Liesbeth Thewissen

Analgosedation in neonates: do we still need additional tools after 30 years of clinical research?

Approximately 30 years ago, the myth that nervous system immaturity precluded neonates from pain perception and its negative effects was rejected. Neurobiologists further explored neurodevelopmental nociception. These observations strongly suggest that early pain experience contributes to neurodevelopmental outcome, pain thresholds, pain or stress-related behaviour and physiological responses in later life. Effective management of pain therefore remains an important indicator of the quality of care provided to neonates, not only from an ethical, but also from a short and long-term outcome perspective. Simultaneously, neonatal care itself has changed and data on neuro-apoptosis and impaired synaptogenesis following exposure to analgosedatives emerged. When developmental pharmacology concepts are applied to neonatal analgosedation, this means that this should be based on systematic assessment, followed by titrated administration of the most appropriate analgesic(s) with subsequent re-assessment to adapt treatment. This review will focus on the limitations of the available assessment tools, newly emerging analgosedatives in neonates to illustrate how these compounds can be integrated into the changing concepts of neonatal care.

Propofol Dose-Finding to Reach Optimal Effect for (Semi-)Elective Intubation in Neonates

OBJECTIVE To define the effective dose for 50% of patients (ED50) of propofol for successful intubation and to determine the rate of successful extubation in those patients with planned intubation, surfactant administration, and immediate extubation (INSURE procedure). In addition, pharmacodynamic effects were assessed. STUDY DESIGN Neonates (n = 50) treated with propofol for (semi-)elective endotracheal intubation were stratified in 8 strata by postmenstrual and postnatal age. The first patient in each stratum received an intravenous bolus of 1 mg/kg propofol. Dosing for the next patient was determined using the up-and-down method. A propofol ED50 dose was calculated in each stratum with an effective sample size of at least 6, via the Dixon-Masey method, with simultaneous assessment of clinical scores and continuous vital sign monitoring. RESULTS Propofol ED50 values for preterm neonates <10 days of age varied between 0.713 and 1.350 mg/kg. Clinical recovery was not attained at the end of the 21-minute scoring period. Mean arterial blood pressure showed a median decrease between 28.5% and 39.1% from baseline with a brief decrease in peripheral and regional cerebral oxygen saturation. Variability in mean arterial blood pressure area under the curve could not be explained by weight or age. CONCLUSIONS Low propofol doses were sufficient to sedate neonates for intubation. Clinical recovery was accompanied by permissive hypotension (no clinical shock and no treatment). The propofol ED50 doses can be administered at induction, with subsequent up-titration if needed, while monitoring blood pressure. They can be used for further dosing optimalization and validation studies. TRIAL REGISTRATION ClinicalTrials.gov: NCT01621373; EudraCT: 2012-002648-26.

Design and feasibility of “PREMATurity as predictor of children's Cardiovascular–renal Health” (PREMATCH): A pilot study

Abstract The microvasculature and macrovasculature undergo extensive, organ-specific perinatal maturation. Multiple studies show associations between low birth weight and subsequent cardiovascular dysfunction in adulthood, suggesting that extreme preterm birth interferes with this maturation process. Therefore, we designed PREMATCH (PREMATurity as predictor of Cardiovascular–renal Health) to phenotype the microcirculation and macrocirculation during childhood in former preterm infants. A well-characterized cohort of former extreme preterm birth survivors and gender- and age-matched controls (aged 8–13 years) will be investigated for microvascular and macrovascular structure and function. In addition to cognitive performance and anthropometrics, we will investigate (i) the microvascular structure and function by endothelial function (photoplethysmography), sublingual capillary glycocalyx function (sidestream dark field imaging) and retinal structure (diameters of arterioles and venules); and (ii) the macrovascular phenotype by cardiac and renal ultrasound, repeated blood pressure measurements and arterial pulse-wave recordings. The PREMATCH study is unique in its design, and ongoing recruitment demonstrates excellent feasibility. The expectation is that the results of this study will identify risk factors during childhood for subsequent cardiovascular–renal disease in the adult life of former preterm infants, while further analysis on mediators in neonatal life of this cardiovascular–renal outcome may provide new information on perinatal risk factors. Trial registration: ClinicalTrials.gov identifier: NCT02147457.

