Pupil Size and Reactivity in Pediatric Patients With Sickle Cell Disease.

Pupil size and reactivity have been studied to objectively measure pain utilizing pupillometry measurements. Given the challenges associated with treating vaso-occlusive pain in pediatric patients with sickle cell disease, better assessment tools are needed. The objective of this study is to establish normative values for pupil size and reactivity in pediatric patients with sickle cell disease with the hope that pupillometry can be used as a tool to objectively measure pain and response to treatment with analgesic medications. Readings were performed using a NeurOptics PLR-2000 pupillometer. Forty-four males and 38 females, all black, were studied. Their median age was 11 years (range: 2 to 21). When comparing our participants with white participants in a previously published pediatric study, there was a significant difference in maximum constriction velocity ( t =3.45, P =0.009), maximum pupil size ( t =-5.57 mm, P <0.0001), and minimum pupil size ( t =-3.24, P =0.002). There was no significant difference in pupil size and reactivity between patients with sickle cell disease and black patients without the disease when compared with the previously published study. Therefore, further investigation of pupillometry within the black population during vaso-occlusive crisis and in the "well state" is warranted in pediatric patients with sickle cell disease.

Pharmacokinetics of bleomycin sclerotherapy in patients with vascular malformations.

Bleomycin, a chemotherapy agent that inhibits synthesis of DNA, has been increasingly utilized in sclerotherapy for patients with vascular malformations. A serious long-term risk of intravenous bleomycin is dose-dependent interstitial pneumonitis. Little is known about absorption and circulating levels of bleomycin when used in sclerotherapy for patients with vascular malformations. This is an Institutional Review Board (IRB)-approved prospective study on patients receiving bleomycin sclerotherapy in the management of vascular malformations. Depending on the type of vascular malformation, bleomycin was administered either in the lumen or interstitial space of the involved lesion. A bleomycin assay measured serum bleomycin plasma concentrations versus time at seven intervals following treatment. Pharmacokinetic parameters were obtained for each participant and included peak plasma concentration (Cmax ), time to reach peak plasma concentration (Tmax ), volume of distribution (Vd ), elimination half-life (t1/2 ), the volume of plasma cleared of the drug per unit time (CL), and total systemic exposure area under the curve (AUC). Fifteen patients were enrolled (5: lymphatic, 4: venous, 6: arteriovenous malformations). Bleomycin was administered interstitially (IS) in 11 patients and intraluminal (IL) in four; median age of 13 years (range: 2-67). Pharmacokinetic analysis revealed terminal elimination half-life (t1/2λz ) of 88.51 (±23.09) and 111.61 (±37.75) minutes for the IS and IL groups, respectively. Vd was 4.86 L (±6.74) and 1.55 L (±0.54) for the IS and IL groups, respectively. AUC was 53.9 (±23.45) and 129.17 (±93.57) mg min/L for the IS and IL groups, respectively. There were no statistically significant differences in t1/2λz , Vd , or AUC parameters between groups. Bleomycin is absorbed systemically when used as a sclerosant for vascular malformations when injected either IS or IL.

Primary prevention of stroke in children with sickle cell anemia in sub-Saharan Africa: rationale and design of phase III randomized clinical trial.

Strokes in children with sickle cell anemia (SCA) are associated with significant morbidity and premature death. Primary stroke prevention in children with SCA involves screening for abnormal transcranial Doppler (TCD) velocity coupled with regular blood transfusion therapy for children with abnormal velocities, for at least one year. However, in Africa, where the majority of children with SCA live, regular blood transfusions are not feasible due to inadequate supply of safe blood, cost, and the reluctance of caregivers to accept transfusion therapy for their children. We describe the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria Trial [StrokePreventioninNigeria (SPRING) trial, NCT02560935], a three-center double-blinded randomized controlled Phase III clinical trial to 1) determine the efficacy of moderate fixed-dose (20 mg/kg/day) versus low fixed-dose (10 mg/kg/day) hydroxyurea therapy for primary stroke prevention; 2) determine the efficacy of moderate fixed-dose hydroxyurea for decreasing the incidence of all cause-hospitalization (pain, acute chest syndrome, infection, other) compared to low fixed-dose hydroxyurea. We will test the primary hypothesis that there will be a 66% relative risk reduction of strokes in children with SCA and abnormal TCD measurements, randomly allocated, for a minimum of three years to receive moderate fixed-dose versus low fixed-dose hydroxyurea (total n = 220). The results of this trial will advance the care of children with SCA in sub-Saharan Africa, while improving research capacity for future studies to prevent strokes in children with SCA.

