Grading the level of evidence of neonatal pharmacotherapy: midazolam and phenobarbital as examples.

BACKGROUND: Many drugs are used off-label or unlicensed in neonates. This does not mean they are used without evidence or knowledge. We aimed to apply and evaluate the Grading and Assessment of Pharmacokinetic-Pharmacodynamic Studies (GAPPS) scoring system for the level of evidence of two commonly used anti-epileptic drugs. METHODS: Midazolam and phenobarbital as anti-epileptics were evaluated with a systematic literature search on neonatal pharmacokinetic (PK) and/or pharmacodynamic [PD, (amplitude-integrated) electroencephalography effect] studies. With the GAPPS system, two evaluators graded the current level of evidence. Inter-rater agreement was assessed for dosing evidence score (DES), quality of evidence (QoE), and strength of recommendation (REC). RESULTS: Seventy-two studies were included. DES scores 4 and 9 were most frequently used for PK, and scores 0 and 1 for PD. Inter-rater agreements on DES, QoE, and REC ranged from moderate to very good. A final REC was provided for all PK studies, but only for 25% (midazolam) and 33% (phenobarbital) of PD studies. CONCLUSIONS: There is a reasonable level of evidence concerning midazolam and phenobarbital PK in neonates, although using a predefined target without integrated PK/PD evaluation. Further research is needed on midazolam use in term neonates with therapeutic hypothermia, and phenobarbital treatment in preterms. IMPACT: There is a reasonable level of evidence concerning pharmacotherapy of midazolam and phenobarbital in neonates. Most evidence is however based on PK studies, using a predefined target level or concentration range without integrated, combined PK/PD evaluation. Using the GAPPS system, final strength of recommendation could be provided for all PK studies, but only for 25% (midazolam) to 33% (phenobarbital) of PD studies. Due to the limited PK observations of midazolam in term neonates with therapeutic hypothermia, and of phenobarbital in preterm neonates these subgroups can be identified for further research.

Intra- and Inter-rater Agreement of Superior Vena Cava Flow and Right Ventricular Outflow Measurements in Late Preterm and Term Neonates.

OBJECTIVES: To explore the intra- and inter-rater agreement of superior vena cava (SVC) flow and right ventricular (RV) outflow in healthy and unwell late preterm neonates (33-37 weeks' gestational age), term neonates (≥37 weeks' gestational age), and neonates receiving total-body cooling. METHODS: The intra- and inter-rater agreement (n = 25 and 41 neonates, respectively) rates for SVC flow and RV outflow were determined by echocardiography in healthy and unwell late preterm and term neonates with the use of Bland-Altman plots, the repeatability coefficient, the repeatability index, and intraclass correlation coefficients. RESULTS: The intra-rater repeatability index values were 41% for SVC flow and 31% for RV outflow, with intraclass correlation coefficients indicating good agreement for both measures. The inter-rater repeatability index values for SVC flow and RV outflow were 63% and 51%, respectively, with intraclass correlation coefficients indicating moderate agreement for both measures. CONCLUSIONS: If SVC flow or RV outflow is used in the hemodynamic treatment of neonates, sequential measurements should ideally be performed by the same clinician to reduce potential variability.

A Literature Review of the Pharmacokinetics and Pharmacodynamics of Dobutamine in Neonates.

Since its discovery in 1975 dobutamine has been used off-label for treating hemodynamic insufficiency in newborns and children. We present a structured literature review of pharmacokinetic and pharmacodynamic data for dobutamine in the pediatric population. Structured searches were conducted to identify relevant articles according to pre-defined inclusion criteria. Where possible, results for the pharmacodynamic and pharmacokinetic effect of dobutamine were reported as pooled data. Forty-six papers met the inclusion criteria. With regard to pharmacodynamic data a number of studies reported significant increases in a number of clinical parameters such as heart rate, blood pressure, cardiac output across a wide range of pediatric populations. With regard to pharmacokinetic data studies reported that the infusion rate was positively correlated to plasma dobutamine concentration. There was great variability with regard to dobutamine clearance between individuals and as to whether it followed first- or zero-order elimination kinetics. While the pharmacodynamic effects of dobutamine appear to reflect the pharmacological profile of the drug, the pharmacokinetic data are difficult to interpret due to inhomogeneity between study populations ages, comorbidities, dobutamine dosages and methodologies. High-quality prospective pharmacokinetic and pharmacodynamic data especially in newborns are urgently required prior to a large randomized study.

