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Hydroxyurea for secondary stroke prevention in children with sickle cell anaemia: a systematic review of clinical evidence and outcomes
Aderinto, N., Olatunji, G., Kokori, E., Abdulbasit, M.
Annals of medicine and surgery (2012). 2024;86(2):1042-1047
Abstract
BACKGROUND Stroke remains one of the leading complications of sickle cell anaemia (SCA) in children. Traditionally, SCA treatment focused on symptom relief. However, the high incidence of strokes in children has prompted a reevaluation of treatment, particularly hydroxyurea, for secondary stroke prevention. This study assesses hydroxyurea's effectiveness and safety in preventing secondary strokes in paediatric SCA patients. METHODS This systematic review followed a pre-defined protocol registered with PROSPERO. Comprehensive searches were conducted across PubMed, Embase, Scopus, MEDLINE, Google Scholar, and the Cochrane Library up to August 2023. Studies were included involving paediatric SCA patients at risk of secondary stroke, assessing hydroxyurea as the primary intervention. RESULTS A total of six studies meeting inclusion criteria were included. The effectiveness of hydroxyurea in preventing secondary strokes, with variable responses reported across studies. Adverse effects, including mild neutropenia, are associated with hydroxyurea treatment but with variability in reported toxicity levels. CONCLUSION Hydroxyurea holds promise in preventing recurrent strokes in children with SCA, though its efficacy and safety profiles vary among individuals. Optimal dosages and treatment durations require further investigation, necessitating vigilant monitoring of haematological parameters. Future research should refine dosing strategies, consider individual patient characteristics, assess long-term effects, and explore ancillary benefits beyond stroke prevention.
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Efficacy and safety of deferoxamine, deferasirox and deferiprone triple iron chelator combination therapy for transfusion-dependent β-thalassaemia with very high iron overload: a protocol for randomised controlled clinical trial
Premawardhena, A., Perera, C., Wijethilaka, M. N., Wanasinghe, S. K., Rajakaruna, Rhmg, Samarasinghe, Rankk, Williams, S., Mettananda, S.
BMJ open. 2024;14(2):e077342
Abstract
INTRODUCTION Despite the improvement in medical management, many patients with transfusion-dependent β-thalassaemia die prematurely due to transfusion-related iron overload. As per the current guidelines, the optimal chelation of iron cannot be achieved in many patients, even with two iron chelators at their maximum therapeutic doses. Here, we evaluate the efficacy and safety of triple combination treatment with deferoxamine, deferasirox and deferiprone over dual combination of deferoxamine and deferasirox on iron chelation in patients with transfusion-dependent β-thalassaemia with very high iron overload. METHODS AND ANALYSIS This is a single-centre, open-label, randomised, controlled clinical trial conducted at the Adult and Adolescent Thalassaemia Centre of Colombo North Teaching Hospital, Ragama, Sri Lanka. Patients with haematologically and genetically confirmed transfusion-dependent β-thalassaemia are enrolled and randomised into intervention or control groups. The intervention arm will receive a combination of oral deferasirox, oral deferiprone and subcutaneous deferoxamine for 6 months. The control arm will receive the combination of oral deferasirox and subcutaneous deferoxamine for 6 months. Reduction in iron overload, as measured by a reduction in the serum ferritin after completion of the treatment, will be the primary outcome measure. Reduction in liver and cardiac iron content as measured by T2* MRI and the side effect profile of trial medications are the secondary outcome measures. ETHICS AND DISSEMINATION Ethical approval for the study has been obtained from the Ethics Committee of the Faculty of Medicine, University of Kelaniya (Ref. P/06/02/2023). The trial results will be disseminated in scientific publications in reputed journals. TRIAL REGISTRATION NUMBER The trial is registered in the Sri Lanka Clinical Trials Registry (Ref: SLCTR/2023/010).
