Abstract

BACKGROUND Intraventricular haemorrhage (IVH) is a major complication of preterm birth. Large haemorrhages are associated with a high risk of disability and hydrocephalus. Instability of blood pressure and cerebral blood in the newborn flow are postulated as causative factors. Another mechanism may involve reperfusion damage from oxygen free radicals. It has been suggested that phenobarbital stabilises blood pressure and may protect against free radicals. This is an update of a review first published in 2001 and updated in 2007 and 2013. OBJECTIVES To assess the benefits and harms of the postnatal administration of phenobarbital in preterm infants at risk of developing IVH compared to control (i.e. no intervention or placebo). SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, CINAHL and clinical trial registries in January 2022. A new, more sensitive search strategy was developed, and searches were conducted without date limits. SELECTION CRITERIA We included randomised controlled trials (RCTs) or quasi-RCTs in which phenobarbital was given within the first 24 hours of life to preterm infants identified as being at risk of IVH because of gestational age below 34 weeks, birth weight below 1500 g or respiratory failure. Phenobarbital was compared to no intervention or placebo. We excluded infants with serious congenital malformations. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were all grades of IVH and severe IVH (i.e. grade III and IV); secondary outcomes were ventricular dilation or hydrocephalus, hypotension, pneumothorax, hypercapnia, acidosis, mechanical ventilation, neurodevelopmental impairment and death. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS We included 10 RCTs (792 infants). The evidence suggests that phenobarbital results in little to no difference in the incidence of IVH of any grade compared with control (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.84 to 1.19; risk difference (RD) 0.00, 95% CI -0.06 to 0.07; I² for RD = 65%; 10 RCTs, 792 participants; low certainty evidence) and in severe IVH (RR 0.88, 95% CI 0.64 to 1.21; 10 RCTs, 792 participants; low certainty evidence). The evidence is very uncertain about the effect of phenobarbital on posthaemorrhagic ventricular dilation or hydrocephalus (RR 0.62, 95% CI 0.31 to 1.26; 4 RCTs, 271 participants; very low certainty evidence), mild neurodevelopmental impairment (RR 0.57, 95% CI 0.15 to 2.17; 1RCT, 101 participants; very low certainty evidence), and severe neurodevelopmental impairment (RR 1.12, 95% CI 0.44 to 2.82; 2 RCTs, 153 participants; very low certainty evidence). Phenobarbital may result in little to no difference in death before discharge (RR 0.88, 95% CI 0.64 to 1.21; 9 RCTs, 740 participants; low certainty evidence) and mortality during study period (RR 0.98, 95% CI 0.72 to 1.33; 10 RCTs, 792 participants; low certainty evidence) compared with control. We identified no ongoing trials. AUTHORS' CONCLUSIONS The evidence suggests that phenobarbital results in little to no difference in the incidence of IVH (any grade or severe) compared with control (i.e. no intervention or placebo). The evidence is very uncertain about the effects of phenobarbital on ventricular dilation or hydrocephalus and on neurodevelopmental impairment. The evidence suggests that phenobarbital results in little to no difference in death before discharge and all deaths during the study period compared with control. Since 1993, no randomised studies have been published on phenobarbital for the prevention of IVH in preterm infants, and no trials are ongoing. The effects of postnatal phenobarbital might be assessed in infants with both neonatal seizures and IVH, in both randomised and observational studies. The assessment of benefits and harms should include long-term outcomes.

Abstract

Intrauterine growth restriction (IUGR) affects nearly 10 to 15% of pregnancies and is responsible for many short- and long-term adverse consequences, including hemostatic derangement. Both thrombotic and hemorrhagic events are described in the perinatal period in these neonates. The aim of this study was to systematically review the literature on the laboratory studies used to evaluate the hemostatic system of the IUGR small for gestational age neonate. We reviewed the current literature via PubMed and Scopus until September 2022. Following our inclusion/exclusion criteria, we finally included 60 studies in our review. Thrombocytopenia, characterized as hyporegenerative and a kinetic upshot of reduced platelet production due to in utero chronic hypoxia, was the main finding of most studies focusing on growth-restricted neonates, in most cases is mild and usually resolves spontaneously with the first 2 weeks of life. In regard to coagulation, growth-restricted newborns present with prolonged standard coagulation tests. Data regarding coagulation factors, fibrinolytic system, and anticoagulant proteins are scarce and conflicting, mainly due to confounding factors. As thromboelastography/rotational thromboelastometry (TEG/ROTEM) provides a more precise evaluation of the in vivo coagulation process compared with standard coagulation tests, its use in transfusion guidance is fundamental. Only one study regarding TEG/ROTEM was retrieved from this population, where no difference in ROTEM parameters compared with appropriate for gestational age neonates was found. Despite the laboratory aberrations, no correlation could be achieved with clinical manifestations of bleeding or thrombosis in the studies included. More studies are needed to assess hemostasis in IUGR neonates and guide targeted therapeutic interventions.

