Management of acute chest wall sickle cell pain with nebulized morphine

This paper describes, for the first time, the utilization of nebulized morphine in the management of severe chest pain in two young adult African-American patients who suffered from generalized acute sickle cell painful episodes. While hospitalized, both patients developed new sharp chest wall pain, and were treated with nebulized morphine started at 20 mg MOSO4 in 3.0- to 5.0-mL physiologic buffered saline solution. Within minutes, both patients reported significant relief of chest wall pain. Patient 1 achieved 90% pain relief as well as a significant decrease in the pain intensity score. Patient 2 reported 40% pain relief, and the pain intensity score decreased to a mean of 5.6/10. Hence, treatment every 6 hr was continued for 10 days, after which the chest wall pain subsided. These findings indicate that nebulized morphine may prove effective in the management of acute chest pain in patients with sickle cell anemia. This is a desirable alternative in patients with difficult venous access and may more specifically target chest pain.     

Hospital readmission for adult acute sickle cell painful episodes: frequency, etiology, and prognostic significance

The acute sickle cell painful episode is the most common cause of hospitalization of patients with sickle cell anemia. Its detailed clinical features and peri-discharge features are not well known. In order to determine the actual pattern of hospital admissions of patients with SS and the causes of frequent hospital readmissions and their prognostic significance, we conducted a prospective longitudinal and observation cohort study of all adult patients with sickle cell anemia admitted to Thomas Jefferson University Hospital between January 1998 and December 2002. Major outcome measures included the frequency, etiology, and prognostic significance of readmissions to the hospital within 1 week and 1 month after discharge. Incidence of mortality among patients during the study period was also determined. Analysis of the data showed that about 50% of hospital admissions for acute painful episodes were readmitted within 1 month after discharge, and about 16% of all admissions were within 1 week after discharge. The intensity of pain score decreased significantly during the first 4 days of hospital admission (P < 0.001) and then reached a plateau until discharge. The mean score of pain intensity was >7 throughout the hospital stay. Causes of hospital readmission included premature discharge, withdrawal syndrome, and recurrence of new acute episodes. Readmission within 1 week after discharge was associated with higher mortality than otherwise. This study shows that hospital readmission of adult patients with sickle cell anemia is common. It suggests that improvement is needed in the management of pain during hospitalization and at home after discharge. Patients who are readmitted frequently within 1 week of discharge have poor prognosis and require careful monitoring.     

Ethical issues in the management of sickle cell pain

Care providers who manage patients with sickle cell disease (SCD) often face several questions. Most prominent among these pertain to the importance of pain and its treatment. The duties of the health care providers concerning pain management are often not well defined and vary considerably among providers and institutions. Despite the availability of national guidelines that address the ethical issues of pain management, patients with SCD often receive suboptimal pain control, especially during acute painful episodes. Although there are many reasons for this situation, an important aspect of the problem pertains to the complexity of applying ethical standards to specific patients with sickle cell pain. Decisions are frequently made according to perceptions and circumstances without taking ethical principles into consideration. The purpose of this paper is to present the range of ethical principles pertinent to sickle pain management and discuss specific examples of physician-patient interactions where ethical dilemmas occur.     

Elevated plasma sVCAM-1 levels in children with sickle cell disease: impact of chronic transfusion therapy

Vascular cell adhesion molecule-1 (VCAM-1) has been implicated as being important in the pathophysiology of acute pain episodes (APE) and acute chest syndrome (ACS) of sickle cell disease (SCD). The frequency of these episodes is reduced by chronic transfusion therapy. The impact of chronic transfusion therapy on VCAM-1 expression is unknown. Soluble VCAM-1 (sVCAM-1) levels were measured in plasma using an ELISA assay (R&D Systems) in 61 patients with SCD (age range 1.5-20 years) and 12 normal controls (2.5-14 years). SCD patients included 20 with ACS, 14 with APE, 12 at well-child visits, and 15 receiving chronic transfusion therapy. Asymptomatic SCD patients had higher sVCAM-1 levels compared to normal subjects (P < 0.001). Levels of sVCAM-1 were further elevated during ACS (P < 0.001) and APE (P = 0.072) and returned to the asymptomatic range on resolution. Levels were significantly lower in transfused patients (P = 0.003) compared to asymptomatic SCD patients. Our findings of increased VCAM-1 expression during ACS and perhaps APE offer a rationale for therapeutic use of cytokine and other VCAM-1 modulators. The reduction of sVCAM-1 levels observed in our transfused SCD patients offers insight into the mechanism of the protective effect of transfusion against ACS and APE and possibly stroke.     

