Infusion In Children Research Articles

The Effect of Systemic Magnesium on Postsurgical Pain in Children Undergoing Tonsillectomies: A Double-Blinded, Randomized, Placebo-Controlled Trial.

Tonsillectomy is a frequently performed surgical procedure in children; however, few multimodal analgesic strategies have been shown to improve postsurgical pain in this patient population. Systemic magnesium infusions have been shown to reliably improve postoperative pain in adults, but their effects in pediatric surgical patients remain to be determined. In the current investigation, our main objective was to evaluate the use of systemic magnesium to improve postoperative pain in pediatric patients undergoing tonsillectomy. We hypothesized that children who received systemic magnesium infusions would have less post-tonsillectomy pain than the children who received saline infusions. The study was a prospective, randomized, double-blinded, clinical trial. Subjects were randomly assigned using a computer-generated table of random numbers to 1 of the 2 intervention groups: systemic magnesium infusion (initial loading dose 30 mg/kg given over 15 minutes followed by a continuous magnesium infusion 10 mg/kg/h) and the same volume of saline. The primary outcome was pain scores in the postanesthesia care unit (PACU) measured by FLACC (Face, Legs, Activity, Cry, Consolability) pain scores. Pain reduction was measured by the decrement in the area under the pain scale versus 90-minute postoperative time curve using the trapezoidal method. Secondary outcomes included opioid consumption in the PACU, emergence delirium scores (measured by the pediatric anesthesia emergence delirium scale), and parent satisfaction. Sixty subjects were randomly assigned and 60 completed the study. The area under pain scores (up to 90 minutes) was not different between the study groups, median (interquartile range [IQR]) of 30 (0-120) score × min and 45 (0-135) score × min for the magnesium and control groups, respectively (P = 0.74). Similarly, there was no clinically significant difference in the morphine consumption in the PACU between the magnesium group, median (IQR) of 2.0 (0-4.44) mg IV morphine, compared with the control, median (IQR) of 2.5 (0-4.99) mg IV morphine (P = 0.25). The serum level of magnesium was significantly lower in the control group than in the treatment group at the end of the surgery (P < 0.001). Despite a large number of studies demonstrating the efficacy of systemic magnesium for preventing postsurgical pain in adults, we could not find evidence for a significant clinical benefit of systemic magnesium infusion in children undergoing tonsillectomies. Our findings reiterate the importance of validating multimodal analgesic strategies in children that have been demonstrated to be effective in the adult population.

Timing of antibiotics, volume and vasoactive infusions in children with sepsis: it is all in the timing.

We share the view of van Paridon et al. [1] that robust data on fluid bolus therapy for sepsis resuscitation are needed, and looked with interest to the Alberta Sepsis Network’s recent report to add to our understanding. We note that the authors chose to exclude children who were expected to die <24 hours from presentation. We would be grateful to know how many cases were excluded on this basis. The majority of the hazard from sepsis lies in this period. We recently defined this risk in a similar cohort of children; 55 % of all sepsis deaths (78 % of these being previously healthy children) occurred within the first 24 hours [2]. Resuscitation interventions such as fluid and vasoactive drugs are guided by changes in physiology. Inasmuch as physiological variables are associated with mortality, these interventions are also likely to have an immediate effect on mortality. The authors suggest potential explanations for the 1-year mortality effect seen with aggressive fluid administration: while all are not only plausible but likely, the effect will only be seen if the acute phase is overcome. By excluding children dying early, the authors also reduce the potential to propensity match children receiving similar levels of interventions. Pediatric Risk of Mortality (PRISM) scores control for severity of illness, but information is lost given that the PRISM score utilises categories of haemodynamic variables rather than age-standardised continuous variables [3]. We wonder whether the modest effect size difference would persist with these alterations to the methodology.

Population pharmacokinetics of meropenem administered as a prolonged infusion in children with cystic fibrosis.

Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children. Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259. A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41 ± 0.23 L/h/kg and 0.30 ± 0.17 L/kg, respectively. Half-life was 1.11 ± 0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home. In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs ≥1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule.

Frequency of dermatological side effects of continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes.