Servant Leadership and Spirituality Among Undergraduate and Graduate Nursing Students.

Nursing students represent the future of nursing. In today's increasingly complex health care environment nurse leaders must develop a distinct leadership style based on methodologically sound research to shape tomorrow's clinical practice. The purpose of this study is to determine the relationship between spirituality and servant leadership characteristics in undergraduate and graduate nursing students. Although the relationship between these two concepts has been studied in the workplace, less is known about the links of servant leadership and spirituality among nursing students. Data from 66 student participants were analyzed using the Servant Leadership and Spirituality Scales. The results indicated nursing students had relatively high levels of spirituality and servant leadership. A significant positive association was found between overall servant leadership and spirituality scores. Servant leadership characteristics increased from Bachelor of Science in Nursing (BSN) to Master of Science in Nursing (MSN) program students, but then decreased among the doctoral students. A decline in servant leadership was also demonstrated in nurses in practice greater than 10 years. Spirituality scores declined slightly in nurses' early years of practice, then rebounded and continued to progress with increased years of practice. The authors concluded that students that select nursing as a professional career may inherently possess characteristics of servant leadership and spirituality.

Measuring hydroxyurea adherence by pharmacy and laboratory data compared with video observation in children with sickle cell disease.

BACKGROUND: Hydroxyurea nonadherence is common among children with sickle cell disease (SCD), but it is unclear if current adherence measures are valid compared with video directly observed therapy (VDOT), a reference method. The objectives were to evaluate if hydroxyurea adherence by pharmacy records, urine assay, mean corpuscular volume (MCV), and/or fetal hemoglobin (HbF) correlated with and was sensitive and specific compared with VDOT. METHODS: This was a cross-sectional analysis of adherence data from 34 children with SCD on a single-arm, six-month hydroxyurea adherence study. Spearman correlation coefficient compared participants' adherence by pharmacy records, MCV, and HbF to adherence by VDOT. The sensitivity and specificity of ≥80% adherence by pharmacy records, two urine samples with hydroxyurea, MCV ≥100 fl/L, and HbF ≥20% compared with ≥80% VDOT adherence were also calculated. RESULTS: Median pharmacy and VDOT adherence rates were similar (87.8% vs 88.1%, P = 0.75) and mildly correlated (rs  = 0.45; P = 0.008) but the sensitivity of ≥80% adherence by pharmacy records was 72.7% and specificity was 45.5%. MCV (rs  = -0.02, P = 0.92) and HbF (rs  = -0.2, P = 0.33) did not significantly correlate with VDOT adherence. Sensitivity and specificity were 83.3% and 33.3% for having two urine samples with hydroxyurea, 35% and 71.4% for MCV ≥100 fl/L, and 75% and 0% for HbF ≥20%, respectively. CONCLUSIONS: Commonly used tools to measure hydroxyurea adherence may not correlate with or be valid compared with video adherence. Future studies to refine these measures are needed to effectively target adherence interventions to children with SCD who have the potential to benefit. (ClinicalTrials.gov NCT02578017).

Hydroxycarbamide in children with sickle cell anaemia after first-dose vs. chronic therapy: pharmacokinetics and predictive models for drug exposure.

