SNAP: Supportive non-invasive ventilation for acute chest syndrome prevention for hospitalized children with sickle cell disease: Perspectives of patients, parents, and the healthcare team.

RATIONALE: Acute chest syndrome (ACS) often develops during hospitalizations for sickle cell disease (SCD) vaso-occlusive episodes and may be triggered by a combination of chest wall splinting, opioid use, hypoventilation, and atelectasis. In 2017, Boston Medical Center's general pediatric inpatient unit instituted the novel use of bi-level positive airway pressure (BiPAP) as "supportive non-invasive ventilation for ACS prevention" (SNAP) to prevent ACS and respiratory decompensation. OBJECTIVE: The goals of this qualitative study were to identify perceived benefits, harms, facilitators, and barriers to use of SNAP. METHODS: We conducted semi-structured key informant interviews at three sites with different levels of SNAP implementation (Site 1: extensive implementation; Site 2: limited implementation; Site 3: not yet implemented) regarding experiences with and/or perceptions of SNAP. Interviews and coding were guided by the Promoting Action on Research Implementation in Health Services (PARiHS) framework. RESULTS: Thirty-four participants (physicians, nurses, respiratory therapists, child life specialists, psychologists, youth with SCD, and parents) completed interviews. Major themes included: (i) participants perceive BiPAP as effective at preventing ACS, and for those with medically stable ACS, for preventing respiratory decompensation. (ii) BiPAP use is appropriate on the general pediatric inpatient unit for medically stable patients with SCD. (iii) Improving the patient experience is the most important factor to optimize acceptance of BiPAP by patients and families. CONCLUSION/FUTURE DIRECTIONS: SNAP is perceived as effective and appropriate for hospitalized pediatric patients with SCD. Improving the patient experience is the biggest challenge. These data will inform a future protocol for a multicenter hybrid effectiveness/implementation trial of SNAP.

SNAP: Supportive noninvasive ventilation for acute chest syndrome prevention in children with sickle cell disease.

BACKGROUND: Acute chest syndrome (ACS) is a leading cause of morbidity and mortality among children with sickle cell disease (SCD). Preventing hypoxemia by optimizing lung aeration during sleep remains a challenge. OBJECTIVES: To explore safety, feasibility, and tolerability of noninvasive, bi-level positive airway pressure ventilation (BiPAP) as preventative, supportive care for hospitalized, medically stable children with SCD on a general pediatric inpatient unit. METHODS: Retrospective chart review of patients ≤22 years of age with SCD admitted to the general pediatric inpatient unit from February 1, 2017 to March 1, 2020 for whom BiPAP was recommended as supportive care. Hospitalizations were excluded if patients were admitted to the pediatric intensive care unit (PICU), required BiPAP for respiratory failure, or used BiPAP at home for obstructive sleep apnea. RESULTS: Twenty-three patients had 53 hospitalizations in which BiPAP was recommended. Fifty-two (98%) hospitalizations included acute SCD pain. Indications for BiPAP included prior ACS (94%), chest or back pain (79%), and/or oxygen desaturation (66%). On 17 occasions, patients already had mild to moderate ACS but were stable when BiPAP was recommended. BiPAP was used successfully during 75% of hospitalizations for a median of two nights. There were no adverse effects associated with BiPAP. PICU transfer for respiratory support occurred during three hospitalizations. In 26 hospitalizations of children at risk for ACS who tolerated BiPAP, 23 (88%) did not develop ACS. CONCLUSIONS: BiPAP is safe, feasible, and well tolerated as supportive care for hospitalized children with SCD. Next steps include an intervention trial to further assess the efficacy of BiPAP on ACS prevention.

A Multinational Trial of Prasugrel for Sickle Cell Vaso-Occlusive Events.

