines in people with sickle cell disease of all types, of any age, in any setting. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, the International StandardRandomised Controlled Trial NumberRegister (ISRCTN) and the Allied and Complimentary Medicine Database (AMED).Dates of most recent searches: Haemoglobinopathies Trials Register: 13 October 2014; 17 January 2015; AMED: 20 January 2015. Randomised or quasi-randomised trials with participants of all ages with sickle cell disease, in all settings, comparing the administration of phytomedicines, by any mode to placebo or conventional treatment, including blood transfusion and hydroxyurea. Both authors independently assessed trial quality and extracted data. Two trials (182 participants) and two phytomedicines Niprisan(®) (also known as Nicosan(®)) and Ciklavit(®) were included. The Phase IIB (pivotal) trial suggests that Niprisan(®) was effective in reducing episodes of severe painful sickle cell disease crisis over a six-month period. It did not affect the risk of severe complications or the level of anaemia. No serious adverse effects were reported. The single trial of Cajanus cajan (Ciklavit(®)) reported a possible benefit to individuals with painful crises, and a possible adverse effect (non-significant) on the level of anaemia. While Niprisan(®) appeared to be safe and effective in reducing severe painful crises over a six-month follow-up period, further trials are required to assess its role in the management of people with sickle cell disease and the results of its multicentre trials are awaited. Currently no conclusions can be made regarding the efficacy of Ciklavit(®). Based on the published results for Niprisan(®) and in view of the limitations in data collection and analysis of both trials, phytomedicines may have a potential beneficial effect in reducing painful crises in sickle cell disease. This needs to be further validated in future trials. More trials are required on the safety and efficacy of phytomedicines used in managing sickle cell disease.

English

A 38-year-old male presented to the emergency department with severe acute-on-chronic abdominal pain. For the previous 20 years, he had experienced daily sharp epigastric pain with generalization to the entire abdomen. The pain typically began late in the morning and could last from hours to days. It was associated with nausea, vomiting, diaphoresis, and occasionally fever, diarrhea, and fatty or bloody bowel movements. These symptoms were not associated with food consumption. Over the previous five years, the patient had lost over 20 kg in weight and had noticed a marked decline in his performance at work and in the quality of his leisure time. He found symptom relief by smoking rolled marijuana cigarettes (“joints”), which he had been using three times per day since his teens. His pain crises were alleviated only with soaking in a tub of “scalding hot” bath water which he drew up ritualistically every morning. The patient’s symptoms had previously been investigated by his family physician, who suspected acute intermittent porphyria (AIP), but it is unclear what medical diagnostics had been performed. Quetiapine (50 mg qhs) had been prescribed and started one year prior to presentation, but during a review of systems, the patient denied having had any psychiatric symptoms. His medical history was significant only for smoking and lactose intolerance. Review of systems and family history were negative for autoimmune, infectious, malignant, or inflammatory bowel disease. When questioned as to why he chose to come to the emergency department just then, the patient replied that his family physician had suggested that he present during one of the more severe pain crises in order to allow laboratory work-up to confirm the diagnosis of AIP. At the time of presentation, the patient had been ill for the previous four days. On examination, the patient was febrile (38.6oC), hypertensive (195/113), and markedly dehydrated. He was of thin habitus and had normal results on cardiorespiratory examination. His abdomen was nondistended but diffusely tender. Abdominal rigidity with guarding was noted by the emergency physician but was absent on reassessment by internal medicine. The patient’s laboratory investigation results were consistent with a stress response and dehydration, including hemoglobin = 193 g/L, white blood cell count = 20 × 109 g/L, creatinine = 164 μmol/L, and lactate = 2.7 mmol/L. Liver enzymes and the results of tests of hepatic synthesis were normal. Urine porphobilinogen at the time of crisis was negative for AIP. Upon a review of the literature, a diagnosis of cannabinoid hyperemesis syndrome was made. To rule out other organic etiologies, the patient underwent abdominal computed tomography, which was unremarkable. Upper gastrointestinal endoscopy with gastric biopsies revealed no pathology.

Vasculopathy and pulmonary hypertension in sickle cell disease.

