Sustained increase in annual transcranial Doppler screening rates in children with sickle cell disease: A quality improvement project.

INTRODUCTION: Individuals with sickle cell disease (SCD) at increased risk for stroke should undergo annual stroke risk assessment using transcranial Doppler (TCD) screening between the ages of 2 and 16. Though this screening can significantly reduce morbidity associated with SCD, screening rates at Boston Children's Hospital (and nationwide) remain below the recommended 100% screening adherence rates. METHODS: Three plan-do-study-act (PDSA) cycles were designed and implemented. The Specific, Measurable, Achievable, Relevant, and Time-Bound (SMART) aim of our quality improvement (QI) initiative was to sustainably increase the proportion of eligible patients receiving a TCD within 15 months of their last TCD to greater than 95%. An interrupted time series (ITS) analysis was performed, comparing TCD adherence rates from PDSA Cycle 1 to those from PDSA Cycles 2 and 3. RESULTS: Mean TCD adherence increased across all three PDSA cycles, from a baseline of 67% in the first cycle (January 2015 to September 2020) to 92% in the third cycle (May 2021 to March 2023). In the ITS analysis of TCD adherence rates, there was a significant difference in the final TCD adherence rate achieved compared to the rate predicted, with a total estimated increase in adherence of 17.9% being attributable to the interventions from PDSA Cycles 2 and 3. DISCUSSION: Although other QI initiatives had demonstrated ability to increase adherence to TCD screening for patients with SCD, this is the first QI project to collect data over such a prolonged period of time to demonstrate a sustained increase in screening rates throughout the intervention (an 8-year period).

The Risk of Kidney Injury in Patients With Sickle Cell Disease Treated With Ketorolac for Acute Pain.

Ketorolac, a nonsteroidal anti-inflammatory drug, is used in combination with opioids to manage vaso-occlusive episodes (VOEs). The relationship between ketorolac use and kidney injury in pediatric patients with sickle cell disease (SCD) remains incompletely understood. We hypothesize that ketorolac is associated with acute kidney injury (AKI) in patients with SCD presenting with pain. All nonsurgical hospitalizations for VOEs treated with ketorolac between January 2014 and December 2022 were included. We used optimal matching methodology to identify control admissions (2:1 ratio) and used nonparametric tests to compare ketorolac administration between cases and controls. A total of 1319 encounters/253 patients were included in this study. AKI was noted in 1.1% of encounters and 5.5% of patients. Cases had significantly higher initial BUN than controls (9.0 vs. 6.0 mg/dL, P=0.012). In cases versus controls, there was significantly lower serum sodium (136.0 vs. 138.0 mmol/L, P=0.021). There was no association between ketorolac dose and development of AKI among children with SCD. Higher BUN and lower sodium in cases suggest that patients with AKI were more volume depleted on admission than controls. This highlights the need for strict assessment of fluid status upon admission for VOE.

Models of care for sickle cell disease in low-income and lower-middle-income countries: a scoping review.

Sickle cell disease has a growing global burden falling primarily on low-income countries (LICs) and lower-middle-income countries (LMICs) where comprehensive care is often insufficient, particularly in rural areas. Integrated care models might be beneficial for improving access to care in areas with human resource and infrastructure constraints. As part of the Centre for Integration Science's ongoing efforts to define, systematise, and implement integrated care delivery models for non-communicable diseases (NCDs), this Review explores models of care for sickle cell disease in LICs and LMICs. We identified 99 models from 136 studies, primarily done in tertiary, urban facilities in LMICs. Except for two models of integrated care for concurrent treatment of other conditions, sickle cell disease care was mostly provided in specialised clinics, which are low in number and accessibility. The scarcity of published evidence of models of care for sickle cell disease and integrated care in rural settings of LICs and LMICs shows a need to implement more integrated models to improve access, particularly in rural areas. PEN-Plus, a model of decentralised, integrated care for severe chronic non-communicable diseases, provides an approach to service integration that could fill gaps in access to comprehensive sickle cell disease care in LICs and LMICs.

Increasing COVID-19 Vaccination Rates for Children With Sickle Cell Disease.

