Cerebral intraventricular hemorrhage and post-hemorrhagic ventricular dilatation in preterm infants: new mechanistic insights and potential treatment strategies

Intraventricular hemorrhage (IVH) is one of the major co-morbidities of premature birth associated with post-hemorrhagic ventricular dilatation (PHVD) development, long-term neurodevelopmental impairment, behavioral problems, special educational needs, and dependency on social security.Hypothesis and aims: We believe that extravasated blood and further release of extracellular hemoglobin (Hb) are crucial in brain injury following IVH and consequent development of PHVD. The overall goal of this project focuses on further pathogenetic insights of white and gray matter (GM) injury following IVH and the development of possible neuroprotective treatment strategies that may promote brain development in preterm infants.Methods: Paper I. We characterized extracellular Hb distribution within preriventricular white matter (WM) in preterm rabbit pups following IVH. Paper II. We evaluated the cerebral biodistribution and possible functional neuroprotection of intracerebroventricularly administered alpha-1-microglobulin (A1M), a heme and free radical scavenger, in preterm rabbit pups following IVH. Paper III. We conducted a comprehensive review of preclinical and clinical studies on WM injury following IVH. Paper IV. We evaluated high-frequency ultrasound (HFU) as a tool for the reconstruction of volumetric volume in preterm rabbit pups with PHVD and compared its accuracy and reliability with that of a gold-standard – magnetic resonance imaging (MRI). Paper V. We established a novel model of PHVD in preterm rabbit pups and characterized the survival, neurobehavior, WM, and GM injury, as well as altered corticogenesis.Results: Paper I. Following IVH extracellular Hb was widely distributed throughout the brain WM, particularly in periventricular white matter areas with high extracellular plasticity following IVH. Paper II. Exogenous A1M (recombinant) was extensively distributed within brain WM with further extension into cerebellar WM following IVH. Moreover, A1M exhibited high co-existence with extracellular Hb. Administration of A1M (human) decreased pro-inflammatory and oxidative damage. Paper III. A wide range of animal models have been used to explore pathogenetic mechanisms of IVH and related brain damage; possible targets involved in enhancing brain damage have been identified. Nevertheless, the effectiveness of potential interventions is still limited. Paper IV. HFU-based volumetric reconstruction of brain ventricles is highly accurate and reliable as compared to MRI and may be a promising bed-side tool for evaluating of progression of PHVD in preterm infants. Paper V. IVH and PHVD lead to a long-term alteration of cortical myelination microstructure, disruption of cortical organization, selectively reduction in neurogenesis and synaptogenesis, reduction in parvalbumin-positive interneurons and their dysmaturation.Conclusions: Extracellular Hb travels easily throughout brain WM following IVH and it may be one of the key factors for induction of brain damage by triggering pro-inflammatory and oxidative cascades. Furthermore, IVH, leading to PHVD, disrupts normal corticogenesis, alters myelin microstructure, causes a selective reduction in neurons, interneurons, and synapses. A1M, as a heme and free radicals scavenger, may attenuate WM damage, confirming that extracellular Hb is causative in ongoing neuroinflammation following IVH. Thus, A1M may be a possible treatment strategy in preterm infants with IVH. HFU represents a highly accurate tool for volumetric reconstruction of ventricles for diagnosis and management of PHVD

Pathophysiology of extracellular haemoglobin : use of animal models to translate molecular mechanisms into clinical significance

The blood's major gas exchange is carried out by haemoglobin, a haeme protein that binds iron and oxygen and can have potentially dangerous side-effects due to redox reactions. Haemoglobin is a very abundant molecule with a concentration of 150 g/l in whole blood, resulting in almost one kg haemoglobin in an adult human body. Normal turnover of red blood cells results in significant haemoglobin release, and pathological conditions that involve haemolysis can lead to massive haemoglobin levels. To control for the potential threat of extracellular haemoglobin, several protective defence systems have evolved. Many pathological conditions, diseases as well as iatrogenic conditions, such as infusion of haemoglobin-based oxygen carriers, cerebral intraventricular haemorrhage, extracorporeal circulation and the pregnancy complication pre-eclampsia, involve abnormal levels of haemolysis and extracellular haemoglobin. Although quite different aetiology, the haemoglobin-induced damage often causes similar clinical sequelae and symptoms. Here, we will give an overview of the pathophysiological mechanisms of extracellular haemoglobin and its metabolites. Furthermore, we will highlight the use of animal models in advancing the understanding of these mechanisms and discuss how to utilize the knowledge in the development of new and better pharmaceutical therapies

Stem cell-based interventions for the treatment of stroke in newborn infants

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To evaluate the benefits and harms of stem cell-based interventions for the treatment of stroke in newborn infants compared to control (placebo or no treatment) or stem-cell based interventions of a different type or source

Intraventricular Hemorrhage and White Matter Injury in Preclinical and Clinical Studies