Sickle cell disease (SCD) is an autosomal recessive disorder in the gene encoding the β-chain of hemoglobin. Deoxygenation causes the mutant hemoglobin S to polymerize, resulting in rigid, adherent red blood cells that are entrapped in the microcirculation and hemolyze. Cardinal features include severe painful crises and episodic acute lung injury, called acute chest syndrome. This population, with age, develops chronic organ injury, such as chronic kidney disease and pulmonary hypertension. A major risk factor for developing chronic organ injury is hemolytic anemia, which releases red blood cell contents into the circulation. Cell free plasma hemoglobin, heme, and arginase 1 disrupt endothelial function, drive oxidative and inflammatory stress, and have recently been referred to as erythrocyte damage-associated molecular pattern molecules (eDAMPs). Studies suggest that in addition to effects of cell free plasma hemoglobin on scavenging nitric oxide (NO) and generating reactive oxygen species (ROS), heme released from plasma hemoglobin can bind to the toll-like receptor 4 to activate the innate immune system. Persistent intravascular hemolysis over decades leads to chronic vasculopathy, with ∼10% of patients developing pulmonary hypertension. Progressive obstruction of small pulmonary arterioles, increase in pulmonary vascular resistance, decreased cardiac output, and eventual right heart failure causes death in many patients with this complication. This review provides an overview of the pathobiology of hemolysis-mediated endothelial dysfunction and eDAMPs and a summary of our present understanding of diagnosis and management of pulmonary hypertension in sickle cell disease, including a review of recent American Thoracic Society (ATS) consensus guidelines for risk stratification and management.

Challenge of Managing Sickle Cell Disease in a Pediatric Population Living in Kinshasa, Democratic Republic of Congo: A Sickle Cell Center Experience

In the Democratic Republic of Congo (DRC), sickle cell disease is not yet really regarded as a health care priority. The patterns of sickle cell disease in patients living in Kinshasa, DRC are discussed and the difficulties encountered in their management are highlighted. The cross-sectional survey is of sickle cell patients and their families attending the Centre de Médecine Mixte et d’Anémie SS de Yolo (CMMASS), Kinshasa, DRC, between January and April 2009. Completed questionnaires were received from 168 respondents (111 girls; 57 boys). Seventy-one percent of the subjects were diagnosed before the age of 2 years but none in the neonatal period. Sickle cell disease was diagnosed in 54.8% of the patients after they had suffered pain crises. Of the 168 subjects, 74.0% had previously received blood transfusions. Seventy-five (45.0%) had more than three severe pain crises per year. A minority of 35.0% reported that they regularly took an antibioprophylaxis. Seventy-five (45.0%) subjects were eligible for hydroxyurea (HU) therapy but in all cases this drug was taken irregularly. Eighty-two percent of drugs were purchased by the parents. One hundred and sixty-three children (97.0%) were vaccinated according to the Expanded Programme on Immunization (EPI), 61.0% against Streptococcus pneumoniae and 16.0% against the Hepatitis B virus (HBV). No case of immunization against Hemophilus influenzae and Salmonella sp was reported. Neonatal screening programs, early educational detection programs for families, use of current method treatments and an implementation of a health insurance system for sickle cell disease will improve detection and management for these and future patients in our population.

The Role of a Low-Dose Ketamine-Midazolam Regimen in the Management of Severe Painful Crisis in Patients With Sickle Cell Disease

ContextAcute pain is one of the main causes of hospital admission in sickle cell disease, with variable intensity and unpredictable onset and duration. ObjectivesWe studied the role of a low-dose intravenous (IV) ketamine-midazolam combination in the management of severe painful sickle cell crisis. MethodsA retrospective analysis was performed with data from nine adult patients who were admitted to the intensive care unit with severe painful sickle cell crises not responding to high doses of IV morphine and other adjuvant analgesics. A ketamine-midazolam regimen was added to the ongoing opioids as an initial bolus of ketamine 0.25mg/kg, followed by infusion of 0.2–0.25mg/kg/h. A midazolam bolus of 1mg followed by infusion of 0.5–1mg/h was added to reduce ketamine emergence reactions. Reduction in morphine daily requirements and improvement in pain scores were the determinants of ketamine-midazolam effect. The t-tests were used for statistical analysis. ResultsNine patients were assessed, with mean age of 27±11 years. Morphine requirement was significantly lower after adding the IV ketamine-midazolam regimen. The mean±SD IV morphine requirement (milligram/day) in the pre-ketamine day (D0) was 145.6±16.5, and it was 112±12.2 on Day 1 (D1) of ketamine treatment (P=0.007). The Numeric Rating Scale scores on D0 ranged from eight to ten (mean 9.1), but improved to range from five to seven (mean 5.7) on D1. There was a significant improvement in pain scores after adding ketamine-midazolam regimen (P=0.01). ConclusionLow-dose ketamine-midazolam IV infusion might be effective in reducing pain and opioid requirements in patients with sickle cell disease with severe painful crisis. Further controlled studies are required to prove this effect.

