Does placental abruption cause neonatal anemia?

INTRODUCTION: Placental abruption can result in serious perinatal morbidity and mortality. However, it is not clear whether placental abruption could lead to neonatal anemia, as a direct relation has not been described yet. The objective of this study is to investigate whether there is a relation between occurrence of placental abruption and neonatal anemia. MATERIAL AND METHODS: All women with a clinical diagnoses of placental abruption between January 2016 and April 2021 in Amsterdam UMC, from both the VU University Medical Center and Amsterdam Medical Center, were included. Demographic data and delivery outcomes were collected retrospectively using the medical files. The primary outcome was neonatal anemia, defined as hemoglobin levels less than the fifth percentile for gestational age. RESULTS: A total of 65 mothers and 65 neonates were included in our study. Average gestational age was 30 + 5 weeks. Mean hemoglobin level of the neonates at birth was 16.5 g/dl (10.2 mmol/L) with hemoglobin levels comparable to the reference curve. Two neonates (3.6%) were diagnosed with anemia based on their hemoglobin level at birth, and six (9.2%) neonates received a blood transfusion within 24 h after birth. CONCLUSIONS: With this study, we found that the hemoglobin levels of the neonates born after placental abruption are comparable to the reference curve and do not show more neonates than expected below the fifth percentile for gestational age. It remains unclear whether there is fetal blood loss during a placental abruption but our results suggest that at least a big amount of fetal blood is not lost, since we did not found a large number of anemic neonates. Severe neonatal anemia in the case of placental abruption does not need to be expected.

Twin Anemia Polycythemia Sequence in a Dichorionic Twin Pregnancy Leading to Severe Cerebral Injury in the Recipient.

Twin anemia polycythemia sequence (TAPS) is a form of chronic imbalanced feto-fetal transfusion through minuscule placental anastomoses leading to anemia in the TAPS donor and polycythemia in the TAPS recipient and has been reported only in monochorionic twins. We report a very unusual case of TAPS which developed in a dichorionic twin pair, born at a gestational age of 33+2. Twin 1 (recipient) was polycythemic and had a hemoglobin value of 22.4 g/dL, whereas twin 2 (donor) was anemic with a hemoglobin value of 9.8 g/dL and an increased reticulocyte count (72‰). Color dye injection of the placenta revealed the presence of a deep-hidden small veno-venous anastomosis. Dichorionicity was confirmed on histologic examination. Aside from respiratory distress syndrome, the donor twin had an uncomplicated neonatal course. The recipient twin developed a post-hemorrhagic ventricular dilatation requiring treatment with a ventriculoperitoneal shunt and Rickham reservoir. This report shows that in dichorionic twins, placental anastomoses can be present, which can lead to the development of TAPS with severe consequences. Therefore, when a pale and plethoric dichorionic twin pair is born, a complete diagnostic work-up is required, including a full blood count with reticulocytes and placental injection, to investigate the presence and nature of potential underlying feto-fetal transfusion. Once the diagnosis of TAPS has been established, cerebral ultrasound, hearing screening, and long-term follow-up are strongly recommended as these twins have increased risk for severe cerebral injury, hearing loss, and long-term neurodevelopmental impairment.

Physiological-based cord clamping in very preterm infants: the Aeration, Breathing, Clamping 3 (ABC3) trial-statistical analysis plan for a multicenter randomized controlled trial.

BACKGROUND: Mortality, cerebral injury, and necrotizing enterocolitis (NEC) are common complications of very preterm birth. An important risk factor for these complications is hemodynamic instability. Pre-clinical studies suggest that the timing of umbilical cord clamping affects hemodynamic stability during transition. Standard care is time-based cord clamping (TBCC), with clamping irrespective of lung aeration. It is unknown whether delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) is more beneficial. This document describes the statistical analyses for the ABC3 trial, which aims to assess the efficacy and safety of PBCC, compared to TBCC. METHODS: The ABC3 trial is a multicenter, randomized trial investigating PBCC (intervention) versus TBCC (control) in very preterm infants. The trial is ethically approved. Preterm infants born before 30 weeks of gestation are randomized after parental informed consent. The primary outcome is intact survival, defined as the composite of survival without major cerebral injury and/or NEC. Secondary short-term outcomes are co-morbidities and adverse events assessed during NICU admission, parental reported outcomes, and long-term neurodevelopmental outcomes assessed at a corrected age of 2 years. To test the hypothesis that PBCC increases intact survival, a logistic regression model will be estimated using generalized estimating equations (accounting for correlation between siblings and observations in the same center) with treatment and gestational age as predictors. This plan is written and submitted without knowledge of the data. DISCUSSION: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management at birth. TRIAL REGISTRATION: ClinicalTrials.gov NCT03808051. Registered on 17 January 2019.