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High-dose intravenous immunoglobulin versus albumin 4% in paediatric toxic shock syndrome: a randomised controlled feasibility study
Portefaix, A., Dhelens, C., Recher, M., Cour-Andlauer, F., Naudin, J., Mortamet, G., Joram, N., Tissières, P., Ginhoux, T., Kassai, B., et al
Archives of disease in childhood. 2024
Abstract
PURPOSE Toxic shock syndrome (TSS) is a rare disease responsible for significant morbidity and mortality. Intravenous immunoglobulin (IG) therapy in paediatric TSS could improve shock and organ failure, but more consistent efficacy and safety data are needed. Our objective was to determine whether a randomised clinical trial (RCT) assessing intravenous IG in TSS in children is feasible. METHODS We performed a multicentre, feasibility, double-blind RCT assessing efficacy of high-dose intravenous IG versus albumin 4% (control group) within the first 12 hours of shock onset. Included patients were aged above 1 month and below 18 years with suspected TSS and septic shock. Feasibility was assessed by measuring inclusion rate, protocol compliance and missing data regarding death and the Pediatric Logistic Organ Dysfunction-2 (PELOD-2) Score. Other secondary clinical outcomes were evaluated during hospital stay, at 60 day and 1 year. RESULTS 28 patients, admitted in 6 paediatric intensive care units during 36 consecutive months and followed for 1 year, received the allocated treatment: 13 in intravenous IG group, 15 in control group. The median age was 10.6 years and the sex ratio was 1. Inclusion rate was above 50%, protocol deviations were below 30% and missing data regarding death and PELOD-2 Score below 10%. No difference concerning secondary clinical outcomes between groups was observed, and more adverse events were reported in the control group. CONCLUSION It seems to be feasible to conduct an RCT assessing intravenous IG efficacy and safety in paediatric TSS but must be realised internationally, with choice of a clinically relevant endpoint and a specific design in order to be realistic. TRIAL REGISTRATION NUMBER NCT02219165.
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Efficacy and safety of infliximab in the treatment of Kawasaki disease: A systematic review and meta-analysis
Wang, L., He, M., Wang, W., Li, S., Zhao, G.
European journal of pediatrics. 2024
Abstract
Infliximab is a monoclonal antibody specifically binding tumor necrosis factor-alpha and has been approved for the treatment of several inflammatory disorders. However, the efficacy of infliximab in primary treatment of Kawasaki disease (KD) or retreatment of intravenous immunoglobulin (IVIG)-resistant KD in children is controversial. Therefore, we conducted a meta-analysis to compare the efficacy of infliximab alone or in combination with IVIG to IVIG. Eligible randomized and non-randomized trials were retrieved by searching literature databases prior to May 31, 2023. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated for dichotomous variables, and mean difference (MD) with 95% CI was estimated for continuous variables. A total of 14 eligible studies comprising 1257 participants were included. In refractory KD, infliximab alone was associated with a higher effectiveness rate (OR = 4.48, 95% CI 2.67-7.52) and defervescence rate (OR = 5.01, 95% CI 2.99-8.37) and resulted in a 1.08-day-shorter duration of fever (95% CI 0.61-1.55, P < 0.001) and 1.36-day-shorter length of hospital stay (95% CI 0.65-2.08) compared with IVIG. Incidences of coronary artery lesions (CALs), newly developing CALs, and CAL regression did not differ between both groups. For initial treatment of KD, infliximab in addition to IVIG led to a nominally significant higher effectiveness rate (OR = 2.26, 95% CI 1.02-5.01) and a larger reduction of right coronary artery Z score (MD = -0.24, 95% CI -0.27 to -0.21) but did not show additional efficacy in improving other outcomes. The safety profile was similar between both groups. Conclusion: The meta-analysis demonstrates that infliximab alone is a well-tolerated and effective treatment for IVIG-resistant KD. The additional efficacy of infliximab to IVIG for initial treatment of KD is limited. More large and high-quality trials are needed to confirm the efficacy of infliximab, especially for intensification of primary treatment for KD. What is Known: • Infliximab is a novel monoclonal antibody specifically blocking tumor necrosis factor-alpha and is approved for treatment of several immune-mediated inflammatory disorders. • The efficacy of infliximab in treating children with Kawasaki disease is controversial. What is New: • Infliximab is an effective and safe treatment for children with refractory Kawasaki disease but adds limited efficacy to intravenous immunoglobulin for initial treatment of Kawasaki disease.
