Sickle cell disease (SCD) is an autosomal recessive genetic blood disorder related to different kinds of defective hemoglobin (Hb) especially common among people with ancestral background from sub-Saharan Africa, South America, the Caribbean, Saudi Arabia, Turkey, Greece, and Italy [1]. Presently, researchers have identified more than 700 structural hemoglobin variants, but only three hemoglobins (Hb) S, C, and E) are widespread. Sickle cell disease is characterized by series of severely painful, recurrent episodes that result from occlusions of small blood vessels leading to frequent emergency room visits. Infections, damage of organs, stroke, and other complications are also common [2]. To date, SCD treatment has been symptomatic with a focus on pain relief with opioids. However, hydroxyurea (HU), the only Federal Drug Administration FDA approved breakthrough in the pharmacotherapy of SCD within the past 20 years, is reportedly capable of modifying the disease pathogenesis, transforming the treatment of sickle cell disease [3].

Despite reports that HU will decrease the incidences of painful crises, and is effective in treating acute chest syndrome, priapism, and increased levels of fetal hemoglobin (HbF) as well as, reduces overall mortality rates in adult patients [4-7], there continues to be minimal use of HU in the management of sickle cell disease. The aim of this project was to perform a systematic review of the literature on the barriers that prevent adolescents aged 12-18 from being compliant with HU. According to the Center for Disease Control and prevention, 2014, the impact of SCD is not only on the patient, but also on the family and society as a whole. The result of this systematic review will be used to recommend a rigorous educational program on the use of HU and to inform patients, their relatives and providers regarding the effects of HU for SCD patients.

Sickle cell disease is an autosomal recessive blood disorder, meaning that the defective gene is on one of the first 22 pairs of chromosomes that do not ascertain gender. As such, SCD affects men and women equally. Getting one copy of the gene from each parent is essential to have the condition; as such, an individual with Hgb SS has acquired the genetic trait for SCD sickle cell disease hemoglobin S (HbS) from both parents [8].

There are three types of genotypes. Healthy individuals have genotype which is the normal hemoglobin (Hb ) AA, unaffected “carriers” have genotype hemoglobin (Hb) AS and are said to have the trait, and those with sickle cell disease have hemoglobin (Hb) SS. If two individuals with HbAS genotypes have children, one child will have a 25% chance of being healthy with HbAA. One child will have a 25% chance of having sickle cell anemia with HbSS genotypes. Two children will have a 50% chance of being an unaffected carrier with HbAS [Figure 1] [8].

Figure 1: Distribution of hemoglobin genotypes.

Other forms of sickle cell disease can also occur if HbS is inherited from one parent and abnormal hemoglobin (for instance hemoglobin C (HbC) or thalassemia β is inherited from the other parent. This will give rise to HbSC or HbSβ respectively. The abnormality in the hemoglobin molecule results from mutation in the β-globin gene where a single nucleotide adenine to thymidine (A to T) in codon for amino acid 6. The change converts a glutamic acid codon (GAG) to a valine codon (GTG) [9]. HbS has a unique property of causing polymerization (cellular aggregation) which changes normal red blood cells from smooth, round (like the letter “O”), and flexible state into a rigid, sticky, sickle-shaped cell (like letter “C”), causing clustering. This change makes movement in the blood vessels difficult. The cluster eventually leads to vaso-occlusion and, as a result: pain crisis, tissue damage, susceptibility to serious infection, and organ failure [9, 10]. In the past, treatment of SCD was mainly symptomatic, with a focus on pain relief using opiates. Hydroxyurea (HU), the only FDA approved medication for SCD has been reported to reduce the damaging effect of SCD and improved some aspects of quality of life of the patients; however, its usage remains minimal [11].

Problem Statement

In the last 100 years, the treatment of SCD has focused on pain management with opioids, and folic acid for increasing fetal hemoglobin (HbF) which according to Ware (2010) [12], is protective against clinical severity. Ware (2010) [12], noted that low-percentage of HbF is linked to a higher risk of developing vaso-occlusive complications, organ damage, and early death. Neither of the early treatment approaches have had a significant impact in decreasing the crisis pain associated with SCD. Other treatments include blood transfusion and other palliative unapproved drugs.