Abstract

OBJECTIVES Extracorporeal membrane oxygenation (ECMO) involves complex coagulation management and frequent hemostatic complications. ECMO practice between centers is variable. To compare results between coagulation studies, standardized definitions and clear documentation of ECMO practice is essential. We assessed how study population, outcome definitions, and ECMO-, coagulation-, and transfusion-related parameters were described in pediatric ECMO studies. DATA SOURCES Embase, Medline, Web of Science, Cochrane Library and Google Scholar. STUDY SELECTION English original studies of pediatric ECMO patients describing hemostatic tests or outcome. DATA EXTRACTION Eligibility was assessed following PRISMA guidelines. Study population, outcome and ECMO-, coagulation, and transfusion parameters were summarized. DATA SYNTHESIS A total of 107 of 1312 records were included. Study population parameters most frequently included (gestational) age (79%), gender (60%), and (birth) weight (59%). Outcomes, including definitions of bleeding (29%), thrombosis (15%), and survival (43%), were described using various definitions. Description of pump type, oxygenator and cannulation mode occurred in 49%, 45%, and 36% of studies, respectively. The main coagulation test (53%), its reference ranges (49%), and frequency of testing (24%) were the most prevalent reported coagulation parameters. The transfusion thresholds for platelets, red blood cells, and fibrinogen were described in 27%, 18%, and 18% of studies, respectively. CONCLUSIONS This systematic review demonstrates a widespread lack of detail or standardization of several parameters in coagulation research of pediatric ECMO patients. We suggest several parameters that might be included in future coagulation studies. We encourage the ECMO community to adopt and refine this list of parameters and to use standardized definitions in future research.

Abstract

Although fresh frozen plasma (FFP) transfusions are common practice in neonatology, robust evidence on their use is lacking. The aim of this study was to systematically review the literature for data on the practice of FFP transfusions in neonates and their association with neonatal morbidity and mortality. The authors identified 40 studies, which met the inclusion criteria for this review. It was demonstrated that the practice of FFP transfusions significantly varies throughout the world. The majority of FFP transfusions are administered "prophylactically", without evidence of active bleeding. Although FFP transfusions may restore coagulation tests results, they do not alter the clinical outcome of the neonates. Reactions following transfusions are probably underestimated in neonates, often undiagnosed and thus, underreported. High quality RCTs aiming to evaluate the effectiveness of FFP in specific clinical conditions are urgently needed, as they could change long-standing FFP transfusion practices, and help reduce neonatal morbidity and mortality.

Abstract

Insulin is used to treat neonatal hyperglycaemia when blood glucose concentrations are consistently high, and to treat neonatal diabetes. Within this brief report, a review of the existing literature is conducted to determine if intravenous administration of insulin should be proceeded by priming of the intravenous system, adding of albumin, or non-priming to get a stable insulin dose. Within this literature search, we focused on experimental insulin adsorption data (in vitro studies).

Abstract

A meta-analysis update of randomized controlled trials investigating recombinant human erythropoietin suggests improved neurodevelopmental outcome in preterm infants. There was substantial heterogeneity, which could be ascribed to a single trial. Exclusion of this trial featuring a high risk of bias abolished heterogeneity and any effects of recombinant human erythropoietin treatment.

Abstract

The aim of this meta-analysis was conducted to assess the effects of different doses of prophylactic rhEPO on neurodevelopmental outcomes and provide reference for rational drug use. The primary outcome was the number of infants with a Mental Developmental Index (MDI) <70 on the Bayley Scales of Infant Development. Five RCTs, comprising 2282 infants, were included in this meta-analysis. Overall, prophylactic rhEPO administration reduced the incidence of infants with an MDI <70, with an odds ratio (95% confidence interval) of 0.55 (0.38-0.79), P <0.05. The low-dose rhEPO subgroup was superior to the placebo subgroup, with an OR (95% CI) of 0.47 (0.25-0.87), P <0.05. However, high-dose rhEPO subgroup had no significant impact on MDI <70 in infants <28 weeks' gestational age. The definitions of the secondary outcome showed that there was no significant effect of rhEPO on cerebral palsy. For neonatal complications, although four studies showed that there were no differences in the pooled results of BPD and ICH events between rhEPO treatment and placebo, the ICH events were significantly lower in the low-dose rhEPO (OR 0.36; 95% CI 0.23-0.59). In addition, in the pooled results of NEC and ROP events, there were significant differences between the two groups (OR 0.63; 95% CI 0.43-0.93) (OR 0.80; 95% CI 0.65-0.98). And the NEC events were significantly lower in the low-dose rhEPO (OR 0.45; 95% CI 0.27-0.73). Sustained low-dose prophylactic early erythropoietin might be more superior than high-dose for improvement of neurological outcomes and several neonatal complications in preterm infants.

