Arginine Therapy and Cardiopulmonary Hemodynamics in Hospitalized Children with Sickle Cell Anemia: A Prospective, Double-blinded, Randomized Placebo-controlled Clinical Trial.

Rationale: Acute changes in cardiopulmonary hemodynamics that include tricuspid regurgitant jet velocity (TRV) elevation measured by Doppler echocardiography are often encountered during sickle cell vasoocclusive pain and acute chest syndrome (ACS). Arginine and nitric oxide depletion develop in patients with these complications. Arginine administration may therefore improve nitric oxide bioavailability and potentiate pulmonary vasodilatation. Objectives: To evaluate effects of l-arginine supplementation on Doppler indices of cardiopulmonary hemodynamics in children with sickle cell anemia experiencing pain. Methods: This was a prospective, double-blinded, randomized placebo-controlled trial of oral arginine in children with sickle cell anemia age 5-17 years hospitalized with severe pain and/or ACS. Measurements and Main Results: Blood biomarkers and Doppler echocardiographic indices of cardiopulmonary hemodynamics were measured before and after supplementation. The mean change in TRV, pulmonary artery systolic pressure, mean pulmonary artery pressure, and other indices of cardiopulmonary hemodynamics were tested with paired Student's t test and correlated with markers of arginine bioavailability using Pearson correlation. Sixty-six children were randomized into arginine versus placebo groups. An elevated TRV ⩾ 2.5 m/s was seen in 40 (61%) patients. A Day 5 Doppler echocardiogram was performed in 47 patients who remained hospitalized. A greater reduction in median TRV occurred in the arginine group than placebo (22.2%, n = 22 vs. 3.8%, n = 25; p < 0.01). A larger percentage increase in global arginine bioavailability was associated with a lower TRV after 5 days of supplementation (r = -0.533; P = 0.001). Significant differences in multiple indices of cardiopulmonary hemodynamics and mean N-terminal pro B-type brain natriuretic peptide were also noted after arginine therapy. Conclusions: Oral arginine supplementation improves cardiopulmonary hemodynamics during sickle cell disease vasoocclusive pain and ACS.Clinical trial registered with Pan African Clinical Trial Registry https://pactr.samrc.ac.za/Search.aspx (PACTR201611001864290).

Impact of oral L-arginine supplementation on blood pressure dynamics in children with severe sickle cell vaso-occlusive crisis.

Sickle cell anaemia (SCA) patients generally have lower blood pressures compared to those with the AA haemoglobin genotype. However, during vaso-occlusive crises (SCA-VOC), blood pressures (BP) may elevate transiently to levels beyond the 95th percentile. The risk of stroke or even death increases with increasing systolic BP in SCA. Therefore, interventions targeted at BP reduction may be essential during severe vaso-occlusive episodes. Reduction in BP was achieved with arginine therapy in a meta-analysis of randomized controlled trials (RCT) in non-sickle cell adults. The impact of oral arginine (given for pain control) on the BP of children with SCA-VOC has not been documented. METHODS: A double-blind RCT of oral L-arginine hydrochloride as adjuvant therapy for pain reduction was conducted in children with SCA-VOC, aged 5-17 years, over a 2-year period. The mean change in BP and the time to achieve BP <90th percentile was added as part of the outcome variables. The anthropometry, pain scores and mercury sphygmomanometry were done following standard procedures. BP percentiles were generated using the Fourth Report guidelines. Differences in the time to normalization of BP in the treatment arms were tested with Kaplan-Meier analysis. RESULTS: Sixty-six children (57.6% male) were randomized into L-arginine (35 patients) or placebo (31 patients) arm. The prevalence of hypertension (BP ≥95th percentile) at presentation tended to increase as the pain scores increased, from a prevalence of 50% in patients with a score of 7 to 65% in those with score of 10 (systolic hypertension) and from 44.4% in patients with pain score of 7 to 50% in patients with pain score of 10 (diastolic hypertension). Patients that received arginine recorded a 12.8±3.2 mmHg decline in mean systolic BP compared to the placebo group, where a mean difference of 7.6±1.5 mmHg was observed, P<0.001. Similarly, the mean diastolic BP reduced by 13% in the arginine group and 7.5% in the placebo group, P<0.001. Children who received arginine tended to achieve BP normalization much faster than the placebo group (P=0.112), and no serious adverse events were documented related to the hypertension or arginine administration. CONCLUSIONS: High blood pressure (≥95th percentile) is common amongst children with SCA-VOC and are mostly asymptomatic. Administration of oral arginine given for pain control achieves a reduction of the BP at a faster rate in children compared to placebo and it is safe.