AIMS: The purposes of this work were to: (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HCnew ) vs. those receiving chronic therapy (HCchronic ), (2) assess the external validity of a published PK dosing strategy, and (3) explore the accuracy of dosing strategies based on a limited number of HC measurements. METHODS: Utilizing data from two prospective, multicenter trials of hydroxycarbamide (Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia; NCT01506544 and Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease), plasma drug concentration vs. time profiles were evaluated with a model independent approach in the HCnew and HCchronic groups. Various predictive scenarios were analysed to evaluate whether systemic exposure with hydroxycarbamide could be accurately predicted. RESULTS: Absorption of hydroxycarbamide was rapid, variable and dose independent. Dose-normalized peak plasma concentrations and drug exposure (AUC) were higher, and weight-normalized apparent oral clearance was lower in the HCnew group. We assessed a PK-guided dosing strategy along with other predictive scenarios and found that inclusion of plasma samples only slightly improved the accuracy of AUC predictions when compared to a population-based method. CONCLUSIONS: Children naïve to hydroxycarbamide exhibit a different PK profile compared to children receiving chronic therapy. Accuracy of population-based dosing is sufficient to target AUCs in individual patients. Further clearance/bioavailability studies are needed to address the factors responsible for variability in the disposition of hydroxycarbamide.

Feasibility trial for primary stroke prevention in children with sickle cell anemia in Nigeria (SPIN trial).

The vast majority of children with sickle cell anemia (SCA) live in Africa, where evidence-based guidelines for primary stroke prevention are lacking. In Kano, Nigeria, we conducted a feasibility trial to determine the acceptability of hydroxyurea therapy for primary stroke prevention in children with abnormal transcranial Doppler (TCD) measurements. Children with SCA and abnormal non-imaging TCD measurements (≥200 cm/s) received moderate fixed-dose hydroxyurea therapy (∼20 mg/kg/day). A comparison group of children with TCD measurements <200 cm/s was followed prospectively. Approximately 88% (330 of 375) of families agreed to be screened, while 87% (29 of 33) of those with abnormal TCD measurements, enrolled in the trial. No participant elected to withdraw from the trial. The average mean corpuscular volume increased from 85.7 fl at baseline to 95.5 fl at 24 months (not all of the children who crossed over had a 24 month visit), demonstrating adherence to hydroxyurea. The comparison group consisted of initially 210 children, of which four developed abnormal TCD measurements, and were started on hydroxyurea. None of the monthly research visits were missed (n = total 603 visits). Two and 10 deaths occurred in the treatment and comparison groups, with mortality rates of 2.69 and 1.81 per 100 patient-years, respectively (P = .67). Our results provide strong evidence, for high family recruitment, retention, and adherence rates, to undertake the first randomized controlled trial with hydroxyurea therapy for primary stroke prevention in children with SCA living in Africa.

Pharmacokinetics of two 6-mercaptopurine liquid formulations in children with acute lymphoblastic leukemia.

BACKGROUND: A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation. METHODS: Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts. Group 1 (n = 11; five males) received a 5 mg/ml liquid formulation and the marketed 50 mg 6-MP tablet on separate occasions, and Group 2 (n = 11; five males) received a 50 mg/ml liquid formulation and the marketed tablet. The usual prescribed 6-MP dose (25-115 mg/m2 ) was given after an 8-hr fast. Serial blood samples were collected over 8 hr postdose. Plasma 6-MP concentrations were determined using a good laboratory practice (GLP)-validated liquid chromatography-tandem mass spectrometry method. PK parameters were calculated using noncompartmental analysis and compared within and between cohorts, and thiopurine methyltransferase (TPMT) genotype was analyzed. RESULTS: No patient had a TPMT genotype reflective of a poor metabolizer phenotype. Comparison of PK parameters between 5 and 50 mg/ml treatments revealed significant differences (P <0.05) in AUCN (where AUC is area under the curve), CmaxN , and Tmax . Comparisons within each group revealed significant differences in AUC0-∞ and Tmax in the 5 mg/ml group. CONCLUSIONS: Pharmacokinetic profiles of 6-MP established in healthy adults with the approved liquid formulation may not reflect the PK profile in children with ALL. Formulation-specific differences in PK may significantly impact the dose-exposure profile in these children and must be considered.