Leptin and Adiponectin Blood Levels in Patients with Steady State Sickle Cell Disease Are Related to Chronic Hemolytic and Inflammatory Biomarkers

Abstract 1012 Background.Vascular endothelial cell activation and chronic inflammatory processes along with concomitant chronic energy deficiency characterize the steady state of sickle cell disease (SCD). Adipose tissue besides its lipid storage has also an endocrine function producing adipokines most important of which are leptin and adiponectin. These two hormones regulate food intake and energy expenditure but they are also involved in the regulation of inflammatory responses, hematopoiesis and angiogenesis. We evaluated leptin and adiponectin blood levels and determined any possible correlations with disease severity and inflammation markers in steady state SCD patients. Methods.We measured leptin and adiponectin using ELISA as well as high sensitivity C-reactive protein (hs-CRP) using nephelometry, in blood serum of 42 patients (24 male-18 female, median age 34 years, range 29–52 years) with steady state sickle cell/beta thalassemia and 40 healthy individuals matched for age, sex and body mass index (BMI) z-score who served as controls. Steady state was defined as a crisis-free period for at least 4 weeks after the previous clinical event and 3 or more months since the last blood transfusion. After natural logarithmic transformation, the measured values were investigated for correlations against hemoglobin, white blood cells, bilirubin, lactate dehydrogenase (LDH), ferritin, insulin levels, fetal hemoglobin (HbF), number of events/year (severe painful crises, transfusions, severe infections or other complications) and treatment with iron-removing agents or hydroxurea. Results.Leptin was found significantly lower in patients compared to controls (median±SD, 2.9±1.9 vs 8.5±4.9 ng/ml, p=0.006), whereas adiponectin and hs-CRP were found significantly elevated (median±SD 11.3±6.1 vs 7.5±3.1 μg/ml, p=0.003 and 2.8±1.1 mg/L vs 1.4±0.9; p=0.018, respectively). No correlations were found between adipokines and age, gender, chelation or hydroxurea treatment, ferritin, insulin, HbF, hemoglobin or clinical events. Leptin, but not adiponectin, levels were positively correlated with BMI z-score (r= 0.71, p=0.018) and negatively correlated with LDH levels (r=0.69, p=0.012). Concerning adiponectin, significant positive correlation was noted with hs-CRP levels and white blood cell number (r=0.644, p=0.015 and r=0.68, p=0.028). Conclusions.Adipokine blood levels are altered in steady state SCD possibly reflecting the effect of chronic hemolytic and inflammatory state on adipose tissue dysfunction. This could be considered as another endocrinopathy that affects SCD patients. Disclosures:No relevant conflicts of interest to declare.