The incidence of type 1 diabetes is rising, particularly in young infants. The treatment with continuous subcutaneous insulin infusion (CSII) offers certain benefits and has gained popularity. Insulin-pump therapy could be associated with cutaneous-adverse effects. The purpose of our study was to investigate the frequency and characterization of skin-related complications in patients with CSII. In a single center setting, 54 patients (28 male, 26 female) on CSII therapy aged between 3 and 20 years participated in our study. Data including duration of diabetes, duration of CSII, pump model, catheter material, frequency of catheter switch and hygiene procedures at time of puncture were collected through a standardized questionnaire and photographs of affected areas of the skin were made. Statistical analysis was done to verify an association with gender, patients' age, HbA1c values, and body mass index. Our observation revealed skin complications at the site of catheter insertion in 43% (8 f, 15 m) of our patients. A frequent occurrence of scars (24%, 6 f, 7 m), lipohypertrophic areas (20%, 4 f, 7 m) and eczema (11%, 1 f, 5 m) was observed. Furthermore, 6% (1 f, 2 m) showed changes in pigmentation and 6% (1 f, 2 m) lipoatrophy. The catheter localization had to be switched due to skin-complications in 24% (6 f, 7 m) whereas none of our patients discontinued insulin-pump therapy. Skin-related complications during CSII are frequent and regular examination of the insertion sites is crucial. To verify the occurrence of lipoatrophy associated with insulin pump therapy - an otherwise rare complication - larger studies would be needed.

Measured versus predicted blood propofol concentrations in children during scoliosis surgery.

Propofol anesthesia is preferred during scoliosis surgery because it suppresses evoked potential spinal cord function less than other drugs and better enables the detection of spinal cord ischemia. In this study, we determined the difference between the true and predicted blood propofol levels during target-controlled infusions in children during scoliosis surgery. Arterial blood propofol measured concentrations (Cm) were compared with predicted concentrations (Cp) approximately every 30 minutes during the maintenance phase of anesthesia in 20 children. Whole blood propofol concentrations were measured using a point-of-care blood propofol analyzer. Anesthesia management was not affected by the study. The median performance error, median absolute performance error, wobble, and divergence were calculated. Children were aged 9 to 17 years and weighed 26.5 to 95 kg. The Paedfusor model was used in 16 children and the Marsh model in 4 children. In 154 blood propofol measurements, the mean difference between the Cm and Cp was 1.5 µg·mL (limits of agreement, -1.4 to 4.5 µg·mL), and the mean performance error was 44.7% (limits of agreement, -40.1% to 130.2%). The median performance error and median absolute performance error for the whole group were 39.8% (range, -20.9% to 103.3%) and 39.8% (range, 20%-103.3%), respectively. The performance errors improved with increase in duration of infusion (divergence, -2.2 [range, -1.03 to 0.13]). Cm was almost always larger than Cp except in 2 children who had consistently lower Cm than Cp (lowest Cm(s) were 1.74 and 1.96 µg·mL when the Cp was 3 µg·mL); both had the Paedfusor model and their body weights were 28 and 33 kg. Propofol target-controlled infusion models had poor performance characteristics in children undergoing scoliosis surgery. Point-of-care propofol assay may enable adjustment of the infusion to better achieve the intended blood level.

Propofol effect on cerebral oxygenation in children with congenital heart disease.

Propofol is a short-acting, intravenously administered hypnotic agent which is used in procedural sedation in children. Propofol is known to decrease systemic vascular resistance, arterial blood pressure and can lead to desaturations and decreased systemic perfusion in children with cardiac shunting. This may result in a reduction in cerebral blood flow and oxygenation. Near-infrared spectroscopy (NIRS) can monitor cerebral tissue oxygenation in the frontal neocortex. The objective of our study was to measure the changes in cerebral oxygen and blood supply after Propofol infusion in children with congenital heart disease. Propofol infusion may reduce cerebral oxygenation in children with congenital heart disease. The study group consisted of 32 children (f:m=18:14), with median age of 49 (5-112) months and median weight of 15 (5-34) kg. We performed NIRS derived continuous measurement of cerebral oxygenation and cardiac output using Electrical velocimetry for 5min before and after sedation with Propofol (1-2mg/kg i.v.) for cardiac catheterization. Simultaneously, non-invasive arterial blood pressure and transcutaneous oxygen saturation were measured. Propofol sedation led to a significant decrease in mean arterial pressure (79±16 vs. 67±12mmHg) (p=0.01) and cardiac index (3.2±0.8 vs. 2.9±0.6ml/min/m(2)) (p=0.03). In contrast, cerebral tissue oxygenation index, increased significantly from 57±11 to 59±10% (p<0.05). Sedation with Propofol increased cerebral tissue oxygenation despite a decrease in cardiac index and arterial blood pressure. This may be caused by a decreased oxygen consumption of the sedated brain with intact cerebral auto-regulation.