Randomized control trial of oral arginine therapy for children with sickle cell anemia hospitalized for pain in Nigeria.

Low arginine bioavailability is associated with vaso-occlusive painful crisis (VOC) severity in sickle cell anemia (SCA) and predicts need for pediatric hospitalization. Intravenous arginine therapy has opioid-sparing effects and was found to significantly decrease pain scores in children hospitalized with SCA-VOC in a phase-two randomized placebo-controlled trial (RCT). Efficacy of oral arginine is unknown. Our objective was to determine the safety and efficacy of oral arginine therapy in Nigerian children with SCA. A double-blind RCT of oral L-arginine-hydrochloride (100 mg/kg TID) was conducted in children with SCA-VOC, aged 5-17 years, hospitalized at two Nigerian sites. The primary outcome measure was analgesic usage, quantified by difference in the mean Analgesic Medication Quantification Scale (MQS). Secondary outcomes included daily pain scores, time-to-crisis-resolution and length-of-hospital-stay. An intention-to-treat analysis was performed. Sixty-eight children (age 5-17 years, mean 10.6 ± 0.4 years; 56% male), were randomized to receive L-arginine (35 patients) or placebo (33 patients). The mean total MQS for the arginine group was 73.4 (95% CI, 62.4-84.3) vs 120.0 (96.7-143.3) for placebo (P < .001). The mean rate of decline in worst pain scores was faster in the arginine arm vs placebo (1.50 [1.23-1.77] vs 1.09 [0.94-1.24] point/d, P = .009). Children receiving arginine had a shorter time-to-crisis-resolution (P = .02), shorter hospital-stay (P = .002) and experienced no serious adverse event. Pain control was more rapid, total analgesic requirement was significantly reduced, and most notably, time-to-crisis-resolution and length-of-hospital-stay were shorter in children with SCA-VOC receiving arginine vs placebo. Given the established safety and low cost, oral arginine is a promising adjuvant therapy for SCA-VOC management.

Clinical outcomes and cost-effectiveness of brief guided parent-delivered cognitive behavioural therapy and solution-focused brief therapy for treatment of childhood anxiety disorders: a randomised controlled trial.