Heated humidified high-flow nasal cannula versus low-flow nasal cannula as weaning mode from nasal CPAP in infants ≤28 weeks of gestation.

UNLABELLED: Despite the paucity of evidence, the practice of weaning nasal continuous positive airway pressure (NCPAP) is widespread. However, the most clinically effective non-invasive ventilatory support strategy remains to be determined. We compared the outcome of very premature infants with respiratory distress syndrome treated with a combination of NCPAP and heated humidified high-flow nasal cannula (HHFNC) versus NCPAP and low-flow nasal cannula (LFNC). Between 2004 and 2008, patients ≤28 weeks of gestation and <1,250 g of birth weight were treated with NCPAP + HHFNC or NCPAP + LFNC. Their respiratory and non-respiratory outcome including cost-effectiveness was compared after matching for antenatal steroid doses, mode of delivery, birth plurality, gestational age, birth weight, gender, surfactant doses, length of mechanical ventilation and clinical risk index for babies-II (CRIB-II) score. Thirty-nine infants received HHFNC + NCPAP, and 40 received NCPAP + LFNC. Median gestational age and birth weight were 27 weeks and 930 g and 27 weeks and 980 g, respectively. The total number of NCPAP days was significantly reduced by 50 % in the HHFNC group. Thirteen percent of the patients on NCPAP suffered from nasal bridge lesions compared to none on HHFNC. Respiratory and non-respiratory outcome was not significantly different otherwise. Combination of NCPAP and HHFNC reduced costs by 33 %. CONCLUSIONS: HHFNC shortens NCPAP time without increasing overall length of non-invasive respiratory support in very preterm infants. Unlike NCPAP, HHFNC does not seem to increase the risk of nasal trauma and appears to improve cost-effectiveness whilst producing otherwise equal respiratory and non-respiratory outcomes.

Modified Seldinger technique for neonatal epicutaneo-caval catheter insertion: A non-randomised retrospective study.

BACKGROUND: Epicutaneo-Caval Catheters (ECCs) are critical for good neonatal care. No previous studies have evaluated which insertion method provides the highest likelihood of success. METHODS: This study aimed to compare the success rates and cost of modified Seldinger technique (MST) and split needle technique (SNT). MST was introduced to St Michael's Neonatal Unit, SNT was already in use. Routinely documented data on ECC insertion was retrospectively collected from the clinical notes. Practitioners were able to use their preferred insertion method. A sub-group analysis of success rates in patients born at ⩾35-weeks GA was performed. RESULTS: There was a significantly higher first pass (53% vs 26%; p = 0.014) and overall (72% vs 40%; p = 0.0046) successful ECC insertion rate with fewer venipunctures per successful ECC with MST (2.5 vs 6.5; p = 0.002). Logrank test demonstrated a significantly higher successful ECC insertion with MST for patients of all GA (p = 0.003) and for neonates born at ⩾35 weeks (p = 0.015). The cost per successful MST ECC was £156.41 versus £152.51 for SNT. CONCLUSION: In this uncontrolled retrospective study, there was a higher chance of successful ECC insertion with MST, with a reduced number of venipunctures and similar costs per successful ECC. Further work in randomised studies is needed to verify this finding and should focus on other clinical outcomes, including rates in central line associated blood stream infections.

A prospective cohort study using non-invasive methods of cardiovascular assessment to compare postnatal adaptation in well late preterm and term infants.

Echocardiography was combined with pulse oximetry plethysmography to investigate postnatal cardiovascular adaptation in late preterm and term infants. Median (IQR) pleth variability decreased over three days and similar, day2 15%(12-18%) preterm versus 16%(15-18%) term infants. Median (IQR) pulse transit time heart rate normalised was lower in term babies, day2 0.55(0.51-0.63) versus 0.64(0.62-0.68).