Purpose Statement

The purpose of this project was to review and disseminate knowledge regarding the barriers that prevent adolescents ages 12-18 with SCD from being compliant with HU therapy. Additionally, this systematic review also recognized the stigma associated with HU and the lack of knowledge concerning the decreased use of HU in the SCD population.

In 1910, Herrick was the first to identify sickle cell anemia when he published a description of peculiar and sickle-shaped red blood corpuscles in a case of a 20-year- old student from Grenada, West Indies. This young man was attending school in Chicago, where he complained of pain and was later diagnosed with severe anemia. No conclusion was drawn from his case until further microscopic examination of his blood work and other patients with similar complaints showed the same abnormal shaped cells [13]. Further investigations continued to surface regarding the shape of the corpuscles. Over the years, several patients emerged with different symptomology. Doctors kept track of these patients and their case studies in an attempt to understand this cell disease. In 1949, Dr. Linus Paulding and others discovered that the peculiar cell was due to an abnormal protein molecule. Dr. Paulding was later awarded for his work in linking genetic disorders and sickle cell disease together. This connection marked the birth of the molecular disease concept [14].

Impact of Sickle Cell Disease

People with sickle cell disease experience chronic pain and acute pain episodes which result in frequent emergency room visits. Infection, organ damage, stroke, and other complications can also occur [2]. This disease also affects individuals psychologically, with affects ranging from depression, inappropriate coping strategies, lowered health-related quality of life, inability to perform activities of daily living, and role limitations [15]. SCD is now recognized by world health organization (WHO) as a global health issue that has impacted society as a whole [16]. The goal of Healthy people 2020 is to acknowledge that this disease has affected all people and all ethnicities.

Individuals who are now living longer and healthier lives need health care that will improve their quality of life, healthy development, and healthy behaviors across all stages of life.

An average of 75,000 hospitalizations due to SCD reportedly occurred in the United States from 1989 through 1993. Medical expenditures during 2005 for children with SCD averaged $11,702 for children with Medicaid coverage and $14,772 for children with employer- sponsored insurance [1]. The impact of SCD on the patient, his/her family, and society in general is significant. People with SCD are stereotyped with behaviors of drug dependency, as “frequent flyers” to the emergency department, unemployed, undereducated, and underserved with limited access to health care [2].

To counteract these negative perceptions, health care providers should be educated regarding the disease process, life-threatening complications, available treatment options, and psychosocial concerns of SCD. Most importantly, the individual with SCD must receive appropriate care when it comes to addressing their pain, as the complaint of pain is the hallmark of SCD [2]. There is a need to identify the barriers preventing the use of HU for the management of this patient population. This systematic review will be used to recommend rigorous education on the effects of HU to patients, patient families, caregivers, and health providers.

Several studies reported the effectiveness of HU and showed significant results in increase fetal hemoglobin level, decreases in the frequency of painful attacks, decreases in the number of emergency room visits, decreases in hospitalizations, and improved health-related quality of life [17-20].

The effectiveness of HU was noted even at low doses; the medication still appeared to raise fetal hemoglobin levels in sickle cell patients [17], but this medication continued to be met with resistance. A systematic review of literature examined the different barriers that are preventing adolescents ages 12 – 18 with SCD from complying with HU.

Risks and Benefits of Hydroxyurea

Hydroxyurea is an antineoplastic agent originally synthesized in Germany in 1869. Close to 50 years ago, HU was developed as an anticancer drug for the treatment of some types of leukemia, melanoma, myeloproliferative syndrome, and ovarian cancer [11]. In 1984 HU was introduced as a treatment for sickle cell patients who meet the following criteria: diagnosis of HbSS or S β-thalassemia, ≥ 3 years of age, three or more severe vaso-occlusive pain events per year, or two episodes of acute chest syndrome per year [21]. SCD patients must take their medications, including HU, regularly in order to treat their disease and improve their health. Therefore, it is important to weigh the risks and benefits of such a treatment.