Platelet activation during pain crisis in sickle cell anemia patients

Platelet activation at sites of enmeshed sickled red cells in the microcirculation may contribute to platelet plug formation and microinfarction in sickle cell anemia. To test this hypothesis platelets from 116 sickle cell anemia patients free of crisis, 32 patients with crisis, 16 convalescents within 1 week of crisis, and 180 normal controls were studied. Platelets store 90% of their ADP in dense secretory granules. During activation ADP is secreted and permanently lost from the cell. This leads to a decrease in cellular ADP concentration and a sharp rise in the ATP/ADP ratio. ATP and ADP were ethanol-extracted from platelet-rich plasma, measured in the luciferase-luciferin assay and expressed in nmoles per 10(8) cells. No adenine nucleotide differences were found in platelets from patients free of crisis compared with normal controls. The ADP concentration of platelets from patients in crisis was significantly lowered, indicating that in vivo platelet secretion of ADP had occurred. Total and released ADP was decreased from 2.69 to 1.66, and from 1.90 to 1.21 respectively, and the total ATP/ADP ratio was increased from 1.85 to 2.84 (P less than 0.001). ADP stores in platelets from convalescents were significantly different from sickle controls (P less than 0.001) but were less abnormal than ADP stores in platelets from crisis patients (P less than 0.01), indicating recovery. Total and released ADP was decreased to 1.97 and 1.31 respectively, and the ATP/ADP ratio was increased to 2.38. Platelets from patients in crisis were able to release their remaining granular ADP in response to thrombin as effectively as normal platelets. Thus significant platelet activation with ADP release occurs during acute sickle pain crisis. This might contribute to platelet plug formation and microvascular obstruction.     

High dose vitamin D therapy for chronic pain in children and adolescents with sickle cell disease: results of a randomized double blind pilot study

We report results of a pilot study of high‐dose vitamin D in sickle cell disease (SCD). Subjects were given a 6‐week course of oral high‐dose cholecalciferol (4000–100 000 IU per week) or placebo and monitored prospectively for a period of six months. Vitamin D insufficiency and deficiency was present at baseline in 82·5% and 52·5% of subjects, respectively. Subjects who received high‐dose vitamin D achieved higher serum 25‐hydroxyvitamin D, experienced fewer pain days per week, and had higher physical activity quality‐of‐life scores. These findings suggest a potential benefit of vitamin D in reducing the number of pain days in SCD. Larger prospective studies with longer duration are needed to confirm these effects.     

Thinking beyond sickling to better understand pain in sickle cell disease

Painful vaso‐occlusive crises (VOCs) are the hallmark of sickle cell disease (SCD); however, many patients experience frequent daily pain that does not follow the pattern of typical VOCs. This pain of variable severity, also referred as persistent pain in the SCD literature, contributes to significant morbidity and poor quality of life and often fails to respond adequately to standard SCD therapies. In this article, we briefly describe types of pain encountered in SCD with a special emphasis on persistent pain. We discuss altered pain processing as a potential contributing mechanism, which may lead to development and maintenance of persistent pain. We describe the advances in the non‐SCD pain field that may help improve the understanding of SCD pain. We highlight the need for further investigation in this area because some of these patients with persistent pain may benefit from receiving adjuvant mechanism‐based therapies used successfully in other non‐SCD chronic pain conditions.     

Elevated plasma levels of fibrinopeptide a during sickle cell anemia pain crisis–evidence for intravascular coagulation

A role for coagulation in the pathogenesis of sickle cell anemia (SCA) pain crisis has long been suspected. We have observed evidence for in vivo coagulation in patients with SCA during pain crisis utilizing a radioimmunoassay for fibrinopeptide A (FPA). Since the proteolytic activity of thrombin results in the release of FPA from fibrinogen, plasma levels of FPA may be used as an index of in vivo thrombin activity. In 20 normal controls FPA plasma levels had a range of 0.6–1.4 ng/ml and a mean of 0.7 ± 0.2 ng/ml. We observed elevations of FPA, values greater than the mean plus 4 standard deviations of the control group, in 21 consecutive plasma samples obtained from 8 SCA patients during pain crisis. FPA determinations on 7 of 10 plasma specimens obtained from 10 SCA patients during pain-free periods were within the normal range. Elevations of FPA in 2 of 3 of these pain-free patients could be explained by recent extensive oral surgery and faulty venopuncture, conditions known to cause elevated levels of the peptide. Plasma specimens were obtained from 2 SCA patients patients with subjective complaints of pain, but who were suspected of malingering prior to FPA determination. In both instances, FPA was within the normal range. In summary, plasma levels of FPA appear to be elevated in SCA patients during crisis as contrasted to pain-free periods and normal controls. This study provides new evidence for the occurrence of intravascular coagulation during SCA pain crisis. Further studies are needed to assess whether this activation of the coagulation system is a cause or an effect of pain crisis.     