Germinal matrix-intraventricular hemorrhage (IVH) occurs in nearly half of infants born at less than 26 weeks' gestation. Up to 50% of survivors with IVH develop cerebral palsy, cognitive deficits, behavioral disorders, posthemorrhagic ventricular dilatation, or a combination of these sequelae. After the initial bleeding and the primary brain injury, inflammation and secondary brain injury might lead to periventricular leukomalacia or diffuse white matter injury. Potential factors that are involved include microglia and astrocyte activation, degradation of blood components with release of "toxic" products, infiltration of the brain by systemic immune cells, death of neuronal and glial cells, and arrest of preoligodendrocyte maturation. In addition, impairment of the blood-brain barrier may play a major role in the pathophysiology. A wide range of animal models has been used to explore causes and mechanisms leading to IVH-induced brain injury. Preclinical studies have identified potential targets for enhancing brain repair. However, little has been elucidated about the effectiveness of potential interventions in clinical studies. A systematic review of available preclinical and clinical studies might help identify research gaps and which types of interventions may be prioritized. Future trials should report clinically robust and long-term outcomes after IVH

Head midline position for preventing the occurrence or extension of germinal matrix-intraventricular haemorrhage in preterm infants

Background: Head position during care may affect cerebral haemodynamics and contribute to the development of germinal matrix-intraventricular haemorrhage (GM-IVH) in very preterm infants. Turning the head toward one side may occlude jugular venous drainage while increasing intracranial pressure and cerebral blood volume. It is suggested that cerebral venous pressure is reduced and hydrostatic brain drainage improved if the infant is cared for in the supine ‘head midline’ position. Objectives: To assess whether head midline position is more effective than other head positions for preventing (or preventing extension) of GM-IVH in very preterm infants (< 32 weeks’ gestation at birth). Search methods: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 9), MEDLINE via PubMed (1966 to 12 September 2019), Embase (1980 to 12 September 2019), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 12 September 2019). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles. Selection criteria: Randomised controlled trials (RCTs) comparing caring for very preterm infants in a supine head midline position versus a prone or lateral decubitus position, or undertaking a strategy of regular position change, or having no prespecified position. We included trials enrolling infants with existing GM-IVH and planned to assess extension of haemorrhage in a subgroup of infants. We planned to analyse horizontal (flat) versus head elevated positions separately for all body positions. Data collection and analysis: We used standard methods of Cochrane Neonatal. For each of the included trials, two review authors independently extracted data and assessed risk of bias. The primary outcomes were GM-IVH, severe IVH, and neonatal death. We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data; and mean, standard deviation (SD), and mean difference (MD) for continuous data. We used the GRADE approach to assess the certainty of evidence. Main results: Three RCTs, with a total of 290 infants (either < 30 weeks' gestational age or < 1000 g body weight), met the inclusion criteria. Two trials compared supine midline head position versus head rotated 90° with the cot flat. One trial compared supine midline head position versus head rotated 90° with the bed tilted at 30°. We found no trials that compared supine versus prone midline head position. Meta-analysis of three trials (290 infants) did not show an effect on rates of GM-IVH (RR 1.11, 95% confidence interval (CI) 0.78 to 1.56; I² = 0%) and severe IVH (RR 0.71, 95% CI 0.37 to 1.33; I² = 0%). Neonatal mortality (RR 0.49, 95% CI 0.25 to 0.93; I² = 0%; RD −0.09, 95% CI −0.16 to −0.01) and mortality until hospital discharge (typical RR 0.50, 95% CI 0.28 to 0.90; I² = 0%; RD −0.10, 95% CI −0.18 to −0.02) were lower in the supine midline head position. The certainty of the evidence was very low for all outcomes because of limitations in study design and imprecision of estimates. We identified one ongoing study. Authors' conclusions: We found few trial data on the effects of head midline position on GM-IVH in very preterm infants. Although meta-analyses suggest that mortality might be reduced, the certainty of the evidence is very low and it is unclear whether any effect is due to cot tilting (a co-intervention in one trial). Further high-quality RCTs would be needed to resolve this uncertainty

Head midline position for preventing the occurrence or extension of germinal matrix-intraventricular hemorrhage in preterm infants

Secondary objectives:Secondary objectives:P Primary objective: To assess whether head midline position compared with any other head position is more effective in prevention or extension of germinal matrix-intraventricular hemorrhage in infants born at ≤ 32 weeks' gestational age. Secondary objectives: To perform subgroup analyses regarding gestational age, birth weight, intubated versus not intubated, and with or without GM-IVH at trial entry (see Subgroup analysis and investigation of heterogeneity)

Clonidine for sedation and analgesia for neonates receiving mechanical ventilation