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

Abstract▪2115▪This icon denotes a clinically relevant abstract Background:Painful vaso-occlusive crises are the most common symptom associated with sickle cell anemia (SCA) and show a large inter-patient variability in the frequency and severity. Historically a high rate of admissions for pain is associated with early mortality in SCA adults. Modern day management of SCA includes screening for life threatening complications such as pulmonary hypertension and disease modifying therapies such as hydroxyurea and chronic blood transfusions. It has also become clear that all acute painful events including some self reported crisis do not lead to ED visit/ hospitalization therefore use of healthcare utilization may underestimate the actual frequency of painful vaso-occlusive crises. The present study determined if ED visit/ hospitalizations for painful vaso-occlusive crises remain a marker of early mortality in the modern era. Methods:To determine the relative contribution of pain and other established risk factors for death in a contemporary adult cohort with sickle cell anemia, we analyzed data of SCA individuals who were evaluated at NIH between February 2001 and June 2007 for screening of the IRB approved protocol to study pulmonary hypertension in sickle cell disease. Self reported history of vaso-occlusive painful events requiring visit to an emergency department (ED) or in-patient hospitalization in 12 months preceding the enrollment was used to stratify study subjects into no-ED visit/ hospitalization or ED visit/hospitalization group. Characteristics between the groups were compared. Doppler echocardiography was used to estimate systolic pulmonary artery pressure through measurement of the tricuspid regurgitation velocity (TRV). Study subjects were followed prospectively and age at death was recorded. Results:One hundred and four (40%) SCA subjects reported no ED visit/ hospitalization while 160 (60%) reported at least one ED visit/ hospitalization in 12 months preceding the enrollment. Although not statistically significant, a higher proportion of study participants in the ED visit/ hospitalization group were on hydroxyurea (38 vs. 69%; P=0.4), and more likely to have received > 10 red cell transfusions (37 vs. 48%; P= 0.09). The no-ED/ hospitalization group and ED/ hospitalization groups were not different in median age (33 vs. 31; P=0.1) or fetal hemoglobin concentration (7.7 vs. 6.9%; P=0.3). Overall forty (15.1%) individuals died during the median follow-up period of 5 years. Cox proportional hazards analysis was performed to determine if severe pain crisis requiring ED visits/hospitalizations were associated with early mortality after adjusting for other known risk factors for mortality (Table 1). Risk for mortality was significantly associated with a history of severe pain crisis requiring ED visit/hospitalization in preceding year (RR 2.81, 95% CI: 1.2–6.4, P= 0.04), elevated TRV ≥ 3 m/s (RR 4.07, 95% CI: 1.3–12.8, P= 0.02) and elevated ferritin (RR 2.31, 95% CI: 1.0–5.0, P= 0.04).Table 1:Cox Proportional Hazards Analysis of MortalityRisk FactorsRR (95% CI)1P2ED visits/hospitalization in past year2.81 (1.2–6.4)0.04TRV, m/sec2.5–2.92.46 (0.8–7.9)0.133.0+4.07 (1.3–12.8)0.02Ferritin2.31 (1.0–5.2)0.041 RR for TRV is given relative to <2.5 m/sec; RR for ED is given relative to zero visits in the past year. RR for ferritin is given for the 75th relative to the 25th percentile.2From Wald χ2 Conclusions:Severe painful episodes requiring health care utilization are associated with premature mortality and despite likely underestimation of actual frequency of pain, remain a marker of disease severity. Elevated TRV a marker of elevated pulmonary arterial pressure and early mortality has a cumulative effect with pain on reduced survival. Consistent with Cooperative Study of Sickle Cell Disease (CSSCD) report, higher hemoglobin (and lower LDH) was associated with reports of ED visit/ hospitalization likely related to increased viscosity. We conclude that as a group, SCA patients reporting severe pain requiring ED visits /hospitalization and elevated TRV are at the highest risk for shortened survival. Disclosures:No relevant conflicts of interest to declare.

Markers of Severe Vaso-Occlusive Painful Episode Frequency in Children and Adolescents with Sickle Cell Anemia

To identify factors associated with frequent severe vaso-occlusive pain crises in a contemporary pediatric cohort of patients with sickle cell anemia (SCA) enrolled in a prospective study of pulmonary hypertension and the hypoxic response in sickle cell disease. Clinical and laboratory characteristics of children with SCA who had ≥3 severe pain crises requiring health care in the preceding year were compared with those of subjects with <3 such episodes. Seventy-five children (20%) reported ≥3 severe pain episodes in the preceding year, and 232 (61%) had none. Frequent pain episodes were associated with older age (OR, 1.2; 95% CI, 1.1-1.3; P < .0001), α-thalassemia trait (OR 3.5; 1.6-6.7; P = .002), higher median hemoglobin (OR 1.7; 95% CI: 1.2-2.4; P < .003), and lower lactate dehydrogenase concentration (OR 1.82; 95% CI: 1.07-3.11; P = .027). Children with high pain frequency also had an increased iron burden (serum ferritin, 480 vs 198 μg/L; P = .006) and higher median tricuspid regurgitation jet velocity (2.41 vs 2.31 m/s; P = .001). Neither hydroxyurea use nor fetal hemoglobin levels were significantly different according to severe pain history. In our cohort of children with SCA, increasing age was associated with higher frequency of severe pain episodes as were α-thalassemia, iron overload, higher hemoglobin and lower lactate dehydrogenase concentration, and higher tricuspid regurgitation velocity.

Epidemiology and Risk Factors for Pain In Children and Adolescent with Sickle Cell Anemia.

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

Sickle Cell Disease Management in the Emergency Department: What Every Emergency Nurse Should Know