A Pilot Study to Examine the Relationship Between Napping and Fatigue in Nurses Practicing on the Night Shift.

OBJECTIVE: The aim of this study is to explore the relationship of night-shift napping on fatigue. BACKGROUND: Nurses' fatigue, especially at night, interferes with quality of life and job performance and impacts safety and health. METHODS: Night-shift nurses completed the Brief Fatigue Inventory and a demographic information sheet to determine differences in fatigue between nurses who napped during their night shift as compared with nurses who did not nap. RESULTS: No statistically significant differences in global fatigue were found; differences in rotating shift, age, and, gender were identified. Rotating shifts, a 2nd job, and caring for family predicted fatigue. CONCLUSIONS: Based on this pilot study, further investigations of fatigue among night-shift nurses are needed as well as evidence-based support to promote sleep.

Implementation of Quiet Time for Noise Reduction on a Medical-Surgical Unit.

OBJECTIVE: The objective of this evidence-based investigation is to determine the efficacy of a quiet-time intervention to reduce noise in the hospital setting. BACKGROUND: For many reasons, noise continues to increase in the hospital setting. METHODS: In a descriptive comparative design, using a convenience sample of hospitalized patients, 80 patients were assessed on their perceptions of noise using the Patient Survey on Noise During Hospital Stay. RESULTS: Data revealed favorable responses to quiet time, with 70% of subjects reporting quiet-time intervention to be effective in reducing noise. Sixty percent of participants felt that 1 hour of quiet time helped to facilitate a quieter, more restful environment for the whole day. CONCLUSION: A quiet-time intervention is effective in addressing patient perception of noise while in the acute care hospital setting.

Health-related quality of life in children with sickle cell anemia: impact of blood transfusion therapy.

The completion of the Multicenter Silent Infarct Transfusion Trial demonstrated that children with pre-existing silent cerebral infarct and sickle cell anemia (SCA) who received regular blood transfusion therapy had a 58% relative risk reduction of infarct recurrence when compared to observation. However, the total benefit of blood transfusion therapy, as assessed by the parents, was not measured against the burden of monthly blood transfusion therapy. In this planned ancillary study, we tested the hypothesis that a patient centered outcome, health-related quality of life (HRQL), would be greater in participants randomly assigned to the blood transfusion therapy group than the observation group. A total of 89% (175 of 196) of the randomly allocated participants had evaluable entry and exit HRQL evaluations. The increase in Change in Health, measured as the child's health being better, was significantly greater for the transfusion group than the observation group (difference estimate = -0.54, P ≤ 0.001). This study provides the first evidence that children with SCA who received regular blood transfusion therapy felt better and had better overall HRQL than those who did not receive transfusion therapy.

Isotope-dilution gas chromatography-mass spectrometry method for the analysis of hydroxyurea.