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Desmopressin to reduce periprocedural bleeding and transfusion: a systematic review and meta-analysis
Wang, C., Lebedeva, V., Yang, J., Anih, J., Park, L. J., Paczkowski, F., Roshanov, P. S.
Perioperative medicine (London, England). 2024;13(1):5
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Abstract
We systematically reviewed the literature to investigate the effects of peri-procedural desmopressin in patients without known inherited bleeding disorders undergoing surgery or other invasive procedures. We included 63 randomized trials (4163 participants) published up to February 1, 2023. Seven trials were published after a 2017 Cochrane systematic review on this topic. There were 38 trials in cardiac surgery, 22 in noncardiac surgery, and 3 in non-surgical procedures. Meta-analyses demonstrated that desmopressin likely does not reduce the risk of receiving a red blood cell transfusion (25 trials, risk ratio [RR] 0.95, 95% confidence interval [CI] 0.86 to 1.05) and may not reduce the risk of reoperation due to bleeding (22 trials, RR 0.75, 95% CI 0.47 to 1.19) when compared to placebo or usual care. However, we demonstrated significant reductions in number of units of red blood cells transfused (25 trials, mean difference -0.55 units, 95% CI - 0.94 to - 0.15), total volume of blood loss (33 trials, standardized mean difference - 0.40 standard deviations; 95% CI - 0.56 to - 0.23), and the risk of bleeding events (2 trials, RR 0.45, 95% CI 0.24 to 0.84). The certainty of evidence of these findings was generally low. Desmopressin increased the risk of clinically significant hypotension that required intervention (19 trials, RR 2.15, 95% CI 1.36 to 3.41). Limited evidence suggests that tranexamic acid is more effective than desmopressin in reducing transfusion risk (3 trials, RR 2.38 favoring tranexamic acid, 95% CI 1.06 to 5.39) and total volume of blood loss (3 trials, mean difference 391.7 mL favoring tranexamic acid, 95% CI - 93.3 to 876.7 mL). No trials directly informed the safety and hemostatic efficacy of desmopressin in advanced kidney disease. In conclusion, desmopressin likely reduces periprocedural blood loss and the number of units of blood transfused in small trials with methodologic limitations. However, the risk of hypotension needs to be mitigated. Large trials should evaluate desmopressin alongside tranexamic acid and enroll patients with advanced kidney disease.
PICO Summary
Population
Children or adults without known inherited bleeding disorders undergoing surgery or other invasive procedures (63 randomised controlled trials, n= 4,163).
Intervention
Desmopressin administered intravenously or subcutaneously before, during, or immediately after a surgical or interventional procedure.
Comparison
Placebo, usual care, or antifibrinolytic agents.
Outcome
Meta-analyses demonstrated that desmopressin likely does not reduce the risk of receiving a red blood cell transfusion (25 trials, risk ratio [RR] 0.95; 95% confidence interval (CI) [0.86, 1.05]) and may not reduce the risk of reoperation due to bleeding (22 trials, RR 0.75; 95% CI [0.47, 1.19]) when compared to placebo or usual care. However, the authors demonstrated significant reductions in number of units of red blood cells transfused (25 trials, mean difference -0.55 units; 95% CI [-0.94, -0.15]), total volume of blood loss (33 trials, standardized mean difference - 0.40 standard deviations; 95% CI [-0.56, -0.23]), and the risk of bleeding events (2 trials, RR 0.45; 95% CI [0.24, 0.84]). The certainty of evidence of these findings was generally low.
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Two-dimensional radiographs and CBCT assessment of concentrated growth factor and platelet-rich fibrin scaffolds in regenerative endodontic treatment of immature incisors with periapical radiolucency: a randomized clinical trial
Elheeny, A. A. H., Tony, G. E.