The feasibility of using dose-banded syringes to improve the safety and availability of patient-controlled opioid analgesic infusions in children

Opioid infusions are essential therapy for children in severe pain. Patient controlled analgesia (PCA) is an attractive treatment option because of the multiple benefits it provides: immediate and effective pain...

Norepinephrine infusion increases urine output in children under sedative and analgesic infusion.

To evaluate the effects of early norepinephrine (NE) infusion in children submitted to mechanical ventilation (MV) requiring continuous sedative and analgesic infusion. Double-blinded, randomized, placebo-controlled trial enrolling children (1 month to 12 years of age) admitted to a Brazilian PICU and expected to require MV and continuous sedative and analgesic drug infusions for at least five days. Children were randomized to receive either norepinephrine (NE) (0.15 mcg/kg/min) or normal saline infusion, started in the first 24 hours of MV, and maintained for 72 hours. We compared hemodynamic variables, fluid intake, renal function and urine output between groups. Forty children were equally allocated to the NE or placebo groups, with no differences in baseline characteristics, laboratorial findings, PRISM II score, length of MV, or mortality between groups. The average norepinephrine infusion was 0.143 mcg/kg/min. The NE group showed higher urine output (p = 0.016) and continuous increment in the mean arterial pressure compared to the baseline (p = 0.043). There were no differences in the remaining hemodynamic variables, fluid requirements, or furosemide administration. Early norepinephrine infusion in children submitted to MV improves mean arterial pressure and increases urine output. These effects were attributed to reversion of vasoplegia induced by the sedative and analgesic drugs.

Increased immunosuppressive treatment combined with unrelated umbilical cord blood infusion in children with severe aplastic anemia

A combination treatment of unrelated umbilical cord blood (UCB) and increased immunosuppressive treatment (IST) were investigated to reveal the potentially curative therapy for the severe aplastic anemia (SAA). A total of 36 children (2–17 ages) with SAA who received UCB infusion after an IST were analyzed. The treatment consisted of 100mg/kg cyclophosphamide, 12.5–15mg/kg antithymocyte globulin and 3mg/kg cyclosporine. After 3months, the hematologic complete response (CR) rate was 22.2% and partial response (PR) rate was 38.9%. After 6months, the CR rate and PR rate was 50.4% and 26.3%, respectively. The probability of 3-year survival was 83.3%. There was no difference in the survival rate either between the horse-ATG and rabbit-ATG or between the SAA and VSAA. The results indicated that the increased IST combined with unrelated UCB infusion has an effective therapeutic potential for children with SAA who lack of compatible donor for transplantation.

Furosemide infusion in children with dengue fever and hypoxemia

ObjectivesTo study the role of furosemide infusion in the management of Acute respiratory distress syndrome (ARDS) associated with dengue fever.MethodsChildren between the ages of 1 month to 18 years, who fulfilled the WHO clinical criteria for dengue infection and American European Consensus Criteria criteria for ARDS with Dengue IgM positivity, were evaluated. Patients were studied as group D (receiving diuretic therapy alone) and group B (both ventilation and diuretics), and compared to a historical control group V (ventilation alone). Furosemide infusion was administered at 0.05–0.1 mg/kg/hour for 48 hours, maintaining a urine output of 2–4 mL/kg/hour.ResultsThere was a significant difference in survival in the three groups. Significant difference was noted between pre- and postintervention arterial blood gases with respect to PCO2 (P=0.02), pO2 (P=0.003), PaO2/FaO2 ratio (P<0.001) and alveolar-arteriolar oxygen gradient (P=0.002).ConclusionDiuretic infusion improves outcome in dengue with ARDS.

