A randomized, controlled clinical trial established the efficacy and safety of short-term use of hydroxyurea in adult sickle cell anemia. To examine the risks and benefits of long-term hydroxyurea usage, patients in this trial were followed for 17.5 years during which they could start or stop hydroxyurea. The purpose of this follow-up was to search for adverse outcomes and estimate mortality. For each outcome and for mortality, exact 95% confidence intervals were calculated, or tests were conducted at a 5 0.05 level (P-value <0.05 for statistical significance). Although the death rate in the overall study cohort was high (43.1%; 4.4 per 100 person-years), mortality was reduced in individuals with long-term exposure to hydroxyurea. Survival curves demonstrated a significant reduction in deaths with long-term exposure. Twenty-four percent of deaths were due to pulmonary complications; 87.1% occurred in patients who never took hydroxyurea or took it for <5 years. Stroke, organ dysfunction, infection, and malignancy were similar in all groups. Our results, while no longer the product of a randomized study because of the ethical concerns of withholding an efficacious treatment, suggest that long-term use of hydroxyurea is safe and might decrease mortality. Am. J. Hematol. 85:403-408, 2010. V
BackgroundThere is increasing interest in actively involving patients in the process of medical research to help ensure research is relevant and important to both researchers and people affected by the disease under study. This project examined the recently formed Vasculitis Patient-Powered Research Network (VPPRN), a rare disease research network, to better understand what investigators and patients learned from working on research teams together.MethodsQualitative interviews were conducted by phone with patients, physician/PhD-investigators, and study managers/staff who participated in the network. The question guiding the interviews and observational analysis was: “What have investigators and patients learned about working together while working on VPPRN teams?” Interview transcripts were analyzed in combination with observations from multiple in-person and telephone meetings.ResultsTranscripts and notes were reviewed and coded from 22 interviews conducted among 13 patient-partners, 5 study managers/staff, and 4 MD or PhD-investigators, and 6 in-person and 42 telephone/web-conference meetings. Patient-partners and investigators characterized their working relationships with one another, what they learned from their collaborations, and provided recommendations for future teams of patient-partners and investigators. Major themes included the great benefits of communicating about activities, being open to listening to each group member, and the importance of setting reasonable expectations.ConclusionsDirect engagement in research design and development by patient-partners and co-learning between investigators and patient-partners can result in a positive and productive working relationship for all members of a medical research team. This bi-directional engagement directly benefits and impacts research design, participant recruitment to studies, and study subject retention.
The objectives of the study were to compare the efficacy and safety of a continuous infusion (CIV) of morphine and intermittent parenteral opioids (IPO) in children with sickle cell vaso-occlusive crises (VOCs); to determine whether 50% oxygen administration through a face mask can reduce the duration of severe pain in patients receiving CIV morphine; and to measure morphine concentration at steady state for pharmacokinetic and pharmacodynamic analysis in patients receiving CIV morphine. The study was designed as a prospective, controlled, "before-and-after" evaluation of two different analgesic regimens. For patients receiving CIV morphine, there was a randomized, double-blind, placebo-controlled study of O2 vs. air. The patients were 66 children with sickle cell disease, 3-18 years old, requiring opioid therapy for severe VOC (32 patients in phase A, 34 in phase B). The analgesic regimens were as follows: phase A: meperidine, morphine, or codeine IM or IV bolus every 3 or 4 hours; phase B: morphine sulfate, loading dose 0.15 mg followed by CIV 0.04 mg/kg/hr. The infusion rate was adjusted every 8 hours according to pain and/or symptoms of opioid toxicity. Pain assessment was by behavioral observation (BPS). In terms of results, the mean opioid dose (morphine equivalent) was similar in both groups (0.032 +/- 0.020 mg/kg/hr in phase A and 0.035 +/- 0.011 in phase B). However, the duration of severe pain was significantly shorter in phase B (0.9 +/- 1.0 days) than in phase A (2.0 +/- 1.8 days). No severe opioid toxicity was observed in either group. Oxygen did not shorten the duration of severe pain compared to the placebo group (0.94 +/- 1.08 and 0.95 +/- 1.19 days, respectively) nor did it prevent the appearance of new pain sites. Pharmacokinetic analysis was performed in 24 patients of phase B. Total body clearance (TBC) of morphine was greater in children before puberty than after (40.4 +/- 10 vs. 28 +/- 11 mL/kg/min; p < 0.05). In conclusion, in children with severe VOCs, continuous infusion of morphine provides better analgesia than intermittent opioid therapy. Fifty percent oxygen inhalation had no effect on the duration of pain.