The association between parent's and healthcare professional's behavior and children's coping and distress during venepuncture.

OBJECTIVES: Examine the association between children's distress and coping during venepuncture with parent's and healthcare professional's behavior in a sample from the UK. METHODS: Fifty children aged 7-16 years accompanied by a carer were videotaped while having venepuncture. Verbalizations of children, parents, and healthcare professionals were coded using the Child-Adult Medical Procedure Interaction Scale-Revised. RESULTS: Children's distress was associated with child's age, anxiety, and distress promoting behavior of adults (R(2) = .91). Children's coping was associated with age, anxiety, and coping promoting behaviors of adults (R(2) = .57). Associations were stronger between healthcare professional's behavior and child coping; and between parent's behaviors and child distress. Empathizing, apologizing, and criticism were not frequently used by adults in this sample (<12%). CONCLUSION: This study supports and extends previous research showing adult's behavior is important in children's distress and coping during needle procedures. Clinical implications and methodological issues are discussed.

Treatment for Post-hemorrhagic Ventricular Dilatation: A Multiple-Treatment Meta-Analysis.

Objective: To perform a systematic review and multiple-treatment meta-analysis for the treatment of premature infants with post-hemorrhagic ventricular dilatation (PHVD), to prevent death or long-term neuro-disability. Design/Method: A systematic review was performed using PubMed, EMBASE, and the Cochrane Library. A free-word search was performed to identify likely relevant literature intervention trials of PHVD in preterm infants. Initially, network mapping was performed followed by performing a Bayesian random-effects model using the Markov chain Monte Carlo method. Areas under the cumulative ranking curve (SUCRA) were calculated as a measure of the probability that each intervention was likely to be the 1st, 2nd, 3rd, etc. best therapy. Primary outcome measure was death or moderate or severe neurodevelopmental outcome at or beyond 12 months of corrected age. Results: Ten different trials were identified, enrolling 700 individuals (449 for the primary outcome). Seven intervention categories were identified, and of the 15 possible pair comparisons, 6 have been studied directly. In the multiple-treatment meta-analysis, no comparison reached conventional levels of statistical significance. Drainage Irrigation and Fibrinolytic Therapy (DRIFT) had the highest probability of being the best treatment for the primary outcome (82.1%), followed by CSF removal (10.8%), conservative management (6.7%), and then diuretic therapy (0.4%). Conclusions: PHVD is a significant cause of death and disability in developed countries, yet few therapeutic options have so far been trialed. While new therapies are urgently needed for these infants, at present, NMA shows that DRIFT appears to be the most likely candidate to improve outcomes after sIVH.

Optiflow vs Vapotherm as extended weaning mode from nasal continuous positive airway pressure in preterm infants ≤ 28 weeks gestational age.

INTRODUCTION: Current evidence supports nasal continuous positive airway pressure (NCPAP) weaning. Heated humidified high-flow nasal cannula (HHFNC) reduces NCPAP time in infants less than 28 weeks gestational age (GA) without increasing morbidity. The aim of the study was to compare the two most frequently used HHFNC devices in weaning from NCPAP. METHODOLOGY: We performed a retrospective matched-pair case-control study of infants less than or equal to 28 GA born in a single tertiary neonatal center managed with Optiflow or Vapotherm after being weaned from NCPAP. Patients were matched for antenatal steroid doses, delivery mode, birth plurality, GA, birthweight, gender, surfactant doses, length of mechanical ventilation, and length of NCPAP. Outcome measures were duration of HHFNC, low-flow nasal cannula, nasal bridge lesions, pneumothorax, bronchopulmonary dysplasia, postnatal steroids, necrotizing enterocolitis, sepsis, intraventricular hemorrhage, retinopathy of prematurity, length of stay, discharge weight, and mortality. Results were displayed as median (interquartile range) or ratio (percentage). Statistical analysis was performed using Mann-Whitney U and χ2 tests. RESULTS: 70 patients were recruited retrospectively. Thirty-five infants were weaned from NCPAP to Optiflow and 35 infants to Vapotherm with gestational ages and birthweights of 27 GA (26-27) and 1010 g (835-1165) and 27 GA (26-28) and 960 g (788-1191), respectively. There was no statistically significant difference in any outcome measure. Infants managed with Vapotherm required a not statistically significant shorter length of time on HHFNC and low-flow nasal cannula. CONCLUSIONS: Optiflow and Vapotherm seem to be equally effective and safe for weaning from NCPAP. However, infants weaned to Vapotherm appear to spend less time on non-invasive respiratory support.