BACKGROUND: Hydroxyurea is used in the treatment of various malignancies and sickle cell disease. There are limited studies on the pharmacokinetics of hydroxyurea, particularly in pediatric patients. An accurate, precise, and sensitive method is needed to support such studies and to monitor therapeutic adherence. We describe a novel gas chromatography-mass spectrometry (GC-MS) method for the determination of hydroxyurea concentration in plasma using stable labeled hydroxyurea C N2 as an internal standard. METHODS: The method involved an organic extraction followed by the preparation of trimethylsilyl (TMS) derivatives of hydroxyurea for GC-MS selected ion-monitoring analysis. The following mass-to-charge (m/z) ratio ions for silated hydroxyurea and hydroxyurea C N2 were monitored: hydroxyurea-quantitative ion 277, qualifier ions 292 and 249; hydroxyurea C N2-quantitative ion 280, qualifier ion 295. This method was evaluated for reportable range, accuracy, within-run and between-run imprecisions, and limits of quantification. RESULTS: The reportable range for the method was 0.1-100 mcg/mL. All results were accurate within an allowable error of 15%. Within-run and between-run imprecisions were <15%. Samples were stable for at least 4 hours at room temperature, 2 months at -20°C, and 6 months at -70°C, and after 3 freeze/thaw cycles. Extraction efficiency for 1-, 5-, 10-, and 50-mcg/mL samples averaged 2.2%, 1.8%, 1.6%, and 1.4%, respectively. CONCLUSIONS: The isotope-dilution GC-MS method for analysis of hydroxyurea described here is accurate, sensitive, precise, and robust. Its characteristics make the method suitable for supporting pharmacokinetic studies and/or clinical therapeutic monitoring.

Primary stroke prevention in Nigerian children with sickle cell disease (SPIN): challenges of conducting a feasibility trial.

BACKGROUND: The majority of children with sickle cell disease (SCD), approximately 75%, are born in sub-Saharan Africa. For children with elevated transcranial Doppler (TCD) velocity, regular blood transfusion therapy for primary stroke prevention is standard care in high income countries, but is not feasible in sub-Saharan Africa. PROCEDURE: In the first U.S. National Institute of Health (NIH) sponsored SCD clinical trial in sub-Saharan Africa, we describe the protocol and challenges unique to starting a clinical trial in this region. We are conducting a single arm pilot trial of hydroxyurea therapy in children with TCD velocity ≥200 cm/sec in the middle cerebral arteries. Eligible children will be placed on hydroxyurea (n = 40) and followed for 3 years at Aminu Kano Teaching Hospital, Nigeria. Adherence will be measured via the Morisky Scale and adverse events will be determined based on hospitalization. RESULTS: Originally, a randomized placebo trial was planned; however, placebo was not approved by the local Ethics Committee. Hence a single arm trial of hydroxyurea will be conducted and five controls per patient with normal TCD measurements will be followed to compare the rate of adverse events to those with abnormal TCD measurements taking hydroxyurea. Using non-NIH funding, over 9 months, multiple face-to-face investigator meetings were conducted to facilitate training. CONCLUSION: A hydroxyurea trial (NCT01801423) for children with SCD is feasible in sub-Saharan Africa; however, extensive training and resources are needed to build a global patient oriented multi-disciplinary research team with a common purpose.

VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children.

BACKGROUND: Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9/VKORC1/CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children. PROCEDURE: Clinical and genetic data for 93 children (age ≤ 18 years) who received warfarin therapy were obtained. DNA was genotyped for 93 selected single nucleotide polymorphisms using a custom assay. RESULTS: With a median age of 4.8 years, our cohort included more young children than most previous studies. Overall, 76.3% of dose variability was explained by weight, indication, VKORC1-1639G/A and CYP2C9 *2/*3, with genotypes accounting for 21.1% of variability. There was a strong correlation (R(2) = 0.68; P < 0.001) between actual and predicted warfarin dose using a pediatric genotype-based dosing model. VKORC1 genotype had a significant impact on time to therapeutic international normalized ratio (INR) (P = 0.047) and time to over-anticoagulation (INR > 4; P = 0.024) during the initiation of therapy. CYP2C9*3 carriers were also at increased risk of major bleeding while receiving warfarin (adjusted OR = 11.28). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose (P = 0.020) in a multivariate clinical and genetic model. CONCLUSIONS: This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of genetic factors on clinical outcomes in children. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children.

Challenges in nursing practice: nurses' perceptions in caring for hospitalized medical-surgical patients with substance abuse/dependence.