The FDA [22], stated that when a medication’s benefits outweigh its known risks, the agency deems it safe enough to approve it. With regards to HU, benefits recorded since its first testing on SCD patients include but are not limited to an increase in HbF, reduction in hospitalizations and pain crisis, reports of better overall HRQL, and better physical HRQL [23,24]. HU has excellent bioavailability after oral administration and requires only once daily dosing, which enhances medication adherence. This benefit also makes it attractive for use in resource-poor countries, where there may not be widespread access to facilities to perform laboratory monitoring [25,26].

On the other hand, recorded risks include reducing sperm count and motility with resultant abnormal morphology, HU-induced dermatomyositis, mild neutropenia, mild thrombocytopenia, severe anemia, rash, or nail changes [27,28]. Despite the reported risks, HU has been shown to be helpful for sickle cell patients. The first major study of the treatment in 1995 was stopped early as it was clear that HU reduced the number and severity of pain episodes in patients with SCD compared with placebo [11]. In 1998, HU was approved by the FDA for adults with SCD. Hydoxy-urea has been recently approved for use on children, Heeney and Ware [25], reported that HU was a powerful therapeutic drug with proven laboratory and clinical efficacy for children with SCD. One significant concern is the limited report on its toxicity and long term usage.

An observational follow-up conducted by Steinberg et al. [7], on individuals with 9 years of treatment, concluded that adult patients taking HU for frequent pain episodes appeared to have reduced mortality. Similarly, to examine the risks and benefits of long-term HU usage, Steinberg et al. [29], followed patients in their trial for 17.5 years and concluded that long-term HU use is safe and might decrease mortality. During the transition of HU in the treatment for SCD, there needs to be more research that will be carried out for appropriate management of HU use in SCD. In obtaining more reliable and valid data, there have to be more patients who are using HU to develop protocols that will be significant with a great emphasis placed on rigorous education on the effects of HU to patients, family, and providers.

Sickle Cell Disease and Quality of Life

The ultimate goal of health care providers is to maintain or improve the quality of life of individuals in general as well as, people with chronic and debilitating disease like SCD in particular. Traditionally, evaluating the disease burden and effect of treatment of SCD were mainly accomplished by determining laboratory values, calculating mortality data, the number of hospitalizations, and incidents of painful crisis [4,30,31].

Researchers of the last decade noted a significant increase in the development and use of tools to evaluate health-related quality of life (HRQOL) measures. These include pediatric health-related quality of life (PHRQOL) measurements or pediatric quality of life (PedsQL) for children and adolescents [32]. There are generic HRQOL tools that can be used for any disease condition and also disease-specific tools which are necessary for understanding a particular disease condition. For example, PedsQL sickle cell module (PedsQL- SCD) is used to assess children with SCD [33,34]. Since the development of the PedsQL sickle cell module (PedsQL-SCD), studies have been shown that the tool is feasible, reliable, and valid to measure HRQOL in children with SCD. A multisite study by Panepinto et al. [35], of 243 pediatric patients with SCD and 313 parents to report on the properties of the tool, noted that the PedsQOL-SCD module has shown acceptable measurement qualities for use on SCD. The report also demonstrated that use of the tool will foster understanding of the health and well-being of children with SCD [35].

PICOT Question

To examine the evidence, formulation of the clinical issue must be presented in a searchable and answerable question using the patient population (P), intervention or issue of interest (I), comparison intervention (C), status-outcome (O), and the time frame (T) for the intervention to achieve the outcome, in the (PICOT) format. The clinical question was formulated in a structured and specific way to assist the reviewer in finding the appropriate evidence to answer the questions and decrease bias [36]. The patient or population to whom the question applies for this review is adolescents ages 12-18 with SCD. The intervention or issue being considered is the barriers that prevent adolescents with SCD from being compliant with HU? The PICO question that guided this review was: what are the barriers that prevent adolescents ages 12 – 18 with SCD from being compliant with HU?

Frameworks for the Project

The JHNEBP was used for this systematic review of the literature. This evidence-based appraisal guide is a comprehensive manual that provides a novice or advanced nurses with specific guidelines about evidence-based practice [37]. It further detailed a step by step appraisal on how to critique evidence-based studies and rating scales which provided information regarding the quality and strength of evidence used. This manual has a wealth of scholarly authors who are experts in the field of evidence-based practice.