Implementation of Nationwide Evidence- and Consensus-Based Guidelines to Harmonize Neonatal Care in The Netherlands.

BACKGROUND: A Dutch committee for National Guidelines in Neonatology developed nineteen evidence- and consensus-based guidelines to be used in all Dutch neonatal intensive care units (NICUs). The primary goal was to make clinical practices more uniform and consistent. OBJECTIVE: This study investigated to what extent the guidelines were implemented and which factors played a role in implementation. STUDY DESIGN: A mixed method study design was used to investigate both the level and the process of implementation. A nationwide, multicenter, cross-sectional survey was performed using a validated instrument for measuring the level of implementation (Normalization MeAsure Development questionnaire, NoMAD). The number of implemented guidelines per NICU and the frequency and content of the amendments that NICUs made to the original consensus guidelines were analyzed. Through semi-structured interviews, perceived barriers and facilitators for implementation were explored. PARTICIPANTS: Fellows and neonatologists working at all ten Dutch level 3-4 NICUs were eligible. RESULTS: On an average, NICUs implemented 12.6 (of 19) guidelines (range 6-17). The Normalization Process Scale was 54 (of 65). Main influencing factors impeding implementation were guideline-related (e.g., unpractical, lengthy guidelines) and personal (e.g., an active representative responsible for local implementation). CONCLUSION: The implementation of our guidelines appears to be successful. Ways for improvement can be distinguished in personal, guideline-related and external factors. Empowerment of local representatives was considered most essential.

Physiological-based cord clamping in very preterm infants: the Aeration, Breathing, Clamping 3 (ABC3) trial-study protocol for a multicentre randomised controlled trial.

BACKGROUND: International guidelines recommend delayed umbilical cord clamping (DCC) up to 1 min in preterm infants, unless the condition of the infant requires immediate resuscitation. However, clamping the cord prior to lung aeration may severely limit circulatory adaptation resulting in a reduction in cardiac output and hypoxia. Delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) allows for an adequately established pulmonary circulation and results in a more stable circulatory transition. The decline in cardiac output following time-based delayed cord clamping (TBCC) may thus be avoided. We hypothesise that PBCC, compared to TBCC, results in a more stable transition in very preterm infants, leading to improved clinical outcomes. The primary objective is to compare the effect of PBCC on intact survival with TBCC. METHODS: The Aeriation, Breathing, Clamping 3 (ABC3) trial is a multicentre randomised controlled clinical trial. In the interventional PBCC group, the umbilical cord is clamped after the infant is stabilised, defined as reaching heart rate > 100 bpm and SpO2 > 85% while using supplemental oxygen < 40%. In the control TBCC group, cord clamping is time based at 30-60 s. The primary outcome is survival without major cerebral and/or intestinal injury. Preterm infants born before 30 weeks of gestation are included after prenatal parental informed consent. The required sample size is 660 infants. DISCUSSION: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management in very preterm infants at birth. TRIAL REGISTRATION: ClinicalTrials.gov NCT03808051. First registered on January 17, 2019.

Propofol for endotracheal intubation in neonates: a dose-finding trial.