I n 2004, the Agency for Healthcare Research and Quality reported that nearly 80% of the 80,000 hospital admissions for acute sickle cell disease (SCD) began their course in the emergency department. SCD is a chronic disease associated with serious pathophysiologic complications (eg, stroke, pulmonary embolus, sepsis, and acute chest syndrome [ACS]), severe pain crises, debilitating chronic pain, and a shortened life span. Morbidity and mortality rates remain high, as reflected by the median age of death: 42 years for men and 48 years for women. Because of the potential for underlying pathophysiologic complications, in addition to the severe pain crises, patients should be evaluated rapidly in the emergency department and receive emergent intervention. The frequency of pain episodes and the need for hospital re-admission after ED visits has been associated with an increased risk of death, suggesting that rapid and thorough evaluation and management of these episodes is indicated. In actual practice, recent data demonstrated lengthy delays before the administration of initial doses of analgesia to patients with SCD. Although some of these delays may be related to overcrowding, other reasons such as general frustration and a poor understanding of the disease may explain suboptimal analgesic management. The literature suggests that caring for patients with SCD is a very frustrating experience for emergency nurses and physicians, and that patients with SCD often are perceived to be addicted to opioids and “drug seeking.” However, studies of addiction in the United States suggest that the incidence of addiction in patients with SCD is no higher than that in the general population. The goal of this article is to describe the pathophysiologic manifestations and associated complications of SCD relevant to the emergency nurse and to recommendmanagement strategies through the 3 distinct phases of ED care: triage and early interventions, medical and nursing management at the bedside, and disposition (admission versus discharge).

The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS)

The aim of this prospective study was to evaluate the long-term efficacy and safety of hydroxyurea (HU) in patients with sickle cell disease (SCD). Thirty-four patients with sickle cell anemia (hemoglobin S [HbS]/HbS), 131 with HbS/beta(0)-thal, and 165 with HbS/beta(+)-thal participated in this trial. HU was administered to 131 patients, whereas 199 patients were conventionally treated. The median follow-up period was 8 years for HU patients and 5 years for non-HU patients. HU produced a dramatic reduction in the frequency of severe painful crises, transfusion requirements, hospital admissions, and incidence of acute chest syndrome. The probability of 10-year survival was 86% and 65% for HU and non-HU patients, respectively (P = .001), although HU patients had more severe forms of SCD. The 10-year probability of survival for HbS/HbS, HbS/beta (0)-thal, and HbS/IVSI-110 patients was 100%, 87%, and 82%, respectively, for HU patients and 10%, 54%, and 66%, for non-HU patients. The multivariate analysis showed that fetal hemoglobin values at baseline and percentage change of lactate dehydrogenase between baseline and 6 months were independently predicted for survival in the HU group. These results highlight the beneficial effect of HU, which seems to modify the natural history of SCD and raise the issue of expanding its use in all SCD patients.

Prolonged Administration of Hydroxyurea Reduces Morbidity and Mortality in Adult Patients with Sickle-Cell Syndromes: Long-Term Experience of a Single Center.