This framework provided the basis for the analysis of evidence available on the barriers preventing SCD patients from using HU. This was achieved by using the model’s application process of practice question, evidence, and translation (PET). This evidence-based practice (EBP) process conceptualizes asking a practice question, finding evidence, and translating the evidence into practice. It therefore, laid the foundation for gathering and assessing additional evidence that was revealed by following the specific steps of the application process. The JHNEBP model is a manual that has been referenced globally for its succinct overview of EBP as well as providing an in-depth and broad structure that is comprehensive and user-friendly.

The JHNEBP has three phases and structures the activities of EBP. According to Newhouse, Dearholt, Poe, Pugh, and White [37], the first phase is the identification of an answerable EBP question, the second phase is the systematic review and synthesis of both research and non- research evidence. This phase has five steps: (a) search for evidence, (b) appraise the evidence,

(c) summarize the evidence, (d) rate the strength and quality of the evidence (See Tables 1 and 2), and (e) develop recommendations. The final phase is translation which is to communicate the findings.

In 1910, Herrick was the first to identify sickle cell anemia when he published a description of peculiar and sickle-shaped red blood corpuscles in a case of a 20-year- old student from Grenada, West Indies. This young man was attending school in Chicago, where he complained of pain and was later diagnosed with severe anemia. No conclusion was drawn from his case until further microscopic examination of his blood work and other patients with similar complaints showed the same abnormal shaped cells [13]. Further investigations continued to surface regarding the shape of the corpuscles. Over the years, several patients emerged with different symptomology. Doctors kept track of these patients and their case studies in an attempt to understand this cell disease. In 1949, Dr. Linus Paulding and others discovered that the peculiar cell was due to an abnormal protein molecule. Dr. Paulding was later awarded for his work in linking genetic disorders and sickle cell disease together. This connection marked the birth of the molecular disease concept [14].

Impact of Sickle Cell Disease

People with sickle cell disease experience chronic pain and acute pain episodes which result in frequent emergency room visits. Infection, organ damage, stroke, and other complications can also occur [2]. This disease also affects individuals psychologically, with affects ranging from depression, inappropriate coping strategies, lowered health-related quality of life, inability to perform activities of daily living, and role limitations [15]. SCD is now recognized by world health organization (WHO) as a global health issue that has impacted society as a whole [16]. The goal of Healthy people 2020 is to acknowledge that this disease has affected all people and all ethnicities.

Individuals who are now living longer and healthier lives need health care that will improve their quality of life, healthy development, and healthy behaviors across all stages of life.

An average of 75,000 hospitalizations due to SCD reportedly occurred in the United States from 1989 through 1993. Medical expenditures during 2005 for children with SCD averaged $11,702 for children with Medicaid coverage and $14,772 for children with employer- sponsored insurance [1]. The impact of SCD on the patient, his/her family, and society in general is significant. People with SCD are stereotyped with behaviors of drug dependency, as “frequent flyers” to the emergency department, unemployed, undereducated, and underserved with limited access to health care [2].

To counteract these negative perceptions, health care providers should be educated regarding the disease process, life-threatening complications, available treatment options, and psychosocial concerns of SCD. Most importantly, the individual with SCD must receive appropriate care when it comes to addressing their pain, as the complaint of pain is the hallmark of SCD [2]. There is a need to identify the barriers preventing the use of HU for the management of this patient population. This systematic review will be used to recommend rigorous education on the effects of HU to patients, patient families, caregivers, and health providers.

Several studies reported the effectiveness of HU and showed significant results in increase fetal hemoglobin level, decreases in the frequency of painful attacks, decreases in the number of emergency room visits, decreases in hospitalizations, and improved health-related quality of life [17-20].

The effectiveness of HU was noted even at low doses; the medication still appeared to raise fetal hemoglobin levels in sickle cell patients [17], but this medication continued to be met with resistance. A systematic review of literature examined the different barriers that are preventing adolescents ages 12 – 18 with SCD from complying with HU.