Journal of endodontics. 2024
Abstract
INTRODUCTION The primary aim of this study was to compare the radiographic changes of immature incisors with periapical radiolucency after treatment with platelet-rich fibrin (PRF) and concentrated growth factor (CGF) platelet concentrate scaffolds as well as assessment of the clinical success rate over 12 months. The secondary aim was to monitor the radiographic changes in terms of reduction of periapical lesion diameter (PALD), root dentine thickness (RDT), root length (RL), and apical foramen width (AFW). The tertiary aim was to assess and pulp responses, after 12 months METHODS Fifty six children withseventy necrotic, single-rooted maxillary incisors with periapical radiolucency were treated with either CGF or PRF scaffolds (35 teeth per group). Two patients with four teeth (two teeth in each group) failed to attain the follow-up recalls. Radiographic changes in terms of reduction of periapical lesion diameter (PALD), root dentine thickness (RDT), root length (RL), and apical foramen width (AFW) were monitored using a two-dimensional radiograph and CBCT scan. The clinical performance of teeth receiving both scaffolds was assessed after 6 and 12 months. Categorical and continuous data were analyzed using the chi-square test and the t-test, respectively. The time and group effects on the means of different radiographic dimensions were tested using the general linear model (GLM). Bland-Altman plots were used to assess the level of agreement between the 2D radiographs and CBCT. The level of significance was defined at 0.05 and a 95% CI. RESULTS The means of PALD and RL showed significant enhancement in the CGF group compared to the PRF group (p< 0.05). While the difference between the two scaffolds in terms of RDT and AFW was not significant (p> .05). The findings of the 2D radiograph and CBCT were consistent. Clinically, both scaffold success rates were similar (93.9%) over the follow-up intervals. The influence of study independent variables had no significant effect on the success of the REPs outcome (p> 0.05). There was no significant difference in the positive pulp responses to the thermal and electric pulp tests after one year of treatment (p> 0.05). CONCLUSIONS According to the short-term follow-up, PRF and CGF were successful in treating immature teeth with periapical radiolucency by regenerative endodontics. Both scaffold systems induced periapical healing and root lengthening with significant superiority of CGF.
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Cardiac assessment and inflammatory markers in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV2 (PIMS-TS) treated with methylprednisolone versus intravenous immunoglobulins: 6-month follow-up outcomes of the randomised controlled Swissped RECOVERY trial
Andre, M. C., Sanchez, C., Bressieux-Degueldre, S., Perez, M. H., Wütz, D., Blanchard-Rohner, G., Grazioli, S., Schöbi, N., Trück, J., Welzel, T., et al
EClinicalMedicine. 2024;67:102358
Abstract
BACKGROUND Previous findings from the Swissped RECOVERY trial showed that patients with Pediatric Inflammatory Multisystem Syndrome-Temporally Associated with SARS-CoV-2 (PIMS-TS) who were randomly assigned to intravenous immunoglobulins or methylprednisolone have a comparable length of hospital stay. Here, we report the 6-month follow-up outcomes of cardiac pathologies and normalisation of clinical or laboratory signs of inflammation from this study population. METHODS This pre-planned follow-up of patients with PIMS-TS included the Swissped RECOVERY Trial reports on the 6-month outcomes of the cohort after randomisation, with a focus on cardiac, haematological, and biochemical findings. The trial was an investigator-initiated randomised multicentre open-label two-arm trial in children and adolescents hospitalised with PIMS-TS at ten hospitals in Switzerland. Cardiological assessments and laboratory analyses were prospectively collected in the intention-to-treat analysis on pre-defined intervals after hospital discharge. Differences between randomised arms were investigated using Chi-square test for categorical and Wilcoxon test for continuous variables. The trial is registered with the Swiss National Clinical Trials Portal (SNCTP000004720) and ClinicalTrials.gov (NCT04826588). FINDINGS Between May 21, 2021 and April 15, 2022, 75 patients with a median age of 9.1 years (IQR 6.2-12.2) were included in the intention-to-treat population (37 in the methylprednisolone group and 38 in the intravenous immunoglobulin group). During follow-up, the incidence of abnormal left ventricular systolic function, coronary artery aneurysms (CAA), and other signs of inflammation were comparable in both groups. However, we detected cardiac abnormalities with low incidence and a mild degree grade of pathology. CAAs were observed in 2/38 children (5.3%) in the IVIG group and 1/37 children (2.7%) in the methylprednisolone group at 6-month follow-up (difference proportion 0.75; 95% confidence interval (CI) -0.05 to 1.0; p = 0.39). INTERPRETATION Methylprednisolone alone may be an acceptable first-line treatment as left ventricular systolic dysfunction and clinical/laboratory evidence for inflammation quickly resolved in all children. However, our findings need further confirmation through larger studies as our sample size is likely to be of insufficient power to address rare clinically relevant adverse outcomes. FUNDING NOMIS, Vontobel, and Gaydoul Foundation.