Clinical response of patients with sickle cell anemia to cromolyn sodium nasal spray

Sickle cell anemia is the most common heritable hematological disease affecting humans. Although hydroxyurea is the most commonly used antisickling agent, several previous studies suggest that cromolyn sodium also prevents sickling when administered acutely. However, no previous studies have evaluated the safety or efficacy of prolonged administration of cromolyn to patients with sickle cell anemia. The purpose of this study, therefore, was to test the hypothesis that prolonged administration of cromolyn alone or in combination with hydroxyurea would decrease the incidence of pain crises and/or alter the chronic pain seen in patients with this disease. In this crossover, single-blind, in vivo and in vitro study, 17 patients with sickle cell disease were studied. Each patient had to fill out a standard pain chart. Every 3 months the patients' medications changed in the following manner: The first 3 months the patients used cromolyn sodium nasal spray; the second 3 months they received placebo nasal spray; the third 3 months they received cromolyn sodium nasal spray and hydroxyurea capsule; and the last 3 months they received hydroxyurea capsule and placebo nasal spray. The least pain was felt with the mixture of hydroxyurea capsule and cromolyn sodium nasal inhaler. Furthermore, with the other combinations of medications, there were no significant statistical changes in the number of sickled red blood cells. Every combination used in this survey had positive effects on decreasing the pain. cromolyn sodium nasal spray is significantly efficient in decreasing sickle cell crisis as well as pain intensity in patients with sickle cell anemia.     

Enhancement of pain control with ketorolac tromethamine in patients with sickle cell vaso-occlusive crisis

Twenty one patients with sickle cell disease admitted to the hospital with the pain of vaso-occlusive crisis (VOC) were treated by continuous IV infusion of ketorolac or normal saline for up to 5 days. All patients received supplemental IM injections of meperidine, 100 mg, as necessary, but not more frequently than every 3 hr. Over the 5 days the ketorolac treated patients (KT) required 33% less meperidine than did the placebo treated patients (PL), P = 0.04, and had significantly better pain relief as assessed by categorical, visual analog, and pain relief scales. By the end of 5 days infusions had been discontinued in six KT and one PL. The time to discontinuation of the infusion was significantly shorter in KT, (P = 0.009). The median duration of hospital stay from the start of treatment was 3.3 days for KT and 7.2 days for PL, P = 0.027. Adverse events were mainly related to the digestive system. This study showed that continuous infusion of ketorolac significantly reduced total meperidine requirement and that the analgesia produced by this combination was superior to that produced by meperidine alone. Further evaluation of this drug in the management of sickle cell VOC is warranted. © 1994 Wiley-Liss, Inc.     

A prophylactic transfusion program for children with sickle cell anemia complicated by CNS infarction

CNS infarction is a devastating complication in sickle cell anemia. Episodes are frequently repetitive and often result in permanent neurologic abnormalities. In an attempt to prevent such recurences a periodic transfusion program was begun at the Children's Hospital of Michigan in 1969. Twenty-one children currently on the program receive buffy-coat poor transfusions on an out-patient basis every 3 weeks. Of 15 who have been on the program for periods of from 9 months to 5 ¾ years, none have had progression of neurologic abnormalities, and several have had definite improvement in neurologic function. One child who was not brought in regularly had recurrent CNS infarction. The only recognized complication has been one instance of serum hepatitis. While such a transfusion of neurologic abnormalities resulting from recurrent CNS infarction in sickle cell anemia.     

Low serum levels of carotenoids in sickle cell anemia

Serum carotenoids, tocopherols and retinol were analyzed in patients with sickle cell anemia (SCA) and in control subjects. The data show the following: the serum levels of the major carotenoids, alpha and beta carotene, cryptoxanthin, lycopene lutein, alpha tocopherol and retinol were significantly lower in SCA patients. These findings reflect an additional abnormality of the antioxidant system in SCA patients. Gamma tocopherol, on the other hand, was significantly elevated, consistent with the previously reported reciprocal relationship between serum alpha and gamma tocopherols. Thus, these data taken together with the earlier findings on the lower levels of plasma alpha tocopherol and ascorbic acid suggest that the entire antioxidant system may be compromised in SCA patients. This may contribute in part to the phenotypic expression of the condition.     

Clinical diversity of sickle cell anemia: genetic and cellular modulation of disease severity

There is a great diversity in the clinical manifestations of sickle cell anemia. Some patients have severe repetitive infarctive episodes culminating in organ failure. Others have minor and nonincapacitating problems. This review focuses on the cellular and genetic factors that may play a role in modulating the clinical effects of the sickle hemoglobin gene. Understanding the role of putative modulators of disease severity may in the future allow the introduction of novel methods of therapy.     

Effect of zinc on hyperammonemia in sickle cell anemia subjects

An increase in plasma ammonia level in human volunteers on restricted zinc intake, and in zinc-deficient rats, has recently been reported. Inasmuch as zinc deficiency has been observed in sickle cell anemia patients, we measured plasma ammonia levels in such subjects. In this report we document hyperammonemia in sickle cell anemia patients that was corrected with zinc therapy.     

Impaired IgM antibody responses to an influenza virus vaccine in adults with sickle cell anemia

Type-specific IgM and IgG antibody responses to a polyvalent influenza vaccine were evaluated in 16 adults with sickle cell anemia, with the use of an enzyme-linked immunosorbent assay. When compared to healthy controls, 8 out of the 16 patients had decreased or undetectable postvaccination anti-influenza IgM antibody levels. These patients were found to have significantly lower serum IgM levels and nondetectable splenic tissue (by 99Tc scans), as compared to those with normal IgM responses. Impaired IgM antibody primary immune responses may play a role in the pathogenesis of infectious complications seen in adult patients with sickle cell anemia.