Hydroxycarbamide (hydroxyurea; HU) is now considered as the main pharmacological agent capable to prevent the painful crises, to reduce the frequency and length of hospital admissions, and to improve the quality of life of patients with sickle-cell disease (SCD); whether HU can prevent the severe chronic complications or modify the mortality of these patients remains still an interesting unresolved question. The present study aims to evaluate the above effects of HU in a large number of SCD patients who received HU over long period of time and were followed in a single Center. To this effect, we evaluated the records of 330 patients with SCD who have been followed in the Thalassemia Center of Laikon Hospital over the last twenty years (136M/194F; median age: 42 years, range: 20- 76 years); 34 with homozygous HbS (SS) and 296 compound heterozygotes for HbS and beta-thalassemia. Of the latter, 131 patients had HbS/beta0-thal and 165 HbS/beta+-thal (107 with the IVSI-110 and 58 with the IVSI-6 thalassemic mutation). Administration of HU was started as early as 1991; progressively, the total number of patients who received HU reached 131 (“group A”); the remaining 199 were treated conventionally (“group B”). The mean age of the patients in the two groups was similar (mean ±SD: 43.3±9.9 years for group A and 44.1±12.6 years for group B) as well as the levels of HbF. The usual dosage of HU was 20 mg/kg/day, except for some patients, where toxicity or lack of effectiveness imposed modifications of the dosage in the range of 15 to 35 mg/kg/day. The median follow-up period was 8 years (range: 0.1–17 years) for the patients who received HU and 5 years (range: 0.1–18 years) for those who did not receive HU. Apart rare exceptions, patients reported every 4–8 weeks to the Outpatient Clinic, where they had a thorough clinical and laboratory evaluation, including FBC and reticulocytes, LDH, bilirubin, other basic biochemistries and HbF using conventional techniques. The percentage of HbS/HbS, HbS/beta0-thal, and HbS/IVSI-110 patients who were given HU was 70%, 49% and 40% respectively; in contrast, very few HbS/IVSI-6 compound heterozygotes had symptoms justifying use of the drug (3.6%). Patients receiving HU showed a dramatic reduction of the frequency of severe painful crises (from 7.4±6.5 episodes per year pre-HU to 0.2±0.4 episodes post-HU; p<0.001) along with a significant reduction of transfusion requirements (mean number of administered packed red cell units: 1.5±5.9 per year pre-HU diminishing to almost zero during HU treatment; p<0.001). These results led to a significant reduction of hospital admissions from 2.1±2.9 per year pre-HU to 0.06±0.02 per year post-HU (p<0.001). Moreover, we noticed a significant reduction of the frequency of chest syndrome from 6.1% pre-HU to 0.8% during the HU period (p=0.013). In contrast, we failed to observe any significant differences in the frequency of aseptic avascular necrosis (p=0.219) or cerebrovascular episodes among the patients who received and those who did not receive HU (p=0.65). Importantly, the death rate in the group of patients receiving HU was significantly lower than that observed among patients who were conventionally treated (12 deaths in group A vs. 47 in group B; 9.1% vs. 23.6%, respectively; p=0.001). The probability of 10-year survival was 91% for the patients treated with HU, while that of the patients conventionally treated was only 70% (Figure). This difference is further magnified if one considers that prior to starting HU the patients of group A had significantly higher transfusion requirements, frequency of painful crises, yearly number of admissions to hospital and intensity of hemolysis in comparison to the group of patients who were not given HU (p=0.004, <0.001, <0.001, and 0.01, respectively). Factors that predicted for a superior survival in the HU group include the increased level of total hemoglobin, a reduced platelet and leukocyte count, increased HbF levels, low reticulocyte counts and low bilirubin and serum LDH levels at 6 months post-HU administration. Side-effects of HU therapy were minimal, predictable and easily manageable. Our study provides evidence that, in addition to reducing the number of painful crises, the frequency of hospital admissions and the transfusion requirements, the long-term administration of HU in adult patients with sickle cell syndromes can improve survival. These results highlight the beneficial effect of HU in SCD and raise the issue of expanding the use of HU in all patients with these conditions. [Display omitted]

DNA polymorphisms at the BCL11A , HBS1L-MYB , and β- globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease

Sickle cell disease (SCD) is a debilitating monogenic blood disorder with a highly variable phenotype characterized by severe pain crises, acute clinical events, and early mortality. Interindividual variation in fetal hemoglobin (HbF) expression is a known and potentially heritable modifier of SCD severity. High HbF levels are correlated with reduced morbidity and mortality. Common single nucleotide polymorphisms (SNPs) at the BCL11A and HBS1L-MYB loci have been implicated previously in HbF level variation in nonanemic European populations. We recently demonstrated an association between a BCL11A SNP and HbF levels in one SCD cohort [Uda M, et al. (2008) Proc Natl Acad Sci USA 105:1620-1625]. Here, we genotyped additional BCL11A SNPs, HBS1L-MYB SNPs, and an SNP upstream of (G)gamma-globin (HBG2; the XmnI polymorphism), in two independent SCD cohorts: the African American Cooperative Study of Sickle Cell Disease (CSSCD) and an SCD cohort from Brazil. We studied the effect of these SNPs on HbF levels and on a measure of SCD-related morbidity (pain crisis rate). We strongly replicated the association between these SNPs and HbF level variation (in the CSSCD, P values range from 0.04 to 2 x 10(-42)). Together, common SNPs at the BCL11A, HBS1L-MYB, and beta-globin (HBB) loci account for >20% of the variation in HbF levels in SCD patients. We also have shown that HbF-associated SNPs associate with pain crisis rate in SCD patients. These results provide a clear example of inherited common sequence variants modifying the severity of a monogenic disease.

Ten-Year Review of Hospital Admissions among Children with Sickle Cell Disease in Kuwait

Objective: This study was designed to document the common causes and patterns of hospitalization among sickle cell disease (SCD) patients in Kuwait. Subjects and Methods: The case files of all SCD patients admitted to the hospital between 1995 and 2004 were studied. Their personal data, hemoglobin genotype, diagnosis on admission, complete blood count, treatment received, length of stay and outcome were documented. Results: Fifty SCD patients aged from 10 months to 14.8 years (mean: 8.7 ± 2.8 years) had 351 admissions over the 10-year period accounting for 0.6% of all admissions to the pediatric wards. The 50 patients were made up of 18 Hb SS, 28 Sβ⁰thal and 4 Hb SD patients. Common causes of admission were vaso-occlusive crisis: 222 (63.2%), acute splenic sequestration crisis: 32 (9.1%), hemolytic crisis: 31 (8.8%) and acute chest syndrome: 23 (6.6%). Stroke was seen in only 1 patient, and bacteriologically proven (Salmonella) acute osteomyelitis in 1 patient. There were no deaths during the study period. Conclusions: Vaso-occlusive crisis was the commonest cause of hospitalization among our SCD patients. Efforts should be intensified to give advice on preventive measures. The use of hydroxyurea should be encouraged in patients with frequent severe pain crises.