Influence of the Maternal Use of Labetalol on the Neurogenic Mechanism for Cerebral Autoregulation Assessed by Means of NIRS

Labetalol is a drug used in the treatment of hypertensive disorders of pregnancy (HDP). In a previous study we investigated the influence of the maternal use of labetalol on the cerebral autoregulation (CA) mechanism of neonates. In that study, we found that labetalol induces impaired CA during the first day of life, with CA returning to a normal status by the third day after birth. This effect was hypothesized to be caused by labetalol-induced vasodilation. However, no strong evidence for this claim was found. In this study we aim to find stronger evidence for the vasodilation effect caused by labetalol, by investigating its effect on the neurogenic mechanism (NM) involved in CA. The status of the NM was assessed by means of transfer function analysis between the low frequency content of the autonomic control activity (LFA), obtained by processing of the heart rate (HR), and the regional cerebral oxygen saturation (rScO₂). We found that neonates from mothers treated with labetalol presented a lower LFA and an impaired NM response during the first day of life, with values returning to normal by the end of the third day. These results reflect a vasodilation effect caused by labetalol, and indicate that the impaired CA observed in the previous study is caused by vasodilation.

Tocolytic indomethacin: effects on neonatal haemodynamics and cerebral autoregulation in the preterm newborn

Background Indomethacin has vasoactive properties in cerebral and systemic vascular beds, and it improves cerebral autoregulatory ability. We speculated that tocolytic indomethacin will improve cerebral autoregulatory ability in the very preterm infant in early postnatal life. Methods Eighteen stable preterm infants gestational age (GA) 25.3–29.6 weeks, birth weight (BW) 660–1430 grams), whose mothers had received 50–150 mg of tocolytic indomethacin within 24 h before birth, and 18 individually matched controls (GA 25.0–29.7 weeks, BW 700–1390 grams) were studied four times for 15 min in the first 24 h of life. Autoregulation was assessed by determining correlations between mean arterial blood pressure (MABP (mm Hg)) and near-infrared spectroscopy-monitored cerebral oxygenation (rScO2). Results MABPs were significantly higher in the indomethacin infants than in the control infants (p=0.03). A decreased ability to autoregulate was found in four of the indomethacin infants, and in six of the control infants, which is not significantly different. Conclusions Prenatally administered indomethacin, given as a tocolytic in doses of 50–150 mg per day, improved transitional circulation in very preterm infants by significantly raising the MABP. It did not have an effect on the ability to autoregulate the cerebral circulation. In this study, no differences in short-term outcomes, like haemorrhagic or ischaemic cerebral lesions, were observed.

Effect of maternal use of labetalol on the cerebral autoregulation in premature infants.

Hypertensive disorders of pregnancy (HDP) are normally treated to avoid maternal complications. In this study we aimed to investigate if there was an effect of maternal HDP treatment on the cerebral autoregulation of the neonates by analysing measurements of mean arterial blood pressure (MABP) and rScO2 by means of correlation, coherence, and transfer function analysis. We found that these infants presented higher values of transfer function gain, which indicates impaired cerebral autoregulation, with a decreasing trend towards normality. We hypothesised that this trend was due to a vasodilation effect of the maternal use of labetalol due to accumulation, which disappeared by the third day after birth. Therefore, we investigated the values of pulse pressure in order to find evidence for a vasodilatory effect. We found that lower values of pulse pressure were present in these infants when compared with a control population, which, together with increased transfer function gain values, suggests an effect of the drug on the cerebral autoregulation.

Choroidal Fissure Cerebrospinal Fluid-Containing Cysts: Case Series, Anatomical Consideration, and Review of the Literature

BACKGROUND Cerebrospinal fluid (CSF)-containing cysts at the level of the choroidal fissure are rare embryological entities infrequently described in the literature because of their benign nature. On the occasion of a case series, we present an overview of the literature and discuss anatomical and embryological location, imaging characteristics, presenting symptoms, and treatment indication of these lesions. METHODS We identified, in a retrospective study of a database with 81 patients harboring 86 supratentorial intracranial cysts, six patients with a CSF-containing cyst at the level of the choroidal fissure. In all cases, presenting symptoms were mild and the cysts were considered a fortuitous diagnosis. None of the patients was treated surgically, and the cysts remained stable at radiological follow-up. We performed a literature search for cerebral cysts and choroidal fissure cysts in particular. RESULTS Only one large study purely addressing choroidal fissure cysts was found in the literature. CONCLUSIONS CSF-containing cysts at the level of the choroidal fissure may be of the arachnoid or the neuroepithelial type, but pathological confirmation of a CSF-containing cyst at this specific location has never been published. Very infrequently they are symptomatic, and surgical treatment is hardly ever necessary.