Design and Clinical Evaluation of Robust PID Control of Propofol Anesthesia in Children

This paper describes the design of a robust proportional-integral derivative (PID) controller for propofol infusion in children and presents the results of clinical evaluation of this closed-loop system during endoscopic investigations in children age 6-17. The controller design is based on a set of models that describes the interpatient variability in the response to propofol infusion in the study population. The PID controller is tuned to achieve sufficient robustness margins for the identified uncertainty. 108 children were enrolled in this study, and anesthesia was closed-loop controlled in 102 of these cases. Clinical evaluation of the system shows that closed-loop control of both induction and maintenance of anesthesia in children based on the WAV <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">CNS</sub> index as a measure of clinical effect is feasible. A robustly tuned PID controller can accommodate the interpatient variability in children and spontaneous breathing can be maintained in most subjects.

Critical incidents related to opioid infusions in children: a five-year review and analysis

Opioids have a narrow therapeutic index and have the potential to cause significant harm. Developmental and pharmacogenetic factors put children, and especially infants, at increased risk of complications. We performed a retrospective root cause analysis to identify the factors associated with critical incidents in children receiving opioid infusions in a tertiary care children's hospital. Following institutional ethical approval, we identified potential critical incidents during 2004 to 2009 from patient safety and pharmacy data. Patients' medical charts were reviewed and a timeline of events that occurred before, during, and following each incident was generated. A safety assessment code score was assigned to each incident according to its severity and probability of recurrence, and incidents with a score ≥8 were selected for root cause analysis. Root causes were identified and classified, formal causal statements were written, and action plans were recommended. One hundred and sixty-six medical charts were reviewed, and 58 of these included one (45/58) or more (13/58) relevant critical incidents. The resulting harms were of minor to moderate severity. Fourteen incidents were submitted for detailed analysis, from which 31 root causes were identified. The most frequent and significant root causes involved defects in pre-printed order sheets, lack of a nursing guidelines for infusions (rate, adjustment, weaning), and inadequate guidelines for monitoring and recording pain, vital signs, and arousal scores. The root causes of a range of critical incidents have been identified, and these have been used to generate recommendations for improving both patient safety and quality of analgesia for children receiving opioid infusions for acute pain management.

Treatment-related cardiotoxicity in survivors of childhood cancer

Treatment advances and higher participation rates in clinical trials have rapidly increased the number of survivors of childhood cancer. However, chemotherapy and radiation treatments are cardiotoxic and can cause cardiomyopathy, conduction defects, myocardial infarction, hypertension, stroke, pulmonary oedema, dyspnoea and exercise intolerance later in life. These cardiotoxic effects are often progressive and irreversible, emphasizing a need for effective prevention and treatment to reduce or avoid cardiotoxicity. Medical interventions, such as angiotensin-converting enzyme inhibitors, β-blockers, and growth hormone therapy, might be used to treat cardiotoxicity in childhood cancer survivors. Preventative strategies should include the use of dexrazoxane, which provides cardioprotection without reducing the oncological efficacy of doxorubicin chemotherapy; less-toxic anthracycline derivatives and the use of antioxidant nutritional supplements might also be beneficial. Continuous-infusion doxorubicin provides no benefit over bolus infusion in children. Identifying patient-related (for example, obesity and hypertension) and drug-related (for example, cumulative dose) risk factors for cardiotoxicity could help tailor treatments to individual patients. However, all survivors of childhood cancer are at increased risk of cardiotoxicity, suggesting that survivor screening recommendations for assessment of global risk of premature cardiovascular disease should apply to all survivors. Optimal, evidence-based monitoring strategies and multiagent preventative treatments still need to be identified.

Vascular function and glucose variability improve transiently following initiation of continuous subcutaneous insulin infusion in children with type 1 diabetes