Acute Painful Crises of Sickle Cell Disease in Egyptian Children: Predictors of Severity for a Preventive Strategy

The objective of this study was to predict which infants with sickle cell disease (SCD) are prone to develop severe painful crises. In a mixed hospital - and community-based population (76 cases), demographic data, SCD diagnostic parameters, and basal blood counts were correlated with 2 indices of SCD severity: pain rate (average number of days of painful episodes per year of follow-up) and serious life-threatening complications, such as hyperhemolytic crises. Data were analyzed blind to these indices. The Student t test, analysis of variance, and Pearson correlation were used to determine association with pain rate. Discriminant analysis was used for the prediction of SCD severity. Pain rate was significantly high in hemoglobin SS patients, especially in those with an early onset of dactylitis. There were statistically significant negative correlations of pain rate with basal hemoglobin level, hematocrit, percent hemoglobin F, and arterial oxygen saturation (P <.01 for all correlations). The top 3 predictors of SCD severity were (in descending order) genotype, basal hemoglobin level, and early dactylitis. Severe forms of SCD could be predicted in early infancy with 100% accuracy by using the basal diagnostic parameters for the disease. These infants should be closely monitored with special attention to ventilation status, even before the development of dactylitis.

Superoxide Inhibits ADAMTS-13 Activity and Regulates Sickle Cell Adhesion.

The major clinical manifestations of sickle cell anemia are due to a vaso-occlusive process that leads to severe pain crises, tissue infarction, and in some instances, death. The pathophysiology of vaso-occlusion is extremely complex, the proximate cause appearing to be an increase in the adhesive interaction between sickle erythrocytes and vascular endothelium. There is ample evidence that it is the highest molecular weight forms of VWF, the ultra-large multimers (ULVWF), expressed on endothelium support sickle erythrocyte adhesion most potently. We postulate that variation in the activity of the plasma metalloprotease, ADAMTS-13, which processes ULVWF to the VWF form normally found in plasma will be an important determinant of the propensity for individuals with sickle cell anemia to develop vaso-occlusive crises. It has also been postulated that increased production of reactive oxygen species (ROS) also contributes to the pathology of sickle cell disease. ROS have been implicated in diverse cellular processes, acting through oxidation of cysteine residues. ADAMTS-13 is a cysteine-rich protein; we therefore hypothesized that its function could be affected by ROS. We measured ADAMTS-13 activity in the plasmas of sickle cell disease patients, both in the “steady state” and at various times during vaso-occlusive crises. We used three assays: a static assay that measures the ability of patient plasma to reduce the size of endothelial-derived ULVWF, a static assay that assesses the ability of patient plasma to cleave a recombinant VWF A2 fragment, and an assay performed under flow that evaluates the ability of patient plasma to cleave ULVWF attached to the surfaces of histamine-stimulated human umbilical vein endothelial cells (HUVECs). Five of nine patients with sickle cell anemia had significantly lower ADAMTS-13 activity than measured in normal controls during the chronic phase of the illness, some with activity measuring below 50% of normal levels. We also evaluated activity in two patients during acute vaso-occlusive crisis. Both patients had levels on the day of hospitalization that were indistinguishable from the levels found in patients with thrombotic thrombocytopenic purpura. Recovery of activity correlated with clinical recovery, to the point that in both cases activity was normal upon hospital discharge. We then compared superoxide generation facilitated by sickle erythrocytes with that generated by normal erythrocytes and found, as others have a significantly higher generation by sickle erythrocytes. We also found that superoxide (produced using a hypoxanthine-xanthine oxidase system) significantly decreased the activity of both plasma and recombinant ADAMTS-13 in vitro. Superoxide was also able to stimulate release of ULVWF and cell-membrane expression from cultured HUVEC. These results suggest that the enhanced production of superoxide in patients with sickle cell disease plays an important role in promoting erythrocyte adhesion to the endothelium by both stimulating release of ULVWF and inhibiting its cleavage by ADAMTS-13.

