Rebecca Sherlock

Preventing Brain Injury in Newborns With Congenital Heart Disease. Brain Imaging and Innovative Trial Designs

Background and Purpose— Newborns with congenital heart disease are at high risk for brain injury and adverse neurodevelopmental outcomes. MRI enables the objective determination of the severity of brain injury in critically ill newborns with congenital heart disease. We will rationalize the use of MRI as a surrogate for neurodevelopmental outcome and describe novel randomization techniques that can be used in trials in this population. Methods— This article describes the evidence for the use of MRI and the link with neurodevelopmental outcome established in newborns. We also discuss the use of adaptive randomization techniques for future clinical trials in newborns with congenital heart disease. These strategies will be highlighted using an example. Results— Brain injuries occur with high frequency in newborns with congenital heart disease. It is not until school age that the full extent of neurological sequelae becomes apparent and the rapid pace of innovation in neonatal cardiac surgery prevents timely evaluation of changes in care. MRI provides a timely, safe, and reliable outcome measure and has been extensively studied in newborns with other conditions in which the link between brain injury and neurodevelopmental outcome has been established. Clinical trials using MRI as an outcome measure as well as adaptive randomization can improve the efficiency of such trials. Conclusions— Clinical trials of brain protection are urgently needed in newborns with congenital heart disease given the unacceptable frequency of brain injury in this population; MRI provides an early surrogate marker of long-term neurodevelopmental outcome and adaptive randomization can be used to improve the efficiency of these clinical trials.

How effective is tetracaine 4% gel, before a venipuncture, in reducing procedural pain in infants: a randomized double-blind placebo controlled trial

BackgroundProcedural pain relief is sub-optimal in neonates. Topical tetracaine provides pain relief in children. Evidence of its efficacy and safety in neonates is limited. The objective of this study was to assess the efficacy and safety of topical tetracaine on the pain response of neonates during a venipuncture.MethodsMedically stable infants greater than or equal to 24 weeks gestation, requiring a venipuncture, were included. Following randomization and double blinding, 1.1 g of tetracaine or placebo was applied to the skin for 30 minutes. Participants received oral sucrose if they met local eligibility criteria. The venipuncture was performed according to a standard protocol. A medium effect size in the pain score (corresponding to about 2 point difference in the PIPP score) was considered clinically significant, leading to a sample size of 142 infants, with 80% statistical power. Local skin reactions and immediate adverse cardiorespiratory events were noted. The primary outcome, PIPP score at 1 minute, was analysed using an independent Students t-test.ResultsOne hundred and forty two infants were included, 33 +/- 4 weeks gestation, 2100 +/- 900 grams and 6 +/- 3 days of age. There was almost no difference in PIPP scores at 1 minute between groups (mean difference -0.09; 95% confidence interval [CI]: -1.68 to 1.50; P = . 91). Similarly, there were no differences in PIPP scores during the 2nd, 3rd and 4th minute. Duration of cry did not differ between the groups (median difference, 0; 95% CI, -3 to 0; P = . 84). The majority of infants in both groups received sucrose 24%. Sucrose had a significant effect on the PIPP score, as assessed by an ANOVA model (p = 0.0026). Local skin erythema was observed transiently in 11 infants (7 in the tetracaine and 4 in the placebo group). No serious side effect was observed.ConclusionTetracaine did not significantly decrease procedural pain in infants undergoing a venipuncture, when used in combination with routine sucrose administration.

How effective is tetracaine 4% gel, before a peripherally inserted central catheter, in reducing procedural pain in infants: a randomized double-blind placebo controlled trial [ISRCTN75884221]

BackgroundProcedural pain relief is sub-optimal in infants, especially small and vulnerable ones. Tetracaine gel 4% (Ametop®, Smith-Nephew) provides pain relief in children and larger infants, but its efficacy in smaller infants and for peripherally inserted central catheters (PICC) remains uncertain. The objective of this trial was to assess the safety and efficacy of tetracaine gel on the pain response of very low birth weight (VLBW) infants during insertion of a PICC.MethodsMedically stable infants greater than or equal to 24 weeks gestation, requiring a non-urgent PICC, were included. Following randomization and double blinding, 1.1 g of tetracaine or placebo was applied to the skin for 30 minutes. The PICC was inserted according to a standard protocol. Pain was assessed using the Premature Infant Pain Profile (PIPP). A 3-point change in the pain score was considered clinically significant, leading to a sample size of 54 infants, with 90% statistical power. Local skin reactions and immediate adverse cardiorespiratory events were noted. The primary outcome, PIPP score at 1 minute, was analysed using an independent Students t-test.ResultsFifty-four infants were included, 27 +/- 2 weeks gestation, 916 +/- 292 grams and 6.5 +/- 3.2 days of age. Baseline characteristics were similar between groups. The mean PIPP score in the first minute was 10.88 in the treatment group as compared to 11.74 in the placebo group (difference 0.86, 95% CI -1.86, 3.58). Median duration of crying in non-intubated infants was 181 seconds in the tetracaine group compared to 68 seconds in the placebo group (difference -78, 95% CI -539, 117). Local skin erythema was observed transiently in 4 infants (3 in the treatment and 1 in the placebo group). No serious harms were observed.ConclusionTetracaine 4% when applied for 30 minutes was not beneficial in decreasing procedural pain associated with a PICC in very small infants.