The effect of continuous subcutaneous insulin infusion (CSII) and glucose variability on vascular health in type 1 diabetes (T1D) is not known. We aimed to determine whether initiation of CSII improves vascular function and reduces glucose variability, independent of changes in HbA1c. Twenty-two children with T1D (12.5 ± 2.9 yr) were reviewed immediately prior, 3 wk, and 12 months after initiation of CSII. Vascular function [flow-mediated dilatation (FMD), glyceryl trinitrate-mediated dilatation (GTN)], glucose variability [mean of daily differences (MODD), mean amplitude of glycaemic excursions (MAGE) and continuous overlapping net glycaemic action (CONGA)], and clinical and biochemical data were measured at each visit. Results for the first two visits were compared to a previously studied cohort of 31 children with T1D who remained on multiple daily injections (MDI). FMD, GTN, blood pressure, HbA1c, fructosamine, and glucose variability significantly improved 3 wk after CSII commencement (all p < 0.05), but there was no change in the MDI control group. At 3 wk, vascular function related to glucose variability [(FMD: MODD, r = -0.62, p = 0.002) and (GTN: MAGE, r = -0.59, p = 0.004; CONGA-4, r = -0.51, p = 0.01; MODD, r = -0.62, p = 0.002)] but not to blood pressure, HbA1c, or fructosamine. At 12 months, FMD, GTN, blood pressure, and glucose variability returned to baseline levels, while HbA1c deteriorated. Carotid intima media thickness was unchanged over 12 months. Initiation of CSII rapidly improves vascular function in association with decreased glucose variability; however, the effects are not sustained with deterioration of metabolic control and glucose variability.

Sodium nitroprusside is not associated with metabolic acidosis during intraoperative infusion in children

BackgroundSodium nitroprusside (SNP) is a potent vasodilator that has been used to induce deliberate hypotension in children during surgery involving significant blood loss, including craniofacial and spinal fusion procedures. SNP metabolism liberates cyanide, which may cause interference with cellular energy metabolism, leading to metabolic acidosis and central nervous system injury. We performed a retrospective, case–control study to determine whether the short-term intra-operative use of SNP for deliberate hypotension is associated with metabolic acidosis in children undergoing surgical procedures for craniofacial or spinal anomalies. Cyanide and thiocyanate concentrations were also recorded in patients who received SNP.MethodsData from 166 children undergoing craniofacial and spinal fusion surgery between 2005 and 2010 at Lucile Packard Children's Hospital (LPCH) at Stanford were analyzed. Records from 60 patients who received SNP (SNP group) as part of a multicenter, randomized, double-blind study were compared with records from 106 eligible patients who had blood pressure reduction using anesthetic agents and did not receive SNP (control group). Metabolic acidosis was defined as serum bicarbonate (HCO3) < 18.5 mEq/L. Whole blood CN, plasma thiocyanate and urinary thiocyanate concentrations were measured in patients in the SNP group. Differences in metabolic acidosis rates between the SNP and control groups were assessed through a test of noninferiority in the rate for the SNP group with a noninferiority threshold of 0.2. A z-test was used to test the null hypothesis. The alternative hypothesis was that the difference in these rates was less than 0.2. The same noninferiority threshold of 0.2 was also used to perform separate, secondary tests for noninferiority in the proportion of patients with HCO3 levels below 18.5 mEq/L and the proportion of patients who required HCO3 administration.ResultsFewer patients in the SNP group experienced metabolic acidosis compared to the control group (31.7% vs. 36.8%, respectively; p < .001). No whole blood CN levels above the lower limit of quantification were detected in any of the 51 patients with validated CN data. Plasma and urinary thiocyanate levels were also low.ConclusionsOur findings suggest that SNP, when used for short-term deliberate hypotension, does not cause an increased incidence of metabolic acidosis compared with the use of anesthetic agents alone.Trial registrationTrial registration number: NCT00135668

Bumetanide continuous-infusion dosing in critically ill pediatric patients

Continuous infusions of loop diuretics are used in neonatal and pediatric intensive care units to induce a more-controlled diuresis with less hemodynamic instability. Although furosemide is the most commonly used loop diuretic administered via continuous infusion in children, recent drug shortages

Comparing Subcutaneous Fluid Infusion with Intravenous Fluid Infusion in Children

This study examined subcutaneous (SC) infusion as a parenteral alternative for children with mild to moderate illness. The purpose was to compare the difference in infusion start time of parenteral fluid between an initial SC order and an initial intravenous (IV) order. In addition, the number of needlesticks a child received for each method was evaluated. This study also sought to address the following question: If SC fluids were given and an IV attempt was made later, did the administration of SC fluids enhance the success of venous cannulation? A retrospective descriptive design was used for review of medical records for 36 children from November 2008 to May 2010 who had received SC fluids only or received SC fluids after 2 or more failed IV attempts. The IV/SC group had significantly longer time to infusion (M = 97.33 minutes) than did the SC group (M = 20.95 minutes; U = .000; P < .001). The IV/SC group included the number of needlesticks for the intravenous attempts plus the needle stick needed for the subcutaneous infusion. A significant difference was found between the 2 groups (mean IV = 4.87; mean SC = 1; Z = .000; P < .001). In a child who is not seriously ill, SC infusions appear to facilitate the initiation of parenteral rehydration. SC infusions minimized the number of needlesticks a child endured. More study is needed to determine if SC fluids enhance success of subsequent venous cannulation.