Risks and Benefits of Hydroxyurea

Hydroxyurea is an antineoplastic agent originally synthesized in Germany in 1869. Close to 50 years ago, HU was developed as an anticancer drug for the treatment of some types of leukemia, melanoma, myeloproliferative syndrome, and ovarian cancer [11]. In 1984 HU was introduced as a treatment for sickle cell patients who meet the following criteria: diagnosis of HbSS or S β-thalassemia, ≥ 3 years of age, three or more severe vaso-occlusive pain events per year, or two episodes of acute chest syndrome per year [21]. SCD patients must take their medications, including HU, regularly in order to treat their disease and improve their health. Therefore, it is important to weigh the risks and benefits of such a treatment.

The FDA [22], stated that when a medication’s benefits outweigh its known risks, the agency deems it safe enough to approve it. With regards to HU, benefits recorded since its first testing on SCD patients include but are not limited to an increase in HbF, reduction in hospitalizations and pain crisis, reports of better overall HRQL, and better physical HRQL [23,24]. HU has excellent bioavailability after oral administration and requires only once daily dosing, which enhances medication adherence. This benefit also makes it attractive for use in resource-poor countries, where there may not be widespread access to facilities to perform laboratory monitoring [25,26].

On the other hand, recorded risks include reducing sperm count and motility with resultant abnormal morphology, HU-induced dermatomyositis, mild neutropenia, mild thrombocytopenia, severe anemia, rash, or nail changes [27,28]. Despite the reported risks, HU has been shown to be helpful for sickle cell patients. The first major study of the treatment in 1995 was stopped early as it was clear that HU reduced the number and severity of pain episodes in patients with SCD compared with placebo [11]. In 1998, HU was approved by the FDA for adults with SCD. Hydoxy-urea has been recently approved for use on children, Heeney and Ware [25], reported that HU was a powerful therapeutic drug with proven laboratory and clinical efficacy for children with SCD. One significant concern is the limited report on its toxicity and long term usage.

An observational follow-up conducted by Steinberg et al. [7], on individuals with 9 years of treatment, concluded that adult patients taking HU for frequent pain episodes appeared to have reduced mortality. Similarly, to examine the risks and benefits of long-term HU usage, Steinberg et al. [29], followed patients in their trial for 17.5 years and concluded that long-term HU use is safe and might decrease mortality. During the transition of HU in the treatment for SCD, there needs to be more research that will be carried out for appropriate management of HU use in SCD. In obtaining more reliable and valid data, there have to be more patients who are using HU to develop protocols that will be significant with a great emphasis placed on rigorous education on the effects of HU to patients, family, and providers.

Sickle Cell Disease and Quality of Life

The ultimate goal of health care providers is to maintain or improve the quality of life of individuals in general as well as, people with chronic and debilitating disease like SCD in particular. Traditionally, evaluating the disease burden and effect of treatment of SCD were mainly accomplished by determining laboratory values, calculating mortality data, the number of hospitalizations, and incidents of painful crisis [4,30,31].

Researchers of the last decade noted a significant increase in the development and use of tools to evaluate health-related quality of life (HRQOL) measures. These include pediatric health-related quality of life (PHRQOL) measurements or pediatric quality of life (PedsQL) for children and adolescents [32]. There are generic HRQOL tools that can be used for any disease condition and also disease-specific tools which are necessary for understanding a particular disease condition. For example, PedsQL sickle cell module (PedsQL- SCD) is used to assess children with SCD [33,34]. Since the development of the PedsQL sickle cell module (PedsQL-SCD), studies have been shown that the tool is feasible, reliable, and valid to measure HRQOL in children with SCD. A multisite study by Panepinto et al. [35], of 243 pediatric patients with SCD and 313 parents to report on the properties of the tool, noted that the PedsQOL-SCD module has shown acceptable measurement qualities for use on SCD. The report also demonstrated that use of the tool will foster understanding of the health and well-being of children with SCD [35].