BACKGROUND: Sickle cell anemia is an inherited blood disorder that is characterized by painful vaso-occlusive crises, for which there are few treatment options. Platelets mediate intercellular adhesion and thrombosis during vaso-occlusion in sickle cell anemia, which suggests a role for antiplatelet agents in modifying disease events. METHODS: Children and adolescents 2 through 17 years of age with sickle cell anemia were randomly assigned to receive oral prasugrel or placebo for 9 to 24 months. The primary end point was the rate of vaso-occlusive crisis, a composite of painful crisis or acute chest syndrome. The secondary end points were the rate of sickle cell-related pain and the intensity of pain, which were assessed daily with the use of pain diaries. RESULTS: A total of 341 patients underwent randomization at 51 sites in 13 countries across the Americas, Europe, Asia, and Africa. The rate of vaso-occlusive crisis events per person-year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P=0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups. CONCLUSIONS: Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.).

Augmented NRF2 activation protects adult sickle mice from lethal acute chest syndrome.

Acute chest syndrome (ACS) mortality in sickle cell disease (SCD) rises sharply in young adult patients and mechanism-based prophylaxis is lacking. In SCD, haem oxygenase-1 (HO-1) declines with age and ACS is associated with low HO-1. To test if enhanced HO-1 can reduce ACS mortality, young SCD mice were treated with D3T (3H-1,2-dithiole-3-thione), an activator of nuclear-factor erythroid 2 like 2, which controls HO-1 expression, for 3 months. Following haem-induced ACS, all vehicle-treated mice succumbed to severe lung injury, while D3T-treated mice had significantly improved survival. Blocking HO-1 activity abrogated the D3T effect. Thus HO-1 may be targeted to reduce ACS severity in adult patients.

The intersection between asthma and acute chest syndrome in children with sickle-cell anaemia.

Acute chest syndrome is a frequent cause of acute lung disease in children with sickle-cell disease. Asthma is common in children with sickle-cell disease and is associated with increased incidence of vaso-occlusive pain events, acute chest syndrome episodes, and earlier death. Risk factors for asthma exacerbation and an acute chest syndrome episode are similar, and both can present with shortness of breath, chest pain, cough, and wheezing. Despite overlapping risk factors and symptoms, an acute exacerbation of asthma or an episode of acute chest syndrome are two distinct entities that need disease-specific management strategies. Although understanding has increased about asthma as a comorbidity in sickle-cell disease and its effects on morbidity, substantial gaps remain in knowledge about best management.

The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial.

BACKGROUND: No consensus exists on whether preoperative blood transfusions are beneficial in patients with sickle-cell disease. We assessed whether perioperative complication rates would be altered by preoperative transfusion. METHODS: We did a multicentre, randomised trial. Eligible patients were aged at least 1 year, had haemoglobin SS or Sß(0)thalassaemia sickle-cell-disease subtypes, and were scheduled for low-risk or medium-risk operations. Patients were randomly assigned no transfusion or transfusion no more than 10 days before surgery. The primary outcome was the proportion of clinically important complications between randomisation and 30 days after surgery. Analysis was by intention to treat. FINDINGS: 67 (96%) of 70 enrolled patients-33 no preoperative transfusion and 34 preoperative transfusion-were assessed. 65 (97%) of 67 patients had the haemoglobin SS subtype and 54 (81%) were scheduled to undergo medium-risk surgery. 13 (39%) of 33 patients in the no-preoperative-transfusion group had clinically important complications, compared with five (15%) in the preoperative-transfusion group (p=0.023). Of these, 10 (30%) and one (3%), respectively, had serious adverse events. The unadjusted odds ratio of clinically important complications was 3.8 (95% CI 1.2-12.2, p=0.027). 10 (91%) of 11 serious adverse events were acute chest syndrome (nine in the no-preoperative-transfusion group and one in the preoperative-transfusion group). Duration of hospital stay and readmission rates did not differ between study groups. INTERPRETATION: Preoperative transfusion was associated with decreased perioperative complications in patients with sickle-cell disease in this trial. This approach could, therefore, be beneficial for patients with the haemoglobin SS subtype who are scheduled to undergo low-risk and medium-risk surgeries. FUNDING: NHS Blood and Transplant.