A phase I trial of AT9283 (a selective inhibitor of Aurora kinases) given for 72 hours every 21 days via intravenous infusion in children and adolescents with relapsed and refractory solid tumours.

9542 Background: AT9283, is a multi-targeted inhibitor, against Aurora A and B, JAK &amp; ABL kinases. Aurora kinases are potential therapeutic targets in paediatric solid cancers. Methods: A phase I dose escalation study was performed using a 72 hour intravenous infusion repeated 3 weekly using a rolling 6 design for patients aged &gt;2 to &lt;19 years with relapsed/ refractory solid tumours. Results: Eighteen patients treated with a median age of 10 (range 3 to 16) years. Four dose cohorts of 7, 9, 11.5 and 14.5 mg/m2/day. The diagnoses included; 5 high grade glioma, 4 rhabdoid tumours, 3 neuroblastomas, 3 sarcomas &amp; 3 others. There has been only one dose limiting toxicity; Grade 3 febrile neutropenia at 11.5 mg/m2/day. The majority of adverse events (AEs) have been grade 1/2 &amp; considered unrelated/ unlikely related to study drug. Two patients have experienced Grade 3 or 4 AEs considered at least possibly related to study drug: Grade 3 haemoglobin and Grade 4 neutrophils in a patient treated at 9 mg/m2/day &amp; Grade 3 lymphopenia, neutrophils, infection with normal neutrophil count and aspartate transaminase in a patient treated at 11.5 mg/m2/day. Pharmacokinetics of AT9283 in this population are largely in keeping with those seen in adult patients at similar doses (Arkenau et al., 2011) although there may be greater variability. Pharmacodynamic evidence of aurora B inhibition, as manifested by a reduction in histone H3 phosphorylation in normal skin biopsies pre &amp; post infusion, has been documented at all dose levels tested. Stable disease (up to 6 cycles) has been observed in 3 patients. Conclusions: This paediatric phase I study has demonstrated AT9283 administered as a 72 hour continuous infusion can be given at a dose level of 11.5 mg/m2/day which is higher than the maximum tolerated dose observed in adult patients (9 mg/m2/day) with advanced solid tumours. Myelosuppresion is the main toxicity but the regimen is well tolerated with preliminary anticancer activity seen in heavily pre-treated paediatric patients. [Table: see text]

A comparison of traditional vs. Canadian tailored prophylaxis dosing of prophylactic factor infusions in children with haemophilia A and B in a single hemophilia treatment center

Prophylactic infusion of clotting factor concentrates is a developing standard of care for individuals with haemophilia. The ideal schedule and techniques of prophylactic infusions remain incompletely defined. Our aim was to determine the optimal techniques and schedules for factor prophylaxis in paediatric patients. A retrospective electronic medical record review of all children treated with prophylactic factor infusions in a single Haemophilia Treatment Center was conducted. Comparison of traditional vs. Canadian dosing regimens and primary vs. secondary prophylaxis was made. Failure of prophylaxis was defined as the first serious bleed. A total of 58 children were identified for review. Five cases were excluded (four due to high titre inhibitors and one due to repeated non-compliance), thus there were 53 total cases: 46 with severe haemophilia, 2 with moderate haemophilia, 5 with mild haemophilia, 44 with haemophilia A and 9 with haemophilia B; 32 Traditional dosing and 21 Canadian dosing regimens. Patients on primary prophylaxis had a decreased failure rate (25%) compared to children treated with secondary prophylaxis (67%) regardless of technique of prophylaxis. When compared to a 'Traditional' factor prophylaxis schedule, the 'Canadian' tailored prophylaxis protocol was comparable with the exception of a decreased use of implanted venous devices in the 'Canadian' group. Ongoing bleeding (primarily joint bleeds) occurs with all prophylactic regimens. The lowest incidence of treatment failure was noted in children who began primary prophylaxis at a young age and before initial joint bleeds. Primary prophylaxis is superior to secondary prophylaxis regardless of dosing regimen. Traditional and Canadian dosing regimens were equivalent in outcome when measured over several years of follow-up.

