Randomized Trial of Platelet-Transfusion Thresholds in Neonates.

BACKGROUND: Platelet transfusions are commonly used to prevent bleeding in preterm infants with thrombocytopenia. Data are lacking to provide guidance regarding thresholds for prophylactic platelet transfusions in preterm neonates with severe thrombocytopenia. METHODS: In this multicenter trial, we randomly assigned infants born at less than 34 weeks of gestation in whom severe thrombocytopenia developed to receive a platelet transfusion at platelet-count thresholds of 50,000 per cubic millimeter (high-threshold group) or 25,000 per cubic millimeter (low-threshold group). Bleeding was documented prospectively with the use of a validated bleeding-assessment tool. The primary outcome was death or new major bleeding within 28 days after randomization. RESULTS: A total of 660 infants (median birth weight, 740 g; and median gestational age, 26.6 weeks) underwent randomization. In the high-threshold group, 90% of the infants (296 of 328 infants) received at least one platelet transfusion, as compared with 53% (177 of 331 infants) in the low-threshold group. A new major bleeding episode or death occurred in 26% of the infants (85 of 324) in the high-threshold group and in 19% (61 of 329) in the low-threshold group (odds ratio, 1.57; 95% confidence interval [CI], 1.06 to 2.32; P=0.02). There was no significant difference between the groups with respect to rates of serious adverse events (25% in the high-threshold group and 22% in the low-threshold group; odds ratio, 1.14; 95% CI, 0.78 to 1.67). CONCLUSIONS: Among preterm infants with severe thrombocytopenia, those randomly assigned to receive platelet transfusions at a platelet-count threshold of 50,000 per cubic millimeter had a significantly higher rate of death or major bleeding within 28 days after randomization than those who received platelet transfusions at a platelet-count threshold of 25,000 per cubic millimeter. (Funded by the National Health Service Blood and Transplant Research and Development Committee and others; Current Controlled Trials number, ISRCTN87736839 .).

Flow cytometry for near-patient testing in premature neonates reveals variation in platelet function: a novel approach to guide platelet transfusion.

BACKGROUND: Neonatal haemorrhaging is often co-observed with thrombocytopenia; however, no evidence of a causal relationship with low platelet count has been reported. Regardless, the administration of a platelet transfusion is often based upon this parameter. Accurate measurement of platelet function in small volumes of adult blood samples by flow cytometry is well established and we propose that the use of the same technology could provide complementary information to guide the administration of platelet transfusions in premature neonates. METHODS: In 28 neonates born at 27-41 weeks gestation, platelet function after stimulation agonists was measured using fibrinogen binding and P-selectin expression (a marker of degranulation). RESULTS: Platelets of neonates with gestation of ≤36 weeks (n = 20) showed reduced fibrinogen binding and degranulation with ADP, and reduced degranulation with CRP-XL. Degranulation Scores of 7837 ± 5548, 22,408 ± 5301 and 53,131 ± 12,102 (mean ± SEM) identified significant differences between three groups: <29, 29-36 and >36 weeks gestation). Fibrinogen binding and degranulation responses to ADP were significantly reduced in suspected septic neonates (n = 6) and the Fibrinogen Binding scores clearly separated the septic and healthy group (88.2 ± 10.3 vs 38.6 ± 12.2, P = 0.03). CONCLUSIONS: Flow cytometric measurement of platelet function identified clinically different neonatal groups and may eventually contribute to assessment of neonates requiring platelet transfusion.

Biomarkers of hepatic injury and function in neonatal hypoxic ischemic encephalopathy and with therapeutic hypothermia.

Therapeutic hypothermia (TH) is now provided as standard care to infants with moderate-severe hypoxic ischemic encephalopathy (HIE). The role of TH in limiting neuronal injury is well recognized, but its effect on hepatic injury which occurs frequently in neonatal HIE is not known. Our objective was to characterize biomarkers of liver injury and function in the setting of neonatal HIE and to describe whether HIE severity and provision of TH influence these hepatic biomarkers. We performed a multicenter retrospective study and compared hepatic biomarkers obtained during the first postnatal week, according to the severity of HIE and whether treated with TH. Of a total of 361 infants with HIE, 223 (62%) received TH and 138 (38%) were managed at normal temperature. Most hepatic biomarkers and C-reactive protein (CRP) were significantly associated with the severity of HIE (p < 0.001). Infants treated with TH had lower peak alanine aminotransferase (ALT) concentrations (p = 0.025) and a delay in reaching peak CRP concentration (p < 0.001). CONCLUSION: We observed a significant association between the clinical grade of HIE and biomarkers of liver metabolism and function. Therapeutic hypothermia was associated with delayed CRP responses and with lower ALT concentrations and so may have the potential to modulate hepatic injury. What is Known: • Ischemic hepatic injury occurs frequently as a part of multiorgan dysfunction in infants with hypoxic ischemic encephalopathy (HIE). • The neuroprotective role of therapeutic hypothermia in management of infants with HIE is well recognized, but the potential hepato-protective effects of hypothermia are unclear. What is New/What this study adds: • Therapeutic hypothermia was associated with lower alanine aminotransferase and albumin concentrations and a delayed C-reactive protein (CRP) response and so may have the potential to modulate hepatic injury. • An elevated CRP concentration during the first postnatal week may be regarded as an expected finding in moderate and severe HIE and, in the overwhelming majority of cases, occurs secondary to hepatic hypoxia-ischemia in the absence of blood culture-positive sepsis.

Skin antisepsis in the neonate: what should we use?