OBJECTIVE: To find propofol doses providing effective sedation without side effects in neonates of different gestational ages (GA) and postnatal ages (PNA). DESIGN AND SETTING: Prospective multicentere dose-finding study in 3 neonatal intensive care units. PATIENTS: Neonates with a PNA <28 days requiring non-emergency endotracheal intubation. INTERVENTIONS: Neonates were stratified into 8 groups based on GA and PNA. The first 5 neonates in every group received a dose of 1.0 mg/kg propofol. Based on sedative effect and side effects, the dose was increased or decreased in the next 5 patients until the optimal dose was found. MAIN OUTCOME MEASURES: The primary outcome was the optimal single propofol starting dose that provides effective sedation without side effects in each age group. RESULTS: After inclusion of 91 patients, the study was prematurely terminated because the primary outcome was only reached in 13% of patients. Dose-finding was completed in 2 groups, but no optimal propofol dose was found. Effective sedation without side effects was achieved more often after a starting dose of 2.0 mg/kg (28%) than after 1.0 mg/kg (3%) and 1.5 mg/kg (9%). Propofol-induced hypotension occurred in 59% of patients. Logistic regression analyses showed that GA and PNA did not predict effective sedation or the occurrence of hypotension. CONCLUSIONS: Effective sedation without side effects is difficult to achieve with propofol and the optimal dose in different age groups of neonates could not be determined. The sedative effect of propofol and the occurrence of hypotension are unpredictable and show large inter-individual variability in the neonatal population.

Pharmacokinetics and analgesic effects of intravenous propacetamol vs rectal paracetamol in children after major craniofacial surgery.

BACKGROUND: The pharmacokinetics and analgesic effects of intravenous and rectal paracetamol were compared in nonventilated infants after craniofacial surgery in a double-blind placebo controlled study. METHODS: During surgery all infants (6 months-2 years) received a rectal loading dose of 40 mg.kg(-1) paracetamol 2 h before anticipated extubation. On admittance to the pediatric surgical ICU, the children were randomized to receive either a 15 min intravenous infusion of 40 mg.kg(-1) propacetamol, a prodrug of paracetamol, or 20 mg.kg(-1) paracetamol rectally every 6 h. A population pharmacokinetic analysis of the paracetamol plasma concentration time-profiles was undertaken using nonlinear mixed effects models. The visual analogue scale (VAS) (score 0-10 cm) and COMFORT Behavior scale (score 6-30) were used to monitor analgesia in the 24-h period following surgery. RESULTS: Twelve infants received intravenous propacetamol and 14 paracetamol suppositories. Paracetamol pharmacokinetics were described according to a two-compartmental model with linear disposition. Pharmacokinetic parameters were standardized to a 70 kg person using allometric '1/4 power' models. Parameter estimates were: absorption half-life from the rectum 4.6 h, propacetamol hydrolysis half-life 0.028 h, clearance 12 l.h(-1).70 kg(-1), intercompartmental clearance 116 l.h(-1).70 kg(-1), central and peripheral volume of distribution 7.9 and 44 l.70 kg(-1), respectively. During the 24-h study period 22 infants exhibited VAS scores <4 cm, which was considered a cutoff point. On single occasions four patients, two in each group, exhibited a VAS score >/=4 cm. Nine patients in the rectal treatment group and three patients in the intravenous treatment group received midazolam for COMFORT-B scores exceeding 17 (P < 0.05). CONCLUSIONS: Intravenous propacetamol proved to be more effective than rectal paracetamol in infants after craniofacial surgery. Midazolam was more frequently administered to patients receiving paracetamol suppositories, indicating that these children experienced more distress, possibly caused by pain.

Continuous noninvasive monitoring of barbiturate coma in critically ill children using the Bispectral index monitor.

INTRODUCTION: Traumatic brain injury and generalized convulsive status epilepticus (GCSE) are conditions that require aggressive management. Barbiturates are used to lower intracranial pressure or to stop epileptiform activity, with the aim being to improve neurological outcome. Dosing of barbiturates is usually guided by the extent of induced burst-suppression pattern on the electroencephalogram (EEG). Dosing beyond the point of burst suppression may increase the risk for complications without offering further therapeutic benefit. For this reason, careful monitoring of EEG parameters is mandatory. A prospective study was conducted to evaluate the usefulness of the bispectral index suppression ratio for monitoring barbiturate coma. METHODS: A prospective observational pilot study was performed at a paediatric (surgical) intensive care unit, including all children with barbiturate-induced coma after traumatic brain injury or GCSE. The BIS (Bispectral index) monitor expresses a suppression ratio, which represents the percentage of epochs per minute in which the EEG was suppressed. Suppression ratios from the BIS monitor were compared with suppression ratios of full-channel EEG as assessed by quantitative visual analysis. RESULTS: Five patients with GCSE and three patients after traumatic brain injury (median age 11.6 years, range 4 months to 15 years) were included. In four patients the correlation between the suppression ratios of the BIS and EEG could be determined; the average correlation was 0.68. In two patients, suppression ratios were either high or low, with no intermediate values. This precluded determination of correlation values, as did the isoelectric EEG in a further two patients. In the latter patients, the mean +/- standard error BIS suppression ratio was 95 +/- 1.6. CONCLUSION: Correlations between suppression ratios of the BIS and EEG were found to be only moderate. In particular, asymmetrical EEGs and EEGs with short bursts (less than 1 second) may result in aberrant BIS suppression ratios. The BIS monitor potentially aids monitoring of barbiturate-induced coma because it provides continuous data on EEG suppression between full EEG registrations, but it should be used with caution.