How I treat acute chest syndrome in children with sickle cell disease.

Acute chest syndrome describes new respiratory symptoms and findings, often severe and progressive, in a child with sickle cell disease and a new pulmonary infiltrate. It may be community-acquired or arise in children hospitalized for pain or other complications. Recognized etiologies include infection, most commonly with atypical bacteria, and pulmonary fat embolism (PFE); the cause is often obscure and may be multifactorial. Initiation of therapy should be based on clinical findings. Management includes macrolide antibiotics, supplemental oxygen, modest hydration and often simple transfusion. Partial exchange transfusion should be reserved for children with only mild anemia (Hb > 9 g/dL) but deteriorating respiratory status. Therapy with corticosteroids may be of value; safety, efficacy and optimal dosing strategy need prospective appraisal in a clinical trial. On recovery, treatment with hydroxyurea should be discussed to reduce the likelihood of recurrent episodes.

Red blood cell alloimmunization in sickle cell disease: prevalence in 2010.

BACKGROUND: Transfusion of red blood cells (RBCs) is frequently required for care of individuals with sickle cell disease (SCD). Alloimmunization rates are high and may be reduced by matching for RBC antigens that can cause alloimmunization. STUDY DESIGN AND METHODS: During the PROACTIVE Feasibility Study, patients with SCD age 2 years or older admitted for pain without acute chest syndrome were enrolled for possible randomization to preventive blood transfusion or standard care. Transfusion and antibody histories were obtained at each site, and antibody screening was done, to assess transfusion burden and alloimmunization prevalence. Participating sites were surveyed regarding antigen matching practice. RESULTS: A total of 237 patients (169 SS, 42 SC, 15 Sß(0) -thalassemia, 11 Sß(+) -thalassemia), 118 males and 119 females, were enrolled. Mean age was 19.3 years (range, 2.0-68.0); there were 122 children and 115 adults. A total of 75.8% had received at least a single transfusion of RBCs before the study. Thirty-four patients (14.4%) had a history of at least one alloantibody and 17 of these had more than one. When surveyed, 19 sites (83% of responders) reported antigen matching to at least include C, E, and K for transfusion of all patients with SCD. CONCLUSION: Though antigen typing before transfusion of people with SCD and providing antigen-negative units is now widely employed by sickle cell centers, the alloimmunization rate remains quite high in contemporary sickle cell populations and may be due in large part to transfusions received at institutions not providing extended matching.

Pain and other non-neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: results from the SWiTCH clinical trial.

To compare the non-neurological events in children with sickle cell anemia (SCA) and previous stroke enrolled in SWiTCH. The NHLBI-sponsored Phase III multicenter randomized clinical trial stroke with transfusions changing to hydroxyurea (SWiTCH) (ClinicalTrials.gov NCT00122980) compared continuation of chronic blood transfusion/iron chelation to switching to hydroxyurea/phlebotomy for secondary stroke prevention and management of iron overload. All randomized children were included in the analysis (intention to treat). The Fisher's Exact test was used to compare the frequency of subjects who experienced at least one SCA-related adverse event (AE) or serious adverse event (SAE) in each arm and to compare event rates. One hundred and thirty three subjects, mean age 13 ± 3.9 years (range 5.2-19.0 years) and mean time of 7 years on chronic transfusion at study entry, were randomized and treated. Numbers of subjects experiencing non-neurological AEs were similar in the two treatment arms, including SCA-related events, SCA pain events, and low rates of acute chest syndrome and infection. However, fewer children continuing transfusion/chelation experienced SAEs (P = 0.012), SCA-related SAEs (P = 0.003), and SCA pain SAEs (P = 0.016) as compared to children on the hydroxyurea/phlebotomy arm. The timing of phlebotomy did not influence SAEs. Older age at baseline predicted having at least 1 SCA pain event. Patients with recurrent neurological events during SWiTCH were not more likely to experience pain. In children with SCA and prior stroke, monthly transfusions and daily iron chelation provided superior protection against acute vaso-occlusive pain SAEs when compared to hydroxyurea and monthly phlebotomy.

Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG).

BACKGROUND: Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects. METHODS: This randomised trial was undertaken in 13 centres in the USA between October, 2003, and September, 2009. Eligible participants had haemoglobin SS (HbSS) or haemoglobin Sß(0)thalassaemia, were aged 9-18 months at randomisation, and were not selected for clinical severity. Participants received liquid hydroxycarbamide, 20 mg/kg per day, or placebo for 2 years. Randomisation assignments were generated by the medical coordinating centre by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxycarbamide and placebo. Patients, caregivers, and coordinating centre staff were masked to treatment allocation. Primary study endpoints were splenic function (qualitative uptake on (99)Tc spleen scan) and renal function (glomerular filtration rate by (99m)Tc-DTPA clearance). Additional assessments included blood counts, fetal haemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every 2-4 weeks. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00006400. FINDINGS: 96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p=0·21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1·73 m(2), p=0·84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p=0·002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p<0·0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia. INTERPRETATION: On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia. FUNDING: The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development.

Cost-effectiveness of adenotonsillectomy in reducing obstructive sleep apnea, cerebrovascular ischemia, vaso-occlusive pain, and ACS episodes in pediatric sickle cell disease.

In children with sickle cell disease (SCD), adenotonsillar hypertrophy or recurrent tonsillitis are frequently linked with an increased risk of obstructive sleep apnea, cerebrovascular ischemia, or frequent pain episodes and often require an adenoidectomy and/or tonsillectomy. Interventions designed to prevent these complications, control vaso-occlusive pain episodes, and avoid hospitalizations may reduce the significant personal and economic burden of SCD. This study compares episode recurrence and treatment costs for cerebrovascular ischemia, vaso-occlusive pain, acute chest syndrome (ACS), and obstructive sleep apnea in children who had an adenotonsillectomy (A/T surgery, N = 256; 11.7%) and a matched cohort of those who did not (N = 512; 23.3%) from a cohort of 2,194 children and adolescents with SCD from South Carolina's Medicaid system. A/T surgery was associated with a significantly reduced rate of visits over time for obstructive sleep apnea and cerebrovascular ischemia (e.g., stroke, transient ischemic attacks), but not with any change in the rate of visits for vaso-occlusive pain or ACS/pneumonia visits. The rate of mean acute (emergency and inpatient) service costs was significantly decreasing over time after an increase about the time the A/T surgery was performed. The cost-effectiveness of adenoidectomy and/or tonsillectomy for treating obstructive sleep apnea and preventing cerebrovascular ischemia without increasing vaso-occlusive pain episodes or long-term acute service costs in routine clinical practice settings was demonstrated. The matched control group of SCD patients without A/T surgery contained more patients with severe vaso-occlusive pain episodes, ACS visits, and higher mean total costs over time and appears to represent a different phenotype of children with SCD.

Acute chest syndrome: sickle cell disease.

Acute chest syndrome (ACS) is a common complication and reason for hospital admission in patients with sickle cell disease (SCD). It is also the most common cause of death in this patient population. Most of the time, the trigger for ACS in an individual patient cannot be identified. However, although infection is the most common identifiable cause for ACS, other important triggers are vaso-occlusive crisis (VOC) and asthma. This comprehensive review will focus on the pathogenesis, clinical characteristics, complications and treatment available to manage ACS. But importantly, this review will highlight new possible etiologies, with the goal of improving oxygenation and, therefore, a reduction in sickling and lung damage in this patient population.

Multi-modal intervention for the inpatient management of sickle cell pain significantly decreases the rate of acute chest syndrome.