PICOT Question

To examine the evidence, formulation of the clinical issue must be presented in a searchable and answerable question using the patient population (P), intervention or issue of interest (I), comparison intervention (C), status-outcome (O), and the time frame (T) for the intervention to achieve the outcome, in the (PICOT) format. The clinical question was formulated in a structured and specific way to assist the reviewer in finding the appropriate evidence to answer the questions and decrease bias [36]. The patient or population to whom the question applies for this review is adolescents ages 12-18 with SCD. The intervention or issue being considered is the barriers that prevent adolescents with SCD from being compliant with HU? The PICO question that guided this review was: what are the barriers that prevent adolescents ages 12 – 18 with SCD from being compliant with HU?

Frameworks for the Project

The JHNEBP was used for this systematic review of the literature. This evidence-based appraisal guide is a comprehensive manual that provides a novice or advanced nurses with specific guidelines about evidence-based practice [37]. It further detailed a step by step appraisal on how to critique evidence-based studies and rating scales which provided information regarding the quality and strength of evidence used. This manual has a wealth of scholarly authors who are experts in the field of evidence-based practice.

This framework provided the basis for the analysis of evidence available on the barriers preventing SCD patients from using HU. This was achieved by using the model’s application process of practice question, evidence, and translation (PET). This evidence-based practice (EBP) process conceptualizes asking a practice question, finding evidence, and translating the evidence into practice. It therefore, laid the foundation for gathering and assessing additional evidence that was revealed by following the specific steps of the application process. The JHNEBP model is a manual that has been referenced globally for its succinct overview of EBP as well as providing an in-depth and broad structure that is comprehensive and user-friendly.

The JHNEBP has three phases and structures the activities of EBP. According to Newhouse, Dearholt, Poe, Pugh, and White [37], the first phase is the identification of an answerable EBP question, the second phase is the systematic review and synthesis of both research and non- research evidence. This phase has five steps: (a) search for evidence, (b) appraise the evidence,

(c) summarize the evidence, (d) rate the strength and quality of the evidence (See Tables 1 and 2), and (e) develop recommendations. The final phase is translation which is to communicate the findings.

Table 1: HNEBP Strength of Research Evidence Rating Scale.

Search Strategy

A systematic review of the literature was carried out in an attempt to meet the project goals of identifying the barriers that prevent SCD patients from being compliant with HU. It also addressed stigma, lack of knowledge concerning treatment, and gaps that exist in the SCD population relating to HU. The search included articles published in English from 2003 to 2013, using the databases: CINAHL, MEDLINE, Pub Med, Academic Search Premier, Cochrane clinical trials, and National Library of Medicine. The electronic computer searches also consisted of the following journals; Sigma Theta Tau International, Nurses Science Quarterly, and Journal of Blood. The literature was briefly summarized on HU usage in the management of SC crisis, the effect of HU on the HRQL of SCD patients, and the state of knowledge in HU use on children with SCD. The literature describing adverse reactions, effectiveness, and toxicity of HU is considered. Studies exploring the concerns of the long term effects of HU were reviewed and critiqued. The limited studies to date of barriers preventing HU usage were evaluated, and the findings from this group of studies were synthesized and conclusions were drawn regarding the gaps in knowledge that can be revealed by this systematic review. Additionally, this section discusses the literature search strategy, including the databases and libraries accessed, search engines used, the extent of the literature, and key terms utilized. This section further addresses the concepts, models, theories, and framework used and the reason for their selection.

For the purpose of this systematic review, the following terms were defined:

Health-related quality of life (HRQOL): is defined as the patient’s perception of his/her well-being and level of functioning compared with a perceived ideal as affected by his/her health. Tools that measures HRQOL are multidimensional and include physical, emotional, and social components, as well as school/work functioning [38].

Hemoglobinopathies: are a group of inherited disorders in which there is abnormal production or structure of the hemoglobin molecule. Examples include HbC, HbS-C, sickle cell anemia, and different types of thalassemia [39].

Hydroxyurea (HU): is defined as an antineoplastic agent approved by FDA for the treatment of adults with sickle cell disease. It induces HbF production, increases erythrocyte hydration, and reduces cell adhesiveness among other things. It has also been reported to be a powerful therapeutic agent with proved laboratory and clinical efficacy for children with SCD [25].