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Immunomodulatory therapy in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS, MIS-C; RECOVERY): a randomised, controlled, open-label, platform trial
The Lancet. Child & adolescent health. 2024
Abstract
BACKGROUND Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also known as multisystem inflammatory syndrome in children (MIS-C) emerged in April, 2020. The paediatric comparisons within the RECOVERY trial aimed to assess the effect of intravenous immunoglobulin or corticosteroids compared with usual care on duration of hospital stay for children with PIMS-TS and to compare tocilizumab (anti-IL-6 receptor monoclonal antibody) or anakinra (anti-IL-1 receptor antagonist) with usual care for those with inflammation refractory to initial treatment. METHODS We did this randomised, controlled, open-label, platform trial in 51 hospitals in the UK. Eligible patients were younger than 18 years and had been admitted to hospital for PIMS-TS. In the first randomisation, patients were randomly assigned (1:1:1) to usual care (no additional treatments), usual care plus methylprednisolone (10mg/kg per day for 3 consecutive days), or usual care plus intravenous immunoglobulin (a single dose of 2 g/kg). If further anti-inflammatory treatment was considered necessary, children aged at least 1 year could be considered for a second randomisation, in which patients were randomly assigned (1:2:2) to usual care, intravenous tocilizumab (12 mg/kg in patients <30 kg; 8mg/kg in patients ≥30 kg, up to a maximum dose of 800 mg), or subcutaneous anakinra (2 mg/kg once per day in patients ≥10 kg). Randomisation was by use of a web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was duration of hospital stay. Analysis was by intention to treat. For treatments assessed in each randomisation, a single Bayesian framework assuming uninformative priors for treatment was used to jointly assess the efficacy of each intervention compared with usual care. The trial was registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). FINDINGS Between May 18, 2020, and Jan 20, 2022, 237 children with PIMS-TS were enrolled and included in the intention-to-treat analysis. Of the 214 patients who entered the first randomisation, 73 were assigned to receive intravenous immunoglobulin, 61 methylprednisolone, and 80 usual care. Of the 70 children who entered the second randomisation (including 23 who did not enter the first randomisation), 28 were assigned to receive tocilizumab, 14 anakinra, and 28 usual care. Mean age was 9·5 years (SD 3·8) in the randomisation and 9·6 years (3·6) in the second randomisation. 118 (55%) of 214 patients in the first randomisation and 39 (56%) of 70 patients in the second randomisation were male. 130 (55%) of 237 patients were Black, Asian, or minority ethnic, and 105 (44%) were White. Mean duration of hospital stay was 7·4 days (SD 0·4) in children assigned to intravenous immunoglobulin and 7·6 days (0·4) in children assigned to usual care (difference -0·1 days, 95% credible interval [CrI] -1·3 to 1·0; posterior probability 59%). Mean duration of hospital stay was 6·9 days (SD 0·5) in children assigned to methylprednisolone (difference from usual care -0·7 days, 95% CrI -1·9 to 0·6; posterior probability 87%). Mean duration of hospital stay was 6·6 days (SD 0·7) in children assigned to second-line tocilizumab and 9·9 days (0·9) in children assigned to usual care (difference -3·3 days, 95% CrI -5·6 to -1·0; posterior probability >99%). Mean duration of hospital stay was 8·5 days (SD 1·2) in children assigned to anakinra (difference from usual care -1·4 days, 95% CrI -4·3 to 1·8; posterior probability 84%). Two persistent coronary artery aneurysms were reported among patients assigned to usual care in the first randomisation. There were few cardiac arrythmias, bleeding, or thrombotic events in any group. Two children died; neither was considered related to study treatment. INTERPRETATION Moderate evidence suggests that, compared with usual care, first-line intravenous methylprednisolone reduces duration of hospital stay for children with PIMS-TS. Good evidence suggests that second-line tocilizumab reduces duration of hospital stay for children with inflammation refractory to initial treatment. Neither intravenous immunoglobulin nor anakinra had any effect on duration of hospital stay compared with usual care. FUNDING Medical Research Council and National Institute of Health Research.