INTRODUCTION: Pain in children with sickle cell disease (SCD) is the leading cause of acute care visits and hospitalizations. Pain episodes are a risk factor for the development of acute chest syndrome (ACS), contributing to morbidity and mortality in SCD. Few strategies exist to prevent this complication. METHODS: We performed a before-and-after prospective multi-modal intervention. All children with SCD admitted for pain during the 2-year study period were eligible. The multi-modal intervention included standardized admission orders, monthly house staff education, and one-on-one patient and caregiver education. RESULTS: A total of 332 admissions for pain occurred during the study period; 159 before the intervention and 173 during the intervention. The ACS rate declined by 50% during the intervention period 25% (39 of 159) to 12% (21 of 173); P = 0.003. Time to ACS development increased from 0.8 days (0.03-5.2) to 1.7 days (0.03-5.8); P = 0.047. No significant difference was found in patient demographics, intravenous fluid amount administered, frequency of normal saline bolus administration, or cumulative opioid amount delivered in the first 24 hr. Patient controlled analgesia-use was more common after the intervention 52% (82 of 159) versus 73% (126 of 173; P = 0.0001) and fewer patients required changes in analgesic dosing within the first 24 hr after admission (26%, 42 of 159 vs. 16%, 28 of 173; P = 0.015). CONCLUSIONS: A multi-modal intervention to educate and subsequently change physician's behavior likely decreased the rate of ACS in the setting of a single teaching hospital.

The use of incentive spirometry in pediatric patients with sickle cell disease to reduce the incidence of acute chest syndrome.

INTRODUCTION: To determine if incentive spirometry (IS) in pediatric patients admitted with sickle cell disease for nonrespiratory complaints will decrease acute chest syndrome (ACS). METHODS: This was an Institutional Review Board-approved before-after 2-year retrospective cohort study evaluating an evidence-based guideline (EBG) initiating mandatory IS in admitted pediatric sickle cell patients from a tertiary children's emergency center. Student t testing and χ² analysis were performed. RESULTS: There were 1551 patient visits. About 258 visits were enrolled in the pre-EBG year, and 230 in the EBG year. Between year characteristics were similar. The EBG year reported higher use of hydroxyurea (P<0.01), analgesics (P=0.02), and chest pain (P=0.03). Sixty-seven patients (25.9%) in the pre-EBG year received transfusions versus 51 (22.5%) in the EBG year (NS). Twenty-five (9.6%) of the pre-EBG patients received blood for ACS versus 14 (6.1%) in the EBG group (absolute risk reduction: 3.5%, 95% confidence interval: -1-8.4%). Subgroup analysis revealed that patients who presented with back pain experienced a significant decrease in the development of ACS in the EBG year (P=0.04, absolute risk reduction: 14%, 95% confidence interval: 1-28%, number needed to treat: 8). CONCLUSION: Mandatory IS for sickle cell disease patients admitted without respiratory complaints reduces transfusions and ACS, particularly for those presenting with back pain.

Indications for transfusion in the management of sickle cell disease.

The transfusion of red blood cells (RBCs) is a crucial treatment for sickle cell disease (SCD). While often beneficial, the frequent use of transfusions is associated with numerous complications. Transfusions should be offered with specific guidelines in mind. Here we present updates to the indications for transfusion of RBCs in SCD. We review recent publications and include expert perspectives from hematology and transfusion medicine. For some clinical indications, such as ischemic stroke, the role of transfusion has been well studied and can be applied almost universally. For many other clinical scenarios, the use of transfusion therapy has less conclusive data and therefore must be tailored to individual needs. We highlight the roles of RBC transfusions in preventing or mitigating neurological disease, in reducing perioperative complications, in managing acute chest syndrome, and in optimizing pregnancy outcomes in SCD. We further highlight various transfusion techniques and when each might be considered. Potential complications of transfusion are also briefly discussed.