Understanding the Stability of Dopamine and Dobutamine Over 24 h in Simulated Neonatal Ward Conditions.

OBJECTIVES: Our objectives were to investigate the possible effects of temperature and light on the stability of dopamine and dobutamine continuous infusions over 24 h when prepared in a variety of dilution vehicles. METHODS: Syringe-driver infusion apparatuses were set up for dopamine and dobutamine diluted with either 0.9% sodium chloride (NaCl) or 5% glucose delivering 3 and 5 µg/kg/min, respectively, via 206-cm extension sets. All infusions were prepared for a neonate weight of 1 kg. Infusions were run over 24 h with approximately half the tubing within an incubator set at 35 °C. Cyclic voltammetry was used to monitor the concentration of the inotrope within the syringe and at the end of the extension set, both initially and after 24 h. RESULTS: The variation in the concentration of dopamine and dobutamine in the vials (n = 6) was 3.58 and 1.22%, respectively. This variation increased to 10.88% for dopamine and 5.76% for dobutamine in the syringe. After 24 h, a significant reduction in the concentration of dopamine was observed at the end of the extension set when prepared in 0.9% NaCl versus 5% glucose (p < 0.001; n = 6-7) and in dobutamine when prepared in 0.9% NaCl (p < 0.001; n = 6-7). No differences in the concentration of dopamine prepared in 0.9% NaCl were observed after 24 h in light-exposed and light-protected extension sets (n = 6-7). CONCLUSIONS: Dobutamine is more stable in dilution vehicles than dopamine, and inotropes are more stable in the 5% glucose dilution vehicle than in 0.9% NaCl. Such findings will provide guidance on the choice of inotropes.

Cardiovascular Drug Therapy for Human Newborn: Review of Pharmacodynamic Data.

BACKGROUND: Circulatory failure in preterm and term newborn infants is commonly treated with inotropes or vasoactive medications. In this structured literature review, the available data on pharmacodynamic effects of the inotropes adrenaline, dobutamine, dopamine, levosimendan, milrinone, noradrenaline, and the vasoactive drugs vasopressin and hydrocortisone are presented. METHODS: Structured searches were conducted to identify relevant articles according to pre-defined inclusion criteria which were human clinical trials published after 2000. RESULTS: Out of 101 identified eligible studies only 22 studies met the criteria for evidence based practice guidelines level I to IV. The most prevalent pharmacodynamic effects were increase in blood pressure and/or heart rate, which were also the most frequently studied circulatory parameters. CONCLUSION: This review demonstrates the need for further systematic studies on all reviewed drugs with incorporation of novel non-invasive biomarkers in this vulnerable patient group, for more timely and appropriate treatment for clinical efficacy.

The association of children's distress during venepuncture with parent and staff behaviours.

Venepuncture and other needle-related procedures can distress children and have a lasting negative impact. Adults' behaviour during these procedures may affect children's reactions. However, the literature is contradictory and rarely considers verbal and non-verbal behaviour together. This study therefore examined the effect of adults' verbal and non-verbal behaviour on children's distress during venepuncture. Participants comprised 51 child and carer dyads and 10 staff members. Child anxiety was measured before the procedure. The procedure was recorded. The resulting audio-visual data were coded using the Child-Adult Medical Procedure Interaction Scale-Revised. Correlation analysis identified variables that were significantly associated with child distress: child anxiety, carer distress-promoting behaviour, staff distress-promoting behaviour and intimate distance. These were included in a path diagram of child distress. Exploration of the diagram identified that children's anxiety was mostly strongly associated with children's distress during venepuncture. Staff and carer behaviour did not increase children's distress. The results suggest interventions to reduce children's distress during venepuncture may be more effective if they focus on reducing children's anxiety beforehand.