Inefficacy of Piracetam in the Prevention of Painful Crises in Children and Adolescents with Sickle Cell Disease

Analgesia and hydration remain the only safe treatment for painful crises of sickle cell disease; hydroxyurea is effective, but the toxicity is still a problem. Piracetam is a nootropic drug that has reportedly been effective and non-toxic in sickle cell patients, but most studies were not placebo-controlled and included a small number of patients. The present study evaluated the drug in a double-blind crossed placebo-controlled clinical trial in 73 children and adolescents suffering from moderate to severe painful crises for 13 months. Information regarding frequency and severity of pain was acquired through monthly clinical evaluation, visits and house calls, and 4,300 weekly questionnaires filled out by the patients in their domiciles. A monthly pain score was calculated for each patient. Pain was the most frequent adverse manifestation of the disease stressing its significant bio-psycho-social impact. Although nearly all patients and relatives reported a better clinical course throughout the whole study, the drug was ineffective in the prevention of painful crises. This placebo effect may be ascribed to an unplanned and unsystematic ‘cognitive-behavioural’ management of the children. The pain score in the second semester of the study – both in the experimental and in the control groups – was significantly smaller than that in the first semester. In conclusion, piracetam was found to be ineffective in the prevention of painful crises; a powerful placebo effect due to adequate patient care was demonstrated.

Unexpected healing of cutaneous ulcers in a short child

A boy aged 10 years was referred to the Paediatric Department of Milan University Hospital, Milan, Italy, with a long history of pain in the lower limbs, alleviated only by exposure to cold. His legs were swollen, with multiple cutaneous ulcers. He had severe painful crises, and was totally incapacitated. After the diagnosis of erythermalgia was made, numerous treatments were tried, but none were successful. After finding growth hormone (GH) deficiency, we started treatment with recombinant GH. He had immediate relief of pain and complete healing of ulcers. We postulate that the healing of the ulcers can be attributed to the GH-promoting effect on dermal connective tissue.

Day-care management of sickle cell painful crisis in Jamaica: a model applicable elsewhere?

In the U.K. and the U.S.A., painful crises account for 80-90% of sickle-related hospital admissions, with average durations of 5-11 d. In Jamaica, many severe painful crises are managed in a day-care centre. Patients (n=1160) with homozygous sickle cell (SS) disease aged 18 years and over were registered with the clinic during a 1-year study period. Of these, 216 patients with 476 painful crises attended the day-care facility for a total of 686 d. Most patients (119 or 55.1%) had single crises and for most crises (338 or 71%), patients attended for only 1 d, when they were given bed rest, assurance, rehydration and analgesia. Patients with complicated painful crises were usually referred for admission after initial pain relief and the rest were monitored during the day. In the evening they were given the option of hospital admission or allowed home with oral analgesia. Hospital admission for complicated painful crises or inadequate pain relief occurred in 42 (8.8%) crises and home management in 434 (91.2%) crises. Of 186 patients initially selecting home management, 20% returned for further day-care and five (2.7%) died during subsequent admission for that painful crisis, one without other known complications, two with acute chest syndrome (one associated with Salmonella septicaemia), another with Salmonella septicaemia, and one with dengue haemorrhagic fever. With suitable oral analgesia, adequate education and support, the majority of severe painful crises in SS disease in Jamaica have been managed on an outpatient basis. This model of patient care may merit assessment in other communities where painful crises are a common clinical problem.

Pain crises in patients with sickle cell diseases. Pathogenesis, clinical aspects, therapy

About 70% of all patients with sickle cell disease suffer from pain crises. Pain crises are recurrent episodes of pain that range in severity from mild to severe, usually occur very abruptly and are often localized around joints. Pain crises are caused by vaso-occlusions in the vascular bed of the bone marrow, leading to necrosis, edema and increased pressure. For effective analgesia morphine or morphine analogues are often required. When treating a pain crisis the patient's complaints need to be taken seriously and analgesic therapy should be started promptly with analgesics in proportion to the severity of the patient's pain. With mild pain oral non-opioid analgesics are sufficient, in moderate pain they are given in combination with oral codeine. Severe pain requires IV morphine, also combined with a non-opioid analgesic. Intravenous morphine makes a thorough monitoring of ventilation and level of consciousness mandatory. Sickle cell patients do not become drug dependent if given morphine for adequate analgesia. While bone marrow transplantation has become an accepted treatment modality for sickle cell patients with severe pain crises, treatment with hydroxyurea to increase HbF levels and reduce incidence and severity of pain crises, however, is still experimental.