PURPOSE OF REVIEW: Neonates in intensive care are more susceptible to sepsis. Infection is commonly acquired via the transcutaneous portal. It is necessary to identify the most effective yet safest topical antiseptics for use in neonates to reduce nosocomial sepsis. RECENT FINDINGS: Recent national surveys indicate that a wide range of topical antiseptic preparations are used in the neonatal nursery. There are very few comparative studies in neonates and no robust evidence in favour of any particular antiseptic. There are significant safety and potential toxicity issues for neonates with all the commonly used antiseptics, particularly in very small immature babies. There are no convincing roles for routine application of emollient creams on the skin, topical antiseptics on the umbilical stump, or maternal vaginal washes with chlorhexidine for the prevention of neonatal infection. SUMMARY: Large multicentre trials are needed to determine the optimal antiseptic to use for neonates undergoing intensive care, especially for extremely preterm infants.

Skin colonisation at the catheter exit site is strongly associated with catheter colonisation and catheter-related sepsis.

AIM: The commonest mode of catheter colonisation is via the extraluminal route with skin bacteria. Catheter-related sepsis causes significant mortality and morbidity in neonates. Our aim was to study the relationships between culture-positive catheter exit site skin swabs, percutaneous central venous catheter segments and blood to determine the magnitude of associations between exit site skin colonisation, catheter colonisation and catheter-related sepsis. METHODS: In a prospective study, an exit site skin swab and three formerly in vivo catheter segments (proximal, middle and tip) were taken for culture at catheter removal. In those neonates who were clinically unwell at catheter removal, a peripheral blood culture was also collected. Univariate and multivariate analyses were used to study associations. RESULTS: Skin swabs were culture positive in 39 (21%) of 187 catheter removals. With a culture-positive skin swab, the risk of associated catheter colonisation was nearly eight times higher (OR: 7.84, 95% CI: 3.59-17.15) and the risk of definite catheter-related sepsis with the same organism was nearly 10 times higher (OR 9.86, 95% CI: 3.13-31.00). CONCLUSION: Culture-positive skin swabs from the catheter exit site were strongly associated with catheter colonisation and with definite catheter-related sepsis with the same organism. These data provide further evidence supporting catheter colonisation via the extraluminal route and highlight the importance of optimising skin disinfection before catheter insertion.

How we decide when a neonate needs a transfusion.

The decision to transfuse a neonate can be approached by addressing a series of questions that cover the cause of anaemia, alternatives to transfusion, the need for transfusion and the risks. Recent clinical trials of red cell transfusions have started to inform evidence-based transfusion practice, but have raised uncertainties about neurological outcomes when policies advocating use of fewer red cell transfusions at lower haemoglobin concentration (Hb) thresholds were tested. Red cell transfusions should be considered when the Hb <120 g/l for premature neonates requiring mechanical ventilation support, with lower thresholds applying for oxygen-dependent neonates not requiring ventilation or for late anaemia (Hb <70-100 g/l, depending on gestational and post-natal age). There is no recent high quality evidence to inform thresholds for prophylactic platelet transfusions in stable non-bleeding premature neonates with platelet count levels of 50 × 10(9) /l, although common practice has become more restrictive, using lower safe thresholds for platelet transfusion between 20 and 30 × 10(9) /l. A more appropriate transfusion strategy for fresh frozen plasma (FFP) in neonates is one that emphasizes the therapeutic use of FFP in the face of bleeding, rather than prophylactic use in stable non-bleeding neonates who often have mild to moderate apparent abnormalities of standard coagulation tests, after allowing for appropriate reference ranges.

Two-year outcomes following a randomised platelet transfusion trial in preterm infants.

OBJECTIVE: Assess mortality and neurodevelopmental outcomes at 2 years of corrected age in children who participated in the PlaNeT-2/MATISSE (Platelets for Neonatal Transfusion - 2/Management of Thrombocytopenia in Special Subgroup) study, which reported that a higher platelet transfusion threshold was associated with significantly increased mortality or major bleeding compared to a lower one. DESIGN: Randomised clinical trial, enrolling from June 2011 to August 2017. Follow-up was complete by January 2020. Caregivers were not blinded; however, outcome assessors were blinded to treatment group. SETTING: 43 level II/III/IV neonatal intensive care units (NICUs) across UK, Netherlands and Ireland. PATIENTS: 660 infants born at less than 34 weeks' gestation with platelet counts less than 50×109/L. INTERVENTIONS: Infants were randomised to undergo a platelet transfusion at platelet count thresholds of 50×109/L (higher threshold group) or 25×109/L (lower threshold group). MAIN OUTCOMES MEASURES: Our prespecified long-term follow-up outcome was a composite of death or neurodevelopmental impairment (developmental delay, cerebral palsy, seizure disorder, profound hearing or vision loss) at 2 years of corrected age. RESULTS: Follow-up data were available for 601 of 653 (92%) eligible participants. Of the 296 infants assigned to the higher threshold group, 147 (50%) died or survived with neurodevelopmental impairment, as compared with 120 (39%) of 305 infants assigned to the lower threshold group (OR 1.54, 95% CI 1.09 to 2.17, p=0.017). CONCLUSIONS: Infants randomised to a higher platelet transfusion threshold of 50×109/L compared with 25×109/L had a higher rate of death or significant neurodevelopmental impairment at a corrected age of 2 years. This further supports evidence of harm caused by high prophylactic platelet transfusion thresholds in preterm infants. TRIAL REGISTRATION NUMBER: ISRCTN87736839.

The safety and efficacy of red cell transfusions in neonates: a systematic review of randomized controlled trials.

Premature neonates commonly receive red blood cell (RBC) transfusions. This study systematically identified and appraised randomized controlled trials (RCTs) where the intervention was 'transfusion of red blood cells' from searches of multiple databases. Primary review outcomes were mortality, neurodevelopmental and respiratory endpoints. Two reviewers extracted data and assigned overall