BACKGROUND: The COVID-19 vaccine is important for children with sickle cell disease (SCD). This quality improvement project's objective was to increase the proportion of children with SCD receiving ≥2 COVID-19 vaccine doses to ≥70% by June 2022. METHODS: We used the Model for Improvement framework. We assessed COVID-19 vaccination rates biweekly. Three plan-do-study-act cycles focusing on patient education, provider awareness, and access were performed. Process measures included the outcome of outreach calls and educational video views. Missed clinic appointments was our balancing measure. Line graphs and statistical process control charts were used to track changes. Interrupted time series was used to model implementation rates while accounting for preexisting trends. RESULTS: A total of 243 patients were included. During the preintervention (September 2021-January 2022) and intervention periods (February 2022-June 2022), overall vaccination rates increased from 33% to 41% and 41% to 64%, respectively. Mean vaccination rate in eligible children in each 2-week period increased from 2.1% to 7.2%. The achieved vaccination rate was 11% greater than predicted for patients with SCD. For the general population the achieved vaccination rate was 23% lower than predicted. The proportion of missed visits did not change (9.0% vs. 9.6%). During outreach calls, 10 patients (13.5%) booked a vaccine. Forty percent of patients watched the promotional video. CONCLUSIONS: A significant number of patients with SCD are not vaccinated against COVID-19. Targeting misinformation and improving vaccine access aided in increasing vaccination. Additional interventions are needed as a large number of patients remain unvaccinated.

Genetic reversal of the globin switch concurrently modulates both fetal and sickle hemoglobin and reduces red cell sickling.

We previously reported initial clinical results of post-transcriptional gene silencing of BCL11A expression (NCT03282656) reversing the fetal to adult hemoglobin switch. A goal of this approach is to increase fetal hemoglobin (HbF) expression while coordinately reducing sickle hemoglobin (HbS) expression. The resulting combinatorial effect should prove effective in inhibiting HbS polymerization at lower physiologic oxygen values thereby mitigating disease complications. Here we report results of exploratory single-cell analysis of patients in which BCL11A is targeted molecularly and compare results with cells of patients treated with hydroxyurea (HU), the current standard of care. We use single-cell assays to assess HbF, HbS, oxygen saturation, and hemoglobin polymer content in RBCs for nine gene therapy trial subjects (BCLshmiR, median HbF% = 27.9) and compare them to 10 HU-treated subjects demonstrating high and comparable levels of HbF (HU High Responders, median HbF% = 27.0). All BCL11A patients achieved the primary endpoint for NCT03282656, which was defined by an absolute neutrophil count greater than or equal to 0.5 × 109 cells/L for three consecutive days, achieved within 7 weeks following infusion. Flow cytometric assessment of single-RBC HbF and HbS shows fewer RBCs with high HbS% that would be most susceptible to sickling in BCLshmiR vs. HU High Responders: median 42% of RBCs with HbS%>70% in BCLshmiR vs. 61% in HU High Responders (p = 0.004). BCLshmiR subjects also demonstrate more RBCs resistant to HbS polymerization at lower physiologic oxygen tension: median 32% vs. 25% in HU High Responders (p = 0.006). Gene therapy-induced BCL11A down-regulation reverses the fetal-to-adult hemoglobin switch and induces RBCs with higher HbF%, lower HbS%, and greater resistance to deoxygenation-induced polymerization in clinical trial subjects compared with a cohort of highly responsive hydroxyurea-treated subjects.