Changes in Oxygenation Levels Precede Changes in Amplitude of the EEG in Premature Infants

Brain function is supported by an appropriate balance between the metabolic demand and the supply of nutrients and oxygen. However, the physiological principles behind the regulation of brain metabolism and demand in premature infants are unknown. Some studies found that changes in hemodynamic variables in this population precede changes in EEG activity; however, these studies only used descriptive statistics. This paper describes the relationship between changes in cerebral oxygenation, assessed by means of near-infrared spectroscopy (NIRS), and changes in EEG, using mathematical methods taken from information dynamics. In a cohort of 35 neonates subjected to sedation by propofol, we quantified the direction of information transfer between brain oxygenation and EEG. The results obtained indicate that, as reported in other studies, changes in NIRS are likely to precede changes in EEG activity.

Neonatal circulatory failure due to acute hypertensive crisis: clinical and echocardiographic clues.

Objective Circulatory failure due to acute arterial hypertension in the neonatal period is rare. This study was undertaken to assess the clinical and echocardiographic manifestations of circulatory failure resulting from acute neonatal hypertensive crisis. Methods Neonatal and cardiology databases from 2007 to 2010 were reviewed. An established diagnosis of circulatory failure due to neonatal hypertension before the age of 14 days was required for inclusion. Six patients were identified. Results Five patients presented with circulatory failure due to an acute hypertensive crisis. The median age at presentation was 8.5 days (range: 6.0–11.0) with a median body weight of 3.58 kg (range: 0.86–4.70). Echocardiography demonstrated mild left ventricular dysfunction [median shortening fraction (SF) 25%, range 10–30) and mild aortic regurgitation in 83% (5/6) of patients. One patient with left ventricular dysfunction (SF = 17%) had a large apical thrombus. Two patients were hypotensive, and hypertension only became evident after restoration of cardiac output. Administration of intravenous milrinone was successful, with rapid improvement of the clinical condition. Left ventricular function normalised in all survivors. Conclusion Early neonatal circulatory collapse due to arterial hypertension is a rare but potentially life-threatening condition. At presentation, hypotension, especially in the presence of a dysfunctional left ventricle, does not exclude a hypertensive crisis being the cause of circulatory failure. The echocardiographic presence of mild aortic regurgitation combined with left ventricular hypocontractility in a structurally normal heart should alert the physician to the presence of underlying hypertension.

Measuring near-infrared spectroscopy derived cerebral autoregulation in neonates: from research tool towards bedside multimodal monitoring.

Introduction: Cerebral autoregulation (CAR), the ability of the human body to maintain cerebral blood flow (CBF) in a wide range of perfusion pressures, can be calculated by describing the relation between arterial blood pressure (ABP) and cerebral oxygen saturation measured by near-infrared spectroscopy (NIRS). In literature, disturbed CAR is described in different patient groups, using multiple measurement techniques and mathematical models. Furthermore, it is unclear to what extent cerebral pathology and outcome can be explained by impaired CAR. Aim and methods: In order to summarize CAR studies using NIRS in neonates, a systematic review was performed in the PUBMED and EMBASE database. To provide a general overview of the clinical framework used to study CAR, the different preprocessing methods and mathematical models are described and explained. Furthermore, patient characteristics, definition of impaired CAR and the outcome according to this definition is described organized for the different patient groups. Results: Forty-six articles were included in this review. Four patient groups were established: preterm infants during the transitional period, neonates receiving specific medication/treatment, neonates with congenital heart disease and neonates with hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia. Correlation, coherence and transfer function (TF) gain are the mathematical models most frequently used to describe CAR. The definition of impaired CAR is depending on the mathematical model used. The incidence of intraventricular hemorrhage in preterm infants is the outcome variable most frequently correlated with impaired CAR. Hypotension, disease severity, dopamine treatment, injury on magnetic resonance imaging (MRI) and long term outcome are associated with impaired CAR. Prospective interventional studies are lacking in all research areas. Discussion and conclusion: NIRS derived CAR measurement is an important research tool to improve knowledge about central hemodynamic fluctuations during the transitional period, cerebral pharmacodynamics of frequently used medication (sedatives-inotropes) and cerebral effects of specific therapies in neonatology. Uniformity regarding measurement techniques and mathematical models is needed. Multimodal monitoring databases of neonatal intensive care patients of multiple centers, together with identical outcome parameters are needed to compare different techniques and make progress in this field. Real-time bedside monitoring of CAR, together with conventional monitoring, seems a promising technique to improve individual patient care.