What is the evidence for the use of adrenaline in the treatment of neonatal hypotension?

AIM: The authors of this review present the current evidence of the physiology, indications and use of adrenaline in neonates, with particular focus on the treatment of hypotension. METHOD: A structured literature search was performed across selected electronic databases, reference lists and related articles. Abstracts arising from the search were screened for relevance according to predefined inclusion criteria. Full articles for the selected abstracts were obtained and then reviewed. Articles were analysed through a two stage process until agreement was reached between the research team on the studies for inclusion. RESULTS: We identified 187 animal and human studies (published between 1924-2011) using various methodologies but with two main themes: the physiology of endogenous adrenaline in neonates and the therapeutic uses of this hormone in neonatal medicine. The physiological studies measured catecholamine levels in cord blood, neonatal urine and blood, some in response to interventions such as suctioning, skin massage or morphine infusion. Within the therapeutic studies there was only one randomised controlled trial (RCT): a comparison of dopamine versus adrenaline involving 60 infants of < 32 weeks gestational age. CONCLUSION: Despite the number of studies identified, we found few adequately-controlled studies on the therapeutic use of adrenaline in neonates. Future research should focus on RCTs comparing adrenaline to other commonly used inotropes.

Parents' perceptions of their infants' participation in randomized controlled trials.

OBJECTIVE: To explore parents' perceptions of their infants' participation in randomized control trials (RCTs) and the implications of the RCT for their infant and themselves. DESIGN: A qualitative study using semistructured interviews. SETTING: Participants were identified from neonatal intensive care unit (NICU) clinical registers and from responses to an advertisement put on the website of United Kingdom special care baby charity, BLISS. Interviews were conducted with parents face-to-face in their homes or over the telephone. PARTICIPANTS: Sixteen parents of 12 infants born prematurely or with complications at full term and who had participated in one of three RCTs while receiving intensive care in one of seven NICUs. METHODS: Interviews were audio-taped or digitally recorded, transcribed verbatim, and analyzed using systematic thematic analysis using WinMax qualitative software. RESULTS: Five main themes emerged from the data. The themes were parents' immediate reactions to being approached about RCT enrollment, interactions between parents and clinicians upon the approach of enrollment and during the RCT, making the decision to enroll their infants, implications of the RCT for parents, and effects of the RCT on the infants. CONCLUSIONS: Clinicians should be encouraged to approach parents about enrollment of their infants in clinical research given that parents reported mostly positive experiences related to this participation. However, appropriate measures should be taken to ensure that the individual needs of parents are being met throughout the entire research process from enrollment to follow-up.

Understanding needle-related distress in children with cystic fibrosis.

OBJECTIVE: To explore the nature and management of needle-related distress in children and adolescents with cystic fibrosis (CF). DESIGN: Qualitative study using semi-structured interviews. METHODS: Fourteen child-parent dyads took part. Children (5 male; 9 female) had a mean age of 12.4 years (range 7-17) and were mostly diagnosed with CF at birth (N= 11). Frequency of needle procedures ranged from once to six times a year. Parents (3 male; 11 female) had a mean age of 41.5 years and were from a variety of socio-economic backgrounds. Interviews were transcribed and analysed using thematic analysis. RESULTS: Most participants identified previous needle experiences and pain as related to their needle anxiety. Over half of parents and children considered 'taking control' to be the optimum coping strategy. The majority of parents and children thought inhaled nitrous oxide gas during needle procedures was helpful in managing needle-related distress. Parent and staff influences on needle-related distress are also examined. CONCLUSIONS: Needle-related distress in children with CF has a substantial impact on children and their parents, and may lead to management problems and treatment refusal. Psychological and pharmacological interventions could reduce distress and aid management.