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.

Percutaneous pulmonary valve implantation in children and adults with an age and gender-specific analysis.

BACKGROUND: There are limited studies with medium-term follow-up following percutaneous pulmonary valve implantation and no studies with a gender-specific analysis. AIMS: To report clinical outcomes up to five years following percutaneous pulmonary valve implantation using the two most common balloon expandable valves in a mixed population of paediatric and adult patients with an age and gender-specific analysis. METHODS: This was a single-centre retrospective observation study. Relevant data were obtained retrospectively from the case files. Age and gender- specific analysis was performed using SPSS. RESULTS: Totally, 58 patients (13 children, 45 adults) underwent percutaneous pulmonary valve implantation. Statistically significant reduction in median right ventricular outflow tract flow velocity following valve implantation was maintained for the whole five years in adults but not in children. There were no gender-specific differences despite the study being adequately powered. Independent of valve type used, there was significant reduction of the right ventricular outflow tract flow velocity in the immediate post valve implantation period (Edwards P = 0.001, Melody P = 0.013). There was a significant negative correlation between implanted valve Z-score and subsequent right ventricular outflow tract gradient during the first two years following valve implantation. CONCLUSION: Gender does not significantly affect valve function following percutaneous pulmonary valve implantation. It is important to consider patients' age and body surface area in relation to existing right ventricular outflow tract size during decisions for percutaneous pulmonary valve implantation.

Assessing patent ductus arteriosus in preterm infants from standard neonatal intensive care monitoring.

Monitoring patent ductus arteriosus (PDA) in premature infants is currently performed intermittently using echocardiography which requires considerable expertise. The aim of this pilot study was to investigate whether PDA status could be assessed from standard neonatal intensive care monitoring. Electrocardiography (ECG) and blood pressure (BP) waveforms were acquired from extremely preterm infants using standard neonatal monitors. We developed software using MATLAB to analyse ECG and BP waveforms and their interrelationships in terms of pulse transit time (PTT) and pulse wave velocity (PWV). The times from peak systolic BP to diastolic trough (BPFt) and from the diastolic trough to peak systolic BP (BPRt) were also calculated. PTT, BPFt and BPRt were normalised for heart rate (HR) termed NPTT, NBPFt and NBPRt, respectively. ECG, invasive aortic BP monitoring and echocardiography were performed in 14 preterm infants < 29 weeks' gestation in the first 3 days after birth. The median (range) birth weight of the infants was 0.90 (0.48-1.31) kg, gestation 26.6 (24.0-28.7) weeks, PDA diameter 1.6 (0.8-3.6) mm and mean BP 32 (16-40) mmHg. We found a significant positive correlation between PDA diameter and NPTT (r = 0.69, P = 0.007) as well as NBPFt (r = 0.65, P = 0.012) and NBPRt (r = 0.71, P = 0.005). No relationship was found between PDA diameter and pulse pressure.Conclusions: Interrelationships between ECG and BP traces as well as BP waveform time analysis are straightforward to measure and associated with PDA diameter. The results of this pilot study suggest that this approach may help provide biomarkers for continuous monitoring PDA diameter and function. What is Known: • Patent ductus arteriosus (PDA) in premature infants is associated with increased risk of developing chronic lung disease, necrotising enterocolitis and cerebral injury. • Currently PDA is assessed intermittently using echocardiography which requires considerable expertise and sometimes is not well tolerated by critically ill preterm infants. What is New: • Blood pressure (BP) and ECG waveform interrelation and BP trace time analysis, taking account of heart rate, relate to PDA diameter. • ECG and BP waveform phase difference as well as BP waveform time analysis may be useful in the continuous assessment of PDA function.

Mechanistic insights on the effect of crocin, an active ingredient of saffron, on atherosclerosis in apolipoprotein E knockout mice.

BACKGROUND: We investigated the effect of crocin treatment on atherosclerosis and serum lipids in apolipoprotein E knockout (ApoE-/-) mice, focusing on the expression of endothelial nitric oxide synthase (eNOS) and hypoxia-induced factor-1 alpha (HIF-1α). METHODS: Sixty-two animals were divided into two groups and randomly allocated to crocin (100 mg/kg/day) in drinking water or no crocin. All mice were maintained on standard chow diet containing 5% fat. Crocin was initiated at the 16th week of age and continued for 16 additional weeks. At 32 weeks of age, after blood sampling for plasma lipid determination and euthanasia, proximal aorta was removed and 3 µm sections were used to measure the atherosclerotic area and determine the expression of eNOS and HIF-1α by immunohistochemistry. RESULTS: Each group consisted of 31 animals (17 males and 14 females in each group). Crocin significantly reduced the atherosclerotic area (mm2 ± SEM) in treated mice compared to controls, both in males (0.0798 ± 0.017 vs. 0.1918 ± 0.028, P < 0.002, respectively) and females (0.0986 ± 0.023 vs. 0.1765 ± 0.025, P < 0.03, respectively). eNOS expression was significantly increased in crocin-treated mice compared to controls, both in males (2.77 ± 0.24 vs. 1.50 ± 0.34, P=0.004, respectively) and females (3.41 ± 0.37 vs. 1.16 ± 0.44, P=0.003, respectively). HIF-1α expression was significantly decreased in crocin-treated mice compared to controls, both in males (21.25 ± 2.14 vs. 156.5 ± 6.67, P < 0.001, respectively) and females (35.3 ± 7.20 vs. 113.3 ± 9.0, P < 0.01, respectively). No difference was noticed in total, low- and high-density lipoprotein cholesterol between treated and control mice. CONCLUSION: Crocin reduces atherosclerosis possibly by modulation of eNOS and HIF-1α expression in ApoE-/- mice without affecting plasma cholesterol.

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.