Regadenoson, An Adenosine 2A Receptor Agonist, Is Safe and Inhibits Invariant NKT Cells in Sickle Cell Disease

Abstract 849▪FN2▪This icon denotes a clinically relevant abstractAdenosine 2A receptor (A2AR) agonists decrease pulmonary inflammation and injury in a murine model of sickle cell disease (SCD) by interrupting invariant NKT (iNKT) cell activation that occurs as a result of vaso-occlusion (Clin Immunol 2011). iNKT cells represent a subpopulation of T lymphocytes that rapidly generates pro-inflammatory cytokines upon activation and thereby may play a role in sustaining or propagating vaso-occlusion in human SCD. To evaluate the effects of A2AR activation in human SCD, we are conducting a dose-seeking and safety study of the FDA-approved, highly selective A2AR agonist regadenoson in patients with SCD ≥ 14 years of age. This is a multi-center, phase I clinical trial of infusional regadenoson that utilizes a 3+3 design and is comprised of four stages to determine maximum tolerated dose and safety during a 12 hour infusion in adults at baseline (defined as absence of increased pain, ED or hospital visit in the past 2 weeks) (stage 1), a 24 hour infusion in adults at baseline (stage 2), a 24 hour infusion in adults during a painful vaso-occlusive crisis (VOC) (stage 3), and a 24 hour infusion in children (≥ 14 years) during a painful VOC (stage 4). Three dose levels of infusional regadenoson have been evaluated thus far: 0.24 (level 0), 0.6 (level 1) and 1.44 mcg/kg/hour (level 2). Samples for plasma levels and iNKT cell activation are obtained at 0, 6, 12, 18 and 30 hours after start of infusion. Two methods are used to identify iNKT cells: 1) CD1d tetramers, loaded with the α-GalCer-like glycolipid PBS57 (defined as tetramer+CD3+), and 2) 6B11 antibody to the invariant T cell receptor (defined as CD45+6B11 high). NF-kB activation is measured using phospho-Ser536-p65 antibody (phospho-NF-kB). To date, 15 subjects have received infusional regadenoson. Regadenoson appears to be safe (devoid of cardiovascular or other side effects) and biologically active in reducing iNKT cell activation markers during a 12 hour infusion at dose levels 1 and 2, and we are currently evaluating the safety of a 24 hour infusion at dose level 2. No dose limiting toxicities occurred in the 15 subjects at dose levels 0, 1 or 2. Pharmacokinetic analyses showed mean peak plasma concentrations of regadenoson for dose levels 0, 1 and 2 were 0.37 ng/ml, 1.16 ng/ml and 2.19 ng/ml, respectively. Based on animal models, we suspect that biologically active plasma concentrations are approximately 1 ng/ml. At baseline, iNKT cells were activated in patients with SCD as defined by elevated levels of phospho-NF-kB expression and A2AR expression as assessed by anti-A2AR immunoreactivity. In particular, CD4+ iNKT cells showed increased phospho-NF-kB expression whereas CD4- iNKT cells were not activated. At dose levels 1 and 2, regadenoson decreased iNKT cell activation in patients with SCD. For example, when pre- and post-12 hour regadenoson infusion measurements were compared at dose level 2 (N=5), mean percent of cells expressing phospho-NF-kB in the activation gate was 40% (90% CI 23–58) at baseline and decreased by 53% at the end of infusion to 19% (90% CI 6–33). Similar results were found in measurements of A2ARs. We conclude that infusional regadenoson administered at 0.6 and 1.44 mcg/kg/hour is safe during a 12 hour infusion and decreases activation of iNKT cells. Our next steps are to determine whether infusions of a longer duration (24 and 48 hours) are safe and similarly biologically effective during a VOC. We then intend to conduct a clinical trial to measure the clinical efficacy of regadenoson infusion during VOC and acute chest syndrome episodes. Disclosures:Off Label Use: Regadenoson is an adenosine 2A receptor agonist that is FDA approved for use during myocardial stress imaging. We are examining the safety of regadenoson in patients with sickle cell disease. Nathan:Astellas: Research Funding.