Sickle cell crisis: is defined as the beginning of painful episodes in patients with SCD resulting from occlusion of blood vessels by sickle-shaped red blood cells. It is manifested as severe pain in the extremities, back, abdomen, or chest, and is usually associated with fever and the passage of dark or red urine [40].

Sickle Cell Disease (SCD): is defined as a chronic autosomal recessive hereditary disorder caused by the presence of hemoglobin S (HbS). This abnormality in the homozygote (SS) induces polymerization of some Hb, impeding movement blood circulation. It is characterized by chronic hemolytic anemia, acute vaso-occlusive crisis, and an increased risk for infection [41].

Initially, the assumptions were focused on the belief that SCD patients felt that HU was an experimental drug used primarily for the treatment for cancer patients. HU has been used for the treatment of many other diseases, including SCD. The evidence has shown that there was limited research done on the long-term effects of the medication on SCD. Other patients believed that the drug is too harmful, and some would rather take the chance of just living without the use of HU. Because of the limited research completed on HU for SCD, there is little knowledge about the drug’s effectiveness and toxicity (Heeney and Ware (2009) [25]. Due to the scant number of patients that participated in the clinical trial for long term use of HU, there is not enough evident to show exactly how efficient HU use is for long-term management. Some research studies that were directly focused on HU tolerance found that the treatment had positive results in the treatment of SCD. In essence, many of the non-compliancy issues were found to be due to fertility concerns [27].

Inclusion and Exclusion Criteria

This systematic review examined studies that included adolescents’ ages 12-18 years old, who were diagnosed with SCD and were being managed with HU therapy. Articles that identified specific barriers were also included. Articles that included title, keywords, or abstracts that were vague and not related to the research question were excluded.

The goal of this search approach was to retrieve both published and unpublished studies. Using a three-step strategy, an initial search of CINAHL and MEDLINE was done to form a list of keywords, next was the analysis of the text words contained in title and abstract, as well as in the index terms used for the description of the article. Using all identified keywords and index terms, a second search was done across all included databases. All studies that met inclusion criteria were retrieved for review. Finally, the reference list of all identified reports and articles were searched for additional studies

The initial search located N=19,932 potentially relevant articles. The articles that had the key words HU and SCD (N=99), based on the title, or abstracts were reviewed. There were (N=31) articles that were specific to different types of SCD, including the thalassemia’s, minor and major as well as sickle cell disease Hgb C. Finally, there were only, (N=5) articles that reported on barriers specific to HU use: from the providers’, patients’, and families’ perspectives. These five articles have shown the different kinds of barriers specific to the use of HU and are illustrated in Table 4. The remaining 26 articles were vague and did not identify the effects of HU for SCD. These articles only briefly mentioned HU as in innovative treatment, but failed to report any significant findings as they relate to the efficacy and safety of the drug. As a result, these articles did not meet the inclusion criteria. The results of the electronic literature search and strategy are shown in Table 3 and Figure 2.

Table 3: SCD and HU Electronic Database Search.

SCD continues to be a complicated disease to manage, despite the innovations in treatment since its discovery in 1910. Although the trajectory of the disease has improved, with individuals living into their forties and fifties, there are many treatment approaches that need to be assessed to improve patients’ quality of life. The utilization of the JHNEBP evidence rating scale was used to assess the quality of various types of non-randomized and randomized studies for strength and quality. The EBP guideline also helped to acquire a better understanding of the barriers preventing SC patients from complying with HU. The extensive search yielded only five articles for synthesis. This systematic review of the literature did not use actual human subjects. As such, the IRB was approved for an exempted review.

Despite the significant findings of the effects of HU, many barriers to treatment still exist.

Some restrictions prevent patients from achieving the effects of a drug that may have increased benefits: decrease crises pain, reduce emergency department visits, increase HbF levels and improve polymerization of the cells, causing less sticking of cells. Despite limited use in children ages < 3, the review of literature also revealed that HU may contribute to the improvement of HRQL of adolescents with SCD. Due to morbidity and mortality associated with SCD, efforts to improve their QOL are of great concerns. The minimal usage of HU continues to be a gap that was identified by this review. Further research needs to be conducted to better understand the barriers that prevent the SCD patients from using HU.