Abstract

Contemporary packed red blood cell transfusion practices in anaemic preterm infants are primarily based on measurement of hemoglobin or haematocrit. In neonatal intensive care units, most preterm infants receive at least 1 packed red cell transfusion as standard treatment for anaemia of prematurity. Clinicians are faced with a common question "at what threshold should anaemic preterm infants receive packed red blood cell transfusion?". While evidence from interventional trials offers a range of haemoglobin levels to clinicians on thresholds to initiate red cell transfusion, it does not offer identification of exact haemoglobin level at which regional oxygenation and perfusion gets compromised. Assessment of regional oxygenation using near infrared spectroscopy and perfusion using ultrasound could offer a personalized transfusion medicine approach to optimize transfusion practices. We conducted a systematic review of the literature to identify the role of both regional oxygenation and/or ultrasound-based perfusion monitoring as a potential trigger to initiate packed red blood cell transfusion in anaemic preterm infants. MEDLINE, Embase, Maternity and Infant Care database were searched up to March 2021. Publications identified were screened and relevant data was extracted. Changes to regional oxygenation and/or perfusion monitoring before and after packed red blood cell transfusion were the primary outcomes. 44 out of 755 studies met the inclusion criteria and were included in the final analysis. Most were prospective, observational studies in stable preterm infants. Overall, studies reported an improvement in regional oxygenation and/or ultrasound-based perfusion after packed red blood cell transfusion. These changes were more consistently observed when hemoglobin <9.6g/dL or hematocrit was <0.30. Significant variation was found for patient characteristics, postnatal age at the time of monitoring, criteria for diagnosis of anaemia, and period of monitoring as well as regional oxygenation monitoring methodology. Regional oxygenation and/or perfusion monitoring can identify at-risk anaemic preterm infants and are promising tools to individualize packed red blood cell transfusion practices. However, there is lack of evidence for incorporating this monitoring, in their present form, into standard clinical practice. Additionally, consistency in reporting of study methodology should be improved.

Abstract

BACKGROUND To assess the efficacy and safety of restrictive versus liberal red blood cell transfusion thresholds in very low birth weight infants. METHODS We searched MEDLINE, EMBASE, and Cochrane database without any language restrictions. The last search was conducted in August 15, 2020. All randomized controlled trials comparing the use of restrictive versus liberal red blood cell transfusion thresholds in very low birth weight (VLBW) infants were selected. Pooled risk ratio (RR) for dichotomous variable with 95% confidence intervals were assessed by a random-effects model. The primary outcome was all-cause mortality. RESULTS Overall, this meta-analysis included 6 randomized controlled trials comprising 3,483 participants. Restrictive transfusion does not increase the risk of all-cause mortality (RR, 0.99; 95% CI, 0.84 to 1.17; I2 = 0%; high-quality evidence), and does not increase the composite outcome of death or neurodevelopmental impairment (RR, 1.01, 95% CI, 0.93-1.09; I2 = 7%; high-quality evidence) or other serious adverse events. Results were similar in subgroup analyses of all-cause mortality by weight of infants, gestational age, male infants, and transfusion volume. CONCLUSIONS In very low birth weight infants, a restrictive threshold for red blood cell transfusion was not associated with increased risk of all-cause mortality, in either short term or long term.

Abstract

AIM: Pulmonary haemorrhage (PH) is an acute catastrophic event with low incidence yet high mortality among neonates. We aimed to systematically review the management of PH. METHODS A search was carried out of the PubMed, Embase and Cochrane databases according to the PRISMA guidelines. Data was extracted on study design and size, patient demographics, primary and adjunctive treatment methods, and treatment outcomes. RESULTS Sixteen studies with 385 newborn infants were included and were significantly heterogenous regarding treatment methods. Primary treatments included surfactant, High Frequency Oscillatory Ventilation (HFOV), epinephrine, coagulopathy management, intermittent positive pressure ventilation, cocaine, and tolazoline. Adjunctive treatment methods included blood products, HFOV, increased positive end expiratory pressure, vitamin K, surfactant, adrenaline, vasopressors, and inotropes. All five studies using surfactant as primary treatment were effective in improving oxygenation index measures and preventing recurrence of PH, and three studies found no association between surfactant and death or long-term disability. Ventilatory support, epinephrine, management of coagulopathy and tolazoline were all found to be effective primary treatments for PH. CONCLUSION There are several effective methods of managing PH in neonates. Further understanding of the aetiology of PH and ongoing research will allow future prevention and improvements in management of PH.