Aims To evaluate compliance with prophylactic penicillin therapy in sickle cell disease (SCD) in children. Methods Forty-five children aged 37±19 (9-84) months [mean±s.d; range] with homozygous SCD were recruited. After a baseline period of 2 months the patients were randomized to either the intervention or non-intervention group. The intervention consisted of a slide show explaining the pathogenesis of sickle cell disease and its complications; weekly phone calls by the clinic social worker; and a calendar. Compliance was again evaluated after the 2 month intervention period and after a further 2 month monitoring period without intervention. Compliance was monitored using the Medication Event Monitoring System. At the end of the 6 months, parents in both groups completed a questionnaire the aims of which were to determine knowledge and understanding of sickle cell disease and previous experience with infection. Patient admissions to the hospital during the study were recorded. Results Compliance during the 2 month baseline assessment was 66.0±32.5 (1.3-98.2)% and 69. 3±25.4 (19.8-96.5)% in the intervention (n=13) and nonintervention (n=10) groups respectively ( P=0.79). During the next 2 months, compliance in the intervention group (n=11) was 79.0±31.4 (11.0-100.0)% and in the non-intervention group (n=9) was 66.0±20.2 (42.2-96.8)% ( P=0.297). In the final 2 month monitoring period compliance was 82.0±34.7 (3.8-100.0)% and 65. 8±25.3 (25.0-98.2)% in the intervention (n=7) and the non-intervention (n= 6) groups respectively ( P=0.366). No statistically significant differences were found when comparing compliance between the groups. Conclusions Compliance with prophylactic antibiotic therapy in children with sickle cell disease is highly variable and its evaluation is problematic.
Several life-threatening complications of the common disorder sickle cell disease require management with red blood cell transfusions and, hence, long-term iron-chelating therapy. The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) has not previously been determined in patients with sickle cell disease. We compared the efficacy of L1 to that of standard-dose subcutaneous deferoxamine in four regularly transfused patients with homozygous sickle cell disease, who had evidence of severe iron overload and a history of poor compliance with deferoxamine. Determination of 24-hour urinary iron excretion conducted over 5 days immediately after transfusion showed that the mean daily urinary iron excretion induced by L1 at 75 mg/kg/d (0.48 +/- 0.23 mg/kg) was equivalent to that induced by deferoxamine at 50 mg/kg/d (0.39 +/- 0.06 mg/kg). In two of three patients studied, a significant (P < .025) increase in mean daily urinary iron excretion was achieved when the dose of L1 was increased to 100 mg/kg/d. Total iron balance studies, which quantitated both urinary and stool iron excretion on L1 and deferoxamine, determined that mean total daily iron excretion induced by deferoxamine (0.88 +/- 0.05 mg/kg) was significantly greater (P < .05) than that induced by L1 (0.53 +/- 0.17 mg/kg), attributable to the significantly greater stool iron excretion during deferoxamine treatment (0.50 +/- 0.16 mg/kg/d) compared with that measured during L1 treatment (0.12 +/- 0.08 mg/kg/d, P < .01). Stool iron excretion accounted for a significantly greater percentage of total iron excretion during deferoxamine treatment (59% +/- 20%) than during L1 treatment (23% +/- 14%, P < .01). These iron balance studies are the first to compare total iron excretion induced by L1 with that achieved by deferoxamine. They demonstrate that the mean total daily iron excretion during L1 treatment (0.53 +/- 0.17 mg/kg) is sufficient to maintain net negative iron balance in most regularly transfused patients with sickle cell disease. Because long-term compliance with L1 has been shown previously to be superior to that with deferoxamine in patients with homozygous beta-thalassemia, the use of L1 should increase the long-term effectiveness of iron chelation in patients with sickle cell disease.
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