Findings

The identified articles were evaluated with the JHNEBP guidelines for strength and quality. This reference provided a framework for analyzing EBP, in which specific indicators provided rating scales and the quality of the tool. This format provided levels of the strength of the evidence. This prioritized the research based on its rigor, systematic approaches, and the type of clinical trials conducted. This kind of leveling differentiates between experimental studies and nonexperimental studies, such as cohort studies, case studies, qualitative studies and quasi- experimental studies (See Table 4).

Table 4: JHNEBP Evidence Rating Scales: Strength and Quality of the Evidence.

There has been limited research conducted on HU therapy for managing SCD, and the barriers to its use. However, published evidence supports the argument that HU induces the production of HbF, decreases the hospitalization rate, and decreases the infection rate of adolescents with SCD. The lack of data concerning adults taking this therapy or the long-term effects of this treatment on children is a major concern. It will be difficult to arrive at a conclusion because of limited evidence.

Two of the five articles included in this review arrived at final decisions based on a minuscule number of studies carried out in this field. The researchers, Lebensburger et al. [44], had some concerns when using African-Americans (AAs) in research studies. Focus group attendance was low, reducing diversity and addressing the common beliefs regarding how AAs see the participation in research. The report of how AAs feel about participating was very obvious. The study identified three main themes related to barriers to clinical trial enrollment:

(a) general barriers to health related research; practical issues, emotional issues, mistrust of doctors or studies, (b) concerns of trial design; randomization, and (c) concerns of HU; long term unknown risks. Despite the small number of participants, focus group n=3; parents/guardian n=14, saturation was achieved, leading to significant contributions to the development of strategies for the recruitment of AA children in clinical studies [44].

Ware (2010), who reported on HU use for young children with SCD, had15 years of experience with the use of HU for SCD patients. He observed hundreds of patients with SCD who participated in the HU trial. The study identified barriers to the use of HU to include provider’s inadequate knowledge about HU, patients and family not offered treatment, and when

offered refuse due to unrealistic fears. Data from randomized controlled trials (RCT) will be needed to provide statistical evidence of the efficacy and toxicity of HU in the management of SCD [12].

Additionally, the survey done by Zumberg et al. identified barriers to the broader use of HU, which include: (a) physicians’ concern about carcinogenic potential, (b) doubts about HU effectiveness, (c) perceived patient apprehension about adverse effects, (d) concerns about the lack of contraceptive use, and (e) non-compliance of patients. The survey was limited to Florida and North Carolina, and as such was not sufficient representation of the sickle cell population. Zumber et al. (2005) addressed the risks of HU use that cannot be disregarded, but rather provide the consumers with needed information necessary to make the best decisions [45].

Zumber et al. reported that a decrease in the neutrophil count is associated with HU which exposes the patient to infection.

Strouse and Heeney [26], recommended treatment guidelines for the use of HU in treating children with SCD. Their recommendations were based on the evidence that HU reduces painful events and hospitalization in children of all ages with HbSS. The evidence is not sufficient enough to convince the authors to start HU in all children with SCD. Because limited research was done for children with SCD, little is known about the efficacy and the complete interactions of HU. However, active research and investigation continue in order to validate the effects of HU use in children with SCD [46]. Poor adherence was identified as the primary reason that HU therapy is ineffective in the treatment of children with SCD. Lack of knowledge about HU continues to be a challenge. The review of evidence illustrates that there is a need for future research on the use of HU.

Implications for Research

The study has demonstrated that research is limited in the area of HU therapy and the non-compliance of therapy among adolescents ages 12–18 with SCD. The reason for this is multifaceted. According to Heeney [26], some reasons for the nonadherence are systemic barriers, patient and family/caregiver barriers, and provider barriers. The care of this patient population cannot be carried out adequately until the reasons related to the limited usage of HU are addressed.

Further research needs to address the barriers that are preventing the SCD patients to adhere to the HU medical regimen. Several studies indicate that the use of HU has been beneficial in the decrease of painful sickle cell crises when HU is maintained [18,38,47,48]. Therefore, it would be beneficial for nurses to identify the causative agents involved in decreased use of HU in SCD.

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