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A systematic review of tourniquet use in paediatric orthopaedic surgery: can we extrapolate from adult guidelines?
Pintar, V., Brookes, C., Trompeter, A., Bridgens, A., Hing, C., Gelfer, Y.
EFORT open reviews. 2024;9(1):80-91
Abstract
PURPOSE Tourniquets are commonly used intraoperatively in orthopaedic surgery to control bleeding and improve visibility in the surgical field. Recent evidence has thrown into question the routine use of tourniquets in the adult population resulting in a British Orthopaedic Association standard for intraoperative use. This systematic review evaluates the evidence on the practice, benefits, and risks of the intraoperative use of tourniquets for trauma and elective orthopaedic surgery in the paediatric population. METHODS A prospectively registered systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO CRD42022359048). A search of MEDLINE, Embase, the Cochrane Library and a Grey literature search was performed from their earliest record to 23 March 2023. Studies reporting tourniquet data in paediatric patients undergoing orthopaedic surgery were included. Data extracted included demographics, involved limb, trauma versus elective use, tourniquet use as primary or secondary measure, and tourniquet parameters and complications. RESULTS Thirty-nine studies were included. Tourniquet practices and information reporting varied considerably. Tourniquets were used uneventfully in the majority of patients with no specific benefits reported. Several physiological and biochemical changes as well as complications including nerve injury, compartment syndrome, skin burns, thrombosis, post-operative limb swelling, and pain were reported. CONCLUSIONS Tourniquets are routinely used in both trauma and elective paediatric orthopaedic surgery with no high-quality research affirming benefits. Severe complications associated with their use are rare but do occur. High-quality studies addressing their benefits, the exact indication in children, and the safest way to use them in this population are necessary.
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10.
Clinical study on the role of platelet-rich plasma in human acellular dermal matrix with razor autologous skin graft repair of giant congenital pigmented nevus in children
Jin, F., Li, X., Chen, J., Liu, J., Wang, Y.
Journal of plastic, reconstructive & aesthetic surgery : JPRAS. 2024;90:305-314
Abstract
BACKGROUND NA OBJECTIVE Evaluate the safety and feasibility of platelet-rich plasma (PRP) in the treatment of giant congenital melanocytic nevi (GCMN) in children with human acellular dermal matrix (HADM) transplantation. PATIENTS AND METHODS A total of 22 children with GCMN were included in the study. They were divided into an experimental and a control group. The experimental group used the method of HADM with Razor Autologous Skin Graft combined with PRP to repair skin and soft tissue defects after giant nevus resection (Group A, n = 11). The control group was treated with HADM with Razor Autologous Skin Graft (Group B, n = 11) only. To compare the survival rate of skin grafts, we used the Vancouver Scar Scale (VSS) for the postoperative skin graft area and the Patient and Observer Scar Assessment Scale (POSAS) to compare the two groups of patients. RESULTS There was no statistically significant difference in age, gender, location of giant nevi, and pathological classification between Group A and Group (P > 0.05). The survival rate of skin grafting and the VSS and POSAS scores of scar tissue in group A were superior to those of group B (P < 0.05). CONCLUSIONS PRP has improved the survival rate of composite skin grafting in children with GCMN, and long-term satisfactory prognosis of scar healing. Therefore, we consider this treatment method a valuable contribution to clinical practice.