F-erythrocytes promote Plasmodium falciparum proliferation in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) remains prevalent because heterozygous carriers (HbAS) are partially resistant to Plasmodium falciparum malaria. Sickle hemoglobin (HbS) polymerization in low and intermediate oxygen (O2 ) conditions is the main driver of HbAS-driven resistance to P. falciparum malaria. However, epidemiological studies have reported mixed malaria morbidity and mortality outcomes in individuals with sickle cell disease (SCD). While maximum-tolerated dose hydroxyurea has been shown to lower malaria incidence, fetal hemoglobin (HbF), an inhibitor of HbS polymerization that is variably packaged in F-erythrocytes, might provide hemoglobin that is accessible to the parasite for feeding. METHODS: To explore that risk, we examined the effect of variable mean corpuscular fetal hemoglobin (MCHF) on P. falciparum proliferation, invasion, and development in HbSS RBCs. RESULTS: We found that greater MCHF in HbSS red blood cells (RBCs) is associated with increased P. falciparum proliferation in O2 environments comparable with the microcirculation. Moreover, both parasite invasion and intracellular growth, the major components of proliferation, occur predominantly in F-erythrocytes and are augmented with increasing MCHF. CONCLUSIONS: HbF modifies P. falciparum infection in HbSS RBCs, further highlighting the complexity of the molecular interactions between these two diseases. Other inhibitors of HbS polymerization that do not increase HbF or F-erythrocytes should be independently assessed for their effects on P. falciparum malaria proliferation in HbSS RBCs.

Ketamine use for management of vaso-occlusive pain in pediatric sickle cell disease.

BACKGROUND: Typical sickle cell disease (SCD) vaso-occlusive pain episode (VOE) management includes opioids, which are often inadequate and can be associated with significant side effects. Ketamine, a dissociative anesthetic, is a potentially effective adjunct to VOE management. OBJECTIVES: This study aimed to characterize ketamine use for VOE management in pediatric SCD. METHOD: This retrospective case series summarizes a single-center experience regarding the use of ketamine for inpatient management of pediatric VOE in 156 admissions from 2014 to 2020. RESULTS: Continuous low-dose ketamine infusion was most commonly prescribed to adolescents and young adults as an adjunct to opioids (median starting dose 2.0 µg/kg/min; median maximum dose 3.0 µg/kg/min). Ketamine was started a median of 13.7 hours after admission. Median ketamine infusion duration was 3 days. In most encounters, ketamine infusion was discontinued prior to opioid patient-controlled analgesia (PCA) discontinuation. The majority of encounters (79.3%) had a reduction in either PCA dose, continuous opioid infusion, or both while receiving ketamine. Low-dose ketamine infusion was associated with side effects noted in 21.8% (n = 34) of encounters. The most common side effects included dizziness (5.6%), hallucinations (5.1%), dissociation (2.6%), and sedation (1.9%). There were no reports of ketamine withdrawal. Most patients who received ketamine went on to receive it again during a subsequent admission. CONCLUSION: Further study is needed to determine the optimal timing of ketamine initiation and dosing. The variability of ketamine administration highlights the need for standardized protocols for ketamine use in VOE management.

Patient Controlled Analgesia for Vaso-Occlusive Episodes in Children: A Retrospective Study.

OBJECTIVE: To describe Patient-Controlled Analgesia (PCA) administration in pediatric patients admitted with sickle cell vaso-occlusive episode (VOE). METHODS: This single-center retrospective study included all inpatient hematology admissions for VOE between 2014 and 2020. PCA-ratio was calculated as the ratio of bolus over continuous IV opioids dose, and time to PCA adjustment as time between first PCA order and a subsequent order that increased dosing or changed opioid medication. RESULTS: A total of 866 encounters (172 unique patients) with PCA for VOE were included. The mean age was 15.4 years old (SD = 5.0). On average, after admission (hospital arrival), the first opioid dose was given at 1 hour, PCA started at 3.5 hours, and mean length of stay was 4.3 days (SD = 2.5). The mean initial PCA-ratio was 1.7 (SD = 0.6). There were no significant associations between age, gender, initial pain score, or admission hemoglobin and PCA-ratio (linear regression model P = 0.443). In 24.7% of encounters, the PCA was adjusted within 6 hours. After adjusting by age and gender, lower admission pain scores (OR = 1.15, P = 0.004), lower PCA-ratio (OR = 2.1, P = 0.003), longer time to PCA start (OR = 1.2, P = 0.001), and no adjuvant ketamine (OR = 2.4, P < 0.001) were associated with PCA unadjusted within 6 hours. CONCLUSION: At our institution, patients with VOE received opioids and PCA within the first hours of admission. PCAs were started at a ratio of 1.5-1.8, considered normal continuous. While no specific PCA-ratio was clearly superior for pain control, lower ratios (high continuous infusion) were associated with not requiring PCA adjustments at 6 hours. Prospective studies are needed.