BACKGROUND: Half of all lifetime anxiety disorders emerge before age 12 years; however, access to evidence-based psychological therapies for affected children is poor. We aimed to compare the clinical outcomes and cost-effectiveness of two brief psychological treatments for children with anxiety referred to routine child mental health settings. We hypothesised that brief guided parent-delivered cognitive behavioural therapy (CBT) would be associated with better clinical outcomes than solution-focused brief therapy and would be cost-effective. METHODS: We did this randomised controlled trial at four National Health Service primary child and mental health services in Oxfordshire, UK. Children aged 5-12 years referred for anxiety difficulties were randomly allocated (1:1), via a secure online minimisation tool, to receive brief guided parent-delivered CBT or solution-focused brief therapy, with minimisation for age, sex, anxiety severity, and level of parental anxiety. The allocation sequence was not accessible to the researcher enrolling participants or to study assessors. Research staff who obtained outcome measurements were masked to group allocation and clinical staff who delivered the intervention did not measure outcomes. The primary outcome was recovery, on the basis of Clinical Global Impressions of Improvement (CGI-I). Parents recorded patient-level resource use. Quality-adjusted life-years (QALYs) for use in cost-utility analysis were derived from the Child Health Utility 9D. Assessments were done at baseline (before randomisation), after treatment (primary endpoint), and 6 months after treatment completion. We did analysis by intention to treat. This trial is registered with the ISCRTN registry, number ISRCTN07627865. FINDINGS: Between March 23, 2012, and March 31, 2014, we randomly assigned 136 patients to receive brief guided parent-delivered CBT (n=68) or solution-focused brief therapy (n=68). At the primary endpoint assessment (June, 2012, to September, 2014), 40 (59%) children in the brief guided parent-delivered CBT group versus 47 (69%) children in the solution-focused brief therapy group had an improvement of much or very much in CGI-I score, with no significant differences between groups in either clinical (CGI-I: relative risk 1·01, 95% CI 0·86-1·19; p=0·95) or economic (QALY: mean difference 0·006, -0·009 to 0·02; p=0·42) outcome measures. However, brief guided parent-delivered CBT was associated with lower costs (mean difference -£448; 95% CI -934 to 37; p=0·070) and, taking into account sampling uncertainty, was likely to represent a cost-effective use of resources compared with solution-focused brief therapy. No treatment-related or trial-related adverse events were reported in either group. INTERPRETATION: Our findings show no evidence of clinical superiority of brief guided parent-delivered CBT. However, guided parent-delivered CBT is likely to be a cost-effective alternative to solution-focused brief therapy and might be considered as a first-line treatment for children with anxiety problems. FUNDING: National Institute for Health Research.

Improving early childhood care and development, HIV-testing, treatment and support, and nutrition in Mokhotlong, Lesotho: study protocol for a cluster randomized controlled trial.

BACKGROUND: Since 1990, the lives of 48 million children under the age of 5 years have been saved because of increased investments in reducing child mortality. However, despite these unprecedented gains, 250 million children younger than 5 years in low- and middle-income countries (LMIC) cannot meet their developmental potential due to poverty, poor health and nutrition, and lack of necessary stimulation and care. Lesotho has high levels of poverty, HIV, and malnutrition, all of which affect child development outcomes. There is a unique opportunity to address these complex issues through the widespread network of informal preschools in rural villages in the country, which provide a setting for inclusive, integrated Early Childhood Care and Development (ECCD) and HIV and nutrition interventions. METHODS: We are conducting a cluster randomised controlled trial in Mokhotlong district, Lesotho, to evaluate a newly developed community-based intervention program to integrate HIV-testing and treatment services, ECCD, and nutrition education for caregivers with children aged 1-5 years living in rural villages. Caregivers and their children are randomly assigned by village to intervention or control condition. We select, train, and supervise community health workers recruited to implement the intervention, which consists of nine group-based sessions with caregivers and children over 12 weeks (eight weekly sessions, and a ninth top-up session 1 month later), followed by a locally hosted community health outreach day event. Group-based sessions focus on using early dialogic book-sharing to promote cognitive development and caregiver-child interaction, health-related messages, including motivation for HIV-testing and treatment uptake for young children, and locally appropriate nutrition education. All children aged 1-5 years and their primary caregivers living in study villages are eligible for participation. Caregivers and their children will be interviewed and assessed at baseline, after completion of the intervention, and 12 months post intervention. DISCUSSION: This study provides a unique opportunity to assess the potential of an integrated early childhood development intervention to prevent or mitigate developmental delays in children living in a context of extreme poverty and high HIV rates in rural Lesotho. This paper presents the intervention content and research protocol for the study. TRIAL REGISTRATION: The Mphatlalatsane: Early Morning Star trial is registered on the International Standard Randomized Controlled Trial Number database, registration number ISRCTN16654287 ; the trial was registered on 3 July 2015.

Background changing patterns of neonatal fungal sepsis in a developing country.