Background: Although routine administration of pharmacologic sedation or analgesia during mechanical ventilation in preterm neonates is not recommended, its use in clinical practice remains common. Alpha-2 agonists, mainly clonidine and dexmedetomidine, are used as adjunctive (or alternative) sedative agents alongside opioids and benzodiazepines. Clonidine has not been systematically assessed for use in neonatal sedation during ventilation. Objectives: To assess whether clonidine administered to term and preterm newborn infants receiving mechanical ventilation reduces morbidity and mortality rates. To compare the intervention versus placebo, no treatment, and dexmedetomidine; and to assess the safety of clonidine infusion for potential harms. To perform subgroup analyses according to gestational age; birth weight; administration method (infusion or bolus therapy); dose, duration, and route of clonidine administration; and pharmacologic sedation as a co-intervention. Search methods: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12) in the Cochrane Library, MEDLINE via PubMed (1966 to January 10, 2017), Embase (1980 to January 10, 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to January 10, 2017). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. Selection criteria: We searched for randomized controlled trials, quasi-randomized controlled trials, and cluster trials comparing clonidine versus placebo, no treatment, or dexmedetomidine administered to term and preterm newborns receiving mechanical ventilation via an endotracheal tube. Data collection and analysis: For the included trial, two review authors independently extracted data (e.g. number of participants, birth weight, gestational age, all-cause death during initial hospitalization, duration of respiratory support, sedation scale, duration of hospital stay) and assessed risk of bias (e.g. adequacy of randomization, blinding, completeness of follow-up). This review considered primary outcomes of all-cause neonatal death, all-cause death during initial hospitalization, and duration of mechanical ventilation in days. Main results: One trial, which included 112 infants, met the inclusion criteria for this review. Term newborn infants on mechanical ventilation with the need for continuous analgesia and sedation with fentanyl and midazolam were eligible for enrollment during the first 96 hours of ventilation. Study authors administered clonidine 1 μg/kg/h or placebo on day 4 after intubation. We found no differences between the two groups in all-cause death during hospitalization (risk ratio [RR] 0.69, 95% confidence interval [CI] 0.12 to 3.98). The quality of the evidence supporting these findings is low owing to imprecision of the estimates (one study; few events). The median (interquartile range) duration of mechanical ventilation was 7.1 days (5.7 to 9.1 days) in the clonidine group and 5.8 days (4.9 to 7.9 days) in the placebo group, respectively (P = 0.070). Among secondary outcomes, we found no differences in terms of duration of stay in the intensive care unit. Sedation scale values (COMFORT) and analgesia scores (Hartwig) during the first 72 hours of infusion of study medication were lower in the clonidine group than in the placebo group. Authors' conclusions: At present, evidence is insufficient to show the efficacy and safety of clonidine for sedation and analgesia in term and preterm newborn infants receiving mechanical ventilation

Clonidine for pain in non-ventilated infants

BACKGROUND: Critically ill newborn infants undergo a variety of painful procedures or experience a variety of painful conditions during their early life in the neonatal unit. In the critically ill paediatric and neonatal population, clonidine is prescribed as an adjunct to opioids or benzodiazepines aiming to reduce the doses of these drugs that are required for analgesia or sedation, or to facilitate weaning from mechanical ventilation. It has been shown that clonidine premedication might have a positive effect on postoperative pain in children. OBJECTIVES: To assess the benefit and harms of clonidine for the prevention or treatment of procedural pain; postoperative pain; or pain associated with clinical conditions in non-ventilated neonates. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the CENTRAL, MEDLINE via PubMed, Embase, and CINAHL to December 2018. We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We ran an updated search from 1 January 2018 to 11 March 2020 in CENTRAL via CRS Web, MEDLINE via Ovid, and CINAHL via EBSCOhost. SELECTION CRITERIA: Randomised controlled trials, quasi-randomised controlled trials, and cluster trials comparing clonidine to placebo or no treatment, opioids, paracetamol, dexmedetomidine, or non-pharmacological pain-reducing interventions for the management of procedural pain, postoperative pain, and pain associated with clinical conditions in preterm and term newborns. DATA COLLECTION AND ANALYSIS: Two review authors independently planned to extract data (e.g. number of participants, birth weight, gestational age, modality of administration, and dose of clonidine) and assess the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). The primary outcome considered was pain: for procedural pain, the mean values of each analgesia scale assessed during the procedure and at one to two hours after the procedure; for postoperative pain and for pain associated with clinical conditions, the mean values of each analgesia scale assessed at 30 minutes, three hours, and 12 hours after the administration of the intervention. We planned to use the GRADE approach to assess the quality of evidence. MAIN RESULTS: Our search strategy yielded 3383 references. Two review authors independently assessed all references for inclusion. We did not find any completed studies for inclusion. We excluded three trials where clonidine was administered for spinal anaesthesia. AUTHORS' CONCLUSIONS: We did not find any studies that met our inclusion criteria and hence there is no evidence to recommend or refute the use of clonidine for the prevention or treatment of procedural or postoperative pain, or pain associated with clinical conditions in neonates

Non-invasive respiratory support for the management of transient tachypnea of the newborn (Protocol)

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The objective of this review is to assess benefits and harms of non-invasive respiratory support for themanagement of transient tachypnea of the newborn