Pharmacokinetics and pharmacodynamics of midazolam and metabolites in nonventilated infants after craniofacial surgery.

BACKGROUND: Because information on the optimal dose of midazolam for sedation of nonventilated infants after major surgery is scant, a population pharmacokinetic and pharmacodynamic model is developed for this specific group. METHODS: Twenty-four of the 53 evaluated infants (aged 3-24 months) admitted to the Pediatric Surgery Intensive Care Unit, who required sedation judged necessary on the basis of the COMFORT-Behavior score and were randomly assigned to receive midazolam, were included in the analysis. Bispectral Index values were recorded concordantly. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD). RESULTS: For midazolam, total clearance was 0.157 l/min, central volume was 3.8 l, peripheral volume was 30.2 l, and intercompartmental clearance was 0.30 l/min. Assuming 60% conversion of midazolam to 1-OH-midazolam, the volume of distribution for 1-OH-midazolam and 1-OH-midazolamglucuronide was 6.7 and 1.7 l, and clearance was 0.21 and 0.047 l/min, respectively. Depth of sedation using COMFORT-Behavior could adequately be described by a baseline, postanesthesia effect (Emax model) and midazolam effect (Emax model).The midazolam concentration at half maximum effect was 0.58 mum with a high interindividual variability of 89%. Using the Bispectral Index, in 57% of the infants the effect of midazolam could not be characterized. CONCLUSION: In nonventilated infants after major surgery, midazolam clearance is two to five times higher than in ventilated children. From the model presented, the recommended initial dosage is a loading dose of 1 mg followed by a continuous infusion of 0.5 mg/h during the night for a COMFORT-Behavior of 12-14 in infants aged 1 yr. Large interindividual variability warrants individual titration of midazolam in these children.

Propofol pharmacokinetics and pharmacodynamics for depth of sedation in nonventilated infants after major craniofacial surgery.

BACKGROUND: To support safe and effective use of propofol in nonventilated children after major surgery, a model for propofol pharmacokinetics and pharmacodynamics is described. METHODS: After craniofacial surgery, 22 of the 44 evaluated infants (aged 3-17 months) in the pediatric intensive care unit received propofol (2-4 mg . kg-1 . h-1) during a median of 12.5 h, based on the COMFORT-Behavior score. COMFORT-Behavior scores and Bispectral Index values were recorded simultaneously. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD). RESULTS: In the two-compartment model, body weight (median, 8.9 kg) was a significant covariate. Typical values were Cl = 0.70 . (BW/8.9)0.61 l/min, Vc = 18.8 l, Q = 0.35 l/min, and Vss = 146 l. In infants who received no sedative, depth of sedation was a function of baseline, postanesthesia effect (Emax model), and circadian night rhythm. In agitated infants, depth of sedation was best described by baseline, postanesthesia effect, and propofol effect (Emax model). The propofol concentration at half maximum effect was 1.76 mg/l (coefficient of variation = 47%) for the COMFORT-Behavior scale and 3.71 mg/l (coefficient of variation = 145%) for the Bispectral Index. CONCLUSIONS: Propofol clearance is two times higher in nonventilated healthy children than reported in the literature for ventilated children and adults. Based on the model, the authors advise a propofol dose of 30 mg/h in a 10-kg infant to achieve values of 12-14 on the COMFORT-Behavior scale and 70-75 on the Bispectral Index during the night. Wide pharmacodynamic variability emphasizes the importance of dose titration.