BACKGROUND: Candida albicans is the predominant isolate in many neonatal fungal bloodstream infections (BSIs), so fluconazole is used as empiric antifungal therapy. AIM: To determine the predominant organisms, antifungal sensitivity patterns, clinical and demographic risk factors and crude mortality rate in neonatal fungal BSI cases. SUBJECTS AND METHODS: This is a review of all neonatal fungal BSI cases between January 2007 and December 2011. RESULTS: Fifty-nine patients were included in the study. Candida parapsilosis (54.2%) was isolated in majority of the cases, followed by C. albicans (27.1%). Fluconazole resistance was present in 16 of 32 cases of C. parapsilosis versus 1 of 16 cases of C. albicans (P = 0.003). Mortality rate was 45.8%. Surgical problems were present in 55.9%. Death was significantly associated with lower birth weight (P = 0.046) and necrotizing enterocolitis (P = 0.034). CONCLUSIONS: The increase in neonatal fungal BSI and resistant organisms highlights the need to review use of routine empiric fluconazole and to implement preventive measures.

Delta inulin: a novel, immunologically active, stable packing structure comprising ß-D-[2 -> 1] poly(fructo-furanosyl) α-D-glucose polymers.

We report a novel isoform of ß-D-[2 → 1] poly(fructo-furanosyl) α-D-glucose termed delta inulin (DI), comparing it with previously described alpha (AI), beta (BI) and gamma (GI) isoforms. In vitro, DI is the most immunologically active weight/weight in human complement activation and in binding to monocytes and regulating their chemokine production and cell surface protein expression. In vivo, this translates into potent immune adjuvant activity, enhancing humoral and cellular responses against co-administered antigens. As a biocompatible polysaccharide particle, DI is safe and well tolerated by subcutaneous or intramuscular injection. Physico-chemically, DI forms as an insoluble precipitate from an aqueous solution of suitable AI, BI or GI held at 37-48°C, whereas the precipitate from the same solution at lower temperatures has the properties of AI or GI. DI can also be produced by heat conversion of GI suspensions at 56°C, whereas GI is converted from AI at 45°C. DI is distinguished from GI by its higher temperature of solution in dilute aqueous suspension and by its lower solubility in dimethyl sulfoxide, both consistent with greater hydrogen bonding in DI's polymer packing structure. DI suspensions can be dissolved by heat, re-precipitated by cooling as AI and finally re-converted back to DI by repeated heat treatment. Thus, DI, like the previously described inulin isoforms, reflects the formation of a distinct polymer aggregate packing structure via reversible noncovalent bonding. DI forms the basis for a potent new human vaccine adjuvant and further swells the growing family of carbohydrate structures with immunological activity.

Thrombin generation assays are superior to traditional tests in assessing anticoagulation reversal in vitro.

Even though new anticoagulants are being devised with the notion that they do not require regular monitoring, when bleeding occurs, it is important to have an antidote and a reliable test to confirm whether the anticoagulant effects are persisting. We examined the effects of five heparinoids, unfractionated heparin (UFH), tinzaparin, enoxaparin, danaparoid and fondaparinux on the traditional APTT and anti-Xa assays as well as on the calibrated automated thrombogram (CAT). We also studied the ability of protamine sulphate (PS), NovoSeven, FEIBA and FFP to reverse maximum anticoagulation induced by the different heparinoids. The CAT was the only test to detect the coagulopathy of all the anticoagulants. PS produced complete reversal of UFH, and this could be monitored with all three tests. Tinzaparin can also be completely neutralised in vitro with high doses of PS, but the maximum enoxaparin reversal achieved with PS is only approximately 60%. Fondaparinux does not significantly affect the APTT and PS has no significant effect on its reversal. Only NovoSeven was able to correct the fondaparinux induced CAT abnormalities whilst having no effect on the anti-Xa level. None of the reversal agents was very effective in danaparoid spiked plasma but NovoSeven, at high dose, increased the ETP by 40% and reduced the anti-Xa level from 0.93 to 0.78 IU/ml. We conclude that the CAT is superior to the traditional coagulation tests in that it not only detects the coagulopathy of all the heparinoids but can be also be used to monitor their reversal.