Reversed umbilical arterial end diastolic flow, sildenafil treatment and early stillbirths

Sir, We are very grateful for the interest shown by Downing and colleagues in our paper describing our initial experience with sildenafil in pregnancies complicated by earlyonset severe intrauterine growth restriction. We recognise the concept of cor placentale, and that it is analogous to pulmonary hypertension, for which sildenafil is an important therapy. However, sildenafil is potentially a powerful vasodilator in a number of vascular beds, given the wide distribution of phosphodiesterase-5 receptors in human tissue. Should the fetus have altered its haemodynamics to support brain sparing (which we assume to be very much the case under these circumstances), and sildenafil opens up non-essential vascular beds that are vasoconstricted as part of the brain-sparing effect (e.g. mesenteric, pulmonary and renal) or altering critical shunts (ductus arteriosus or venosus), the net effect could be to shunt a critical volume of blood away from vital areas, especially the brain and coronary sinuses. Although positive fetal effects have been seen in animal experiments, negative fetal effects have also been documented, suggesting the net sum effect of sildenafil exposure is not yet fully understood. Thus, the potential for fetal harm is still possible. Therefore, as the single case of fetal death upon the initiation of therapy occurred in the presence of reversed end diastolic flow (REDF), we have chosen a conservative approach of excluding such fetuses from our planning of a randomised controlled trial (RCT) that we believe is required. In addition, we plan to add the measurement of placental growth factor as an additional entry criterion for the RCT because of its apparent ability to discriminate between placental and constitutional growth restriction, especially in response to animal data in the absence of placental restriction. However, we respect that others may feel that severely growth restricted fetuses with REDF who have not reached gestational age or weight pre-requisites for resuscitation are prime candidates for a sildenafil RCT, as there are no alternatives at that point. As the risk is that inclusion of such fetuses in an RCT may obfuscate any beneficial effect on fetuses who enter the trial in a more robust state of adaptation, we would encourage stratification by umbilical artery blood flow state upon trial entry. j

Recours au sulfate de magnésium à des fins de neuroprotection fœtale

Resume Objectif Fournir une directive clinique quant a l’administration prenatale de sulfate de magnesium (MgSO 4 ) a des fins de neuroprotection foetale pour ce qui est du nouveau-ne issu d’un accouchement preterme. Options L’administration prenatale de MgSO 4 devrait etre envisagee a des fins de neuroprotection foetale en presence d’un accouchement preterme imminent (defini comme une forte probabilite d’accouchement en raison d’un travail actif en presence d’une dilatation cervicale ≥ 4 cm, avec ou sans rupture pretravail des membranes preterme, et/ou un accouchement preterme planifie en raison d’indications foetales ou maternelles) chez une patiente en etant a ≤ 31+6 semaines. Il n’existe aucun autre agent neuroprotecteur foetal connu. Issues Les criteres d’evaluation sont l’incidence de l’infirmite motrice cerebrale (IMC) et le deces neonatal. Resultats La litterature publiee a ete recuperee par l’intermediaire de recherches menees dans PubMed ou Medline, CINAHL et The Cochrane Library, en mai 2010, au moyen d’un vocabulaire controle et de mots cles adequats (« magnesium sulphate », « cerebral palsy », « preterm birth »). Les resultats ont ete restreints aux analyses systematiques, aux essais comparatifs randomises / essais cliniques comparatifs et aux etudes observationnelles pertinentes. Aucune restriction n’a ete imposee en matiere de date ou de langue. Les recherches ont ete mises a jour de facon reguliere et integrees a la directive clinique jusqu’en aout 2010. La litterature grise (non publiee) a ete identifiee par l’intermediaire de recherches menees dans les sites Web d’organismes s’interessant a l’evaluation des technologies dans le domaine de la sante et d’organismes connexes, dans des collections de directives cliniques, dans des registres d’essais cliniques et aupres de societes de specialite medicale nationales et internationales. Valeurs La qualite des resultats a ete evaluee au moyen des criteres decrits dans le rapport du Groupe d’etude canadien sur les soins de sante preventifs (Tableau 1). Avantages, desavantages et couts L’administration prenatale de sulfate de magnesium a des fins de neuroprotection foetale attenue le risque de « deces ou d’IMC » (RR, 0,85; IC a 95 %, 0,74 – 0,98; 4 essais, 4 446 nouveau-nes), de « deces ou d’IMC allant de moderee a grave » (RR, 0,85; IC a 95 %, 0,73 – 0,99; 3 essais, 4 250 nouveau-nes), de « toute forme d’IMC » (RR, 0,71; IC a 95 %, 0,55 – 0,91; 4 essais, 4 446 nouveaunes), d’« IMC allant de moderee a grave » (RR, 0,60; IC a 95 %, 0,43 – 0,84; 3 essais, 4 250 nouveau-nes) et de « dysfonction substantielle de la motricite globale » (incapacite de marcher sans aide) (RR, 0,60; IC a 95 %, 0,43 – 0,83; 3 essais, 4 287 nouveau-nes) a l’âge de deux ans. Les resultats etaient concordants d’un essai et d’une meta-analyse a l’autre. Nous n’anticipons aucune hausse significative des couts de sante, puisque les femmes admissibles au traitement prenatal au MgSO 4 seront considerees comme etant sur le point de connaitre un accouchement preterme. Validation La directive clinique nationale australienne a ete publiee en mars 2010 par le Antenatal Magnesium Sulphate for Neuroprotection Guideline Development Panel. L’administration prenatale de MgSO 4 a ete recommandee a des fins de neuroprotection foetale en fonction de la meme posologie que celle qui est recommandee dans la presente directive clinique. Cependant, l’administration de MgSO4 n’a ete recommandee qu’a Commanditaire Instituts de recherche en sante du Canada (IRSC).