Haemolysis, elevated liver enzymes and low platelets: Diagnosis and management in critical care.

A thirty-year-old pregnant woman was admitted to hospital with headache and gastrointestinal discomfort. She developed peripheral oedema and had an emergency caesarean section following an episode of tonic-clonic seizures. Her delivery was further complicated by postpartum haemorrhage and she was admitted to the Intensive Care Unit (ICU) for further resuscitation and seizure control which required infusions of magnesium and multiple anticonvulsants. Despite haemodynamic optimisation she developed an acute kidney injury with evidence of liver damage, thrombocytopenia and haemolysis. Haemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome, a multisystem disease of advanced pregnancy which overlaps with pre-eclampsia, was diagnosed. HELLP syndrome is associated with a range of complications which may require critical care support, including placental abruption and foetal loss, acute kidney injury, microangiopathic haemolytic anaemia, acute liver failure and liver capsule rupture. Definitive treatment of HELLP is delivery of the fetus and in its most severe forms requires admission to the ICU for multiorgan support. Therapeutic strategies in ICU are mainly supportive and include blood pressure control, meticulous fluid balance and possibly escalation to renal replacement therapy, mechanical ventilation, neuroprotection, seizure control, and management of liver failure-related complications. Multidisciplinary input is essential for optimal treatment.

Building leadership capabilities in maternity.

BACKGROUND: Over recent years, there has been increasing recognition that effective leadership is critical to establishing positive organisational culture and improving patient outcomes. In maternity, there is a unique interplay between different specialties and disciplines in providing high-quality services. METHODS: Review of literature pertaining to leadership and maternity. RESULTS: Good leadership is the key determinant in ensuring that our multi-professional teams function effectively. The relational aspects of teamworking, linked to safer delivery of services, have been explored in great detail in maternity services. However, there has been less focus on the application of leadership theory in this environment and the impact of interventions used in developing leadership skills within maternity teams. CONCLUSIONS: In this paper, we discuss how leadership theory can be used to understand high profile maternity service failures and how effective team culture, clinical team building and individual leadership skill-development are strong contributors to this thinking. Specific examples are used to describe ongoing work in our drive for improvement and to highlight the current lack of evidence in this area.

Enablers and barriers to newborn screening for sickle cell disease in Africa: results from a qualitative study involving programmes in six countries.

OBJECTIVES: Given the fundamental role of newborn bloodspot screening (NBS) to enable prompt diagnosis and optimal clinical management of individuals with sickle cell disease (SCD), we sought to systematically assess enablers and barriers to implementation of NBS programmes for SCD in Africa using established qualitative research methods. SETTING: Childbirth centres and NBS laboratories from six countries in East, West and Southern Africa. PARTICIPANTS: Eight programme leaders involved with establishing and operating NBS programmes for SCD in Angola, Democratic Republic of Congo, Ghana, Liberia, Nigeria and Tanzania. PRIMARY AND SECONDARY OUTCOME MEASURES: Data obtained through a structured, phased interview approach were analysed using a combination of inductive and deductive codes and used to determine primary themes related to the implementation and sustainability of SCD NBS programmes. RESULTS: Four primary themes emerged from the analysis relating to governance (eg, pragmatic considerations when deploying overcommitted clinical staff to perform NBS), technical (eg, design and execution of operational processes), cultural (eg, variability of knowledge and perceptions of community-based staff) and financial (eg, issues that can arise when external funding may effectively preclude government inputs) aspects. Key learnings included perceived factors that contribute to long-term NBS programme sustainability. CONCLUSIONS: The establishment of enduring NBS programmes is a proven approach to improving the health of populations with SCD. Organising such programmes in Africa is feasible, but initial implementation does not assure sustainability. Our analysis suggests that future programmes should prioritise government partner participation and funding from the earliest stages of programme development.