OBJECTIVE: The objective of this study was to investigate nurses' perceptions of caring for hospitalized medical-surgical patients with comorbid conditions of substance abuse/dependence. BACKGROUND: Critical to this issue of quality patient care is the rising incidence of comorbid drug and alcohol abuse among hospitalized patients. Little research exists on the perceptions of nurses providing care to substance abuse/dependent medical-surgical hospitalized patients. There exists the need to further explore nurses' perceptions regarding caring for this challenging population. METHODS: Using a qualitative inductive approach, a convenience sample of 24 nurses completed research questions regarding their perceptions of caring for hospitalized patients with substance abuse/dependence. RESULTS: Data analysis revealed ethical duty to care, negative perceptions toward patients with substance abuse/dependence, need for further education, sympathy, and issues with pain management. Providing quality nursing care for the hospitalized medical-surgical patient with concomitant alcohol and/or drug dependence is challenging for nursing. Nurses need additional education and professional support in caring for these individuals.

The relationships among health promotion behaviors, compassion fatigue, burnout, and compassion satisfaction in nurses practicing in a community medical center.

OBJECTIVE: The objective of this study was to examine the relationships among health promotion behaviors, compassion fatigue, burnout, and compassion satisfaction among nurses practicing in a community medical center. BACKGROUND: Compassion fatigue and burnout are significant nursing stressors. Programs are available to offset the negative consequence of compassion fatigue and burnout and enhance compassion satisfaction, yet there remains a paucity of literature examining the relationships between health promotion behaviors, compassion fatigue, burnout, and compassion satisfaction. METHODS: A nonexperimental design using a convenience sample of nurses completed the Health Promoting Lifestyle Profile II, the Professional Quality of Life Scale, and a demographic data sheet. FINDINGS: Statistically significant relationships among health promotional behaviors and compassion fatigue, compassion satisfaction, and burnout were identified. CONCLUSIONS: Compassion fatigue, burnout, and compassion satisfaction are outcomes associated with nursing practice. Support for engagement in health promotional behaviors may contribute to nurses' well-being in counteracting compassion fatigue and burnout and enhancing compassion satisfaction.

Suicide in hospitalized medical-surgical patients: exploring nurses' attitudes.

Internationally, suicide represents a major health issue. Inpatient suicide is the second most common sentinel event reported to The Joint Commission, which has identified suicide prevention as a National Patient Safety Goal. Suicide prevention is influenced by nurses' ability to accurately assess a patient's suicide risk. Evidence suggests that lack of knowledge and unfavorable attitudes toward suicide negatively impact health care delivery and patient safety. The purpose of this descriptive replication study was to investigate nurses' attitudes toward suicide in hospitalized medical-surgical patients to gain a better understanding of factors influencing the identification and management of suicide risk and ultimately improve patient safety. Using a convenience sample of 45 nurses, this study found that nurses' age and educational level correlated with positive attitudes toward suicide (p = 0.03) and that religion was also a significant predictor of positive attitudes toward suicide. Implications of this study are the need for further education on suicide prevention, including opportunities for nurses to explore the impact of their attitudes on accurate suicide risk assessment.

Nurses' perceptions of patient rounding.

OBJECTIVE: This descriptive pilot study explored hospital staff nurses' perceptions toward the practice of patient rounding. BACKGROUND: Rounding has re-emerged as a standard practice initiative among nurses in hospitals and has been associated with a decrease in call lights and falls, increased patient satisfaction and safety, and quieter nursing units. Regardless of these outcomes, controversy exists among nurses regarding rounding. METHODS: The Nurses' Perception of Patient Rounding Scale (K. Neville, unpublished manuscript, 2010) was developed to gain an understanding of nurses' perceptions of rounding. RESULTS: Nurses identified rounding as valuable and perceived hourly rounding to be beneficial to patients and families but significantly less beneficial to their own professional practice. Challenges to rounding as a practice include issues of documentation, patient ratios, and skill mix. CONCLUSION: Findings support the need for further research to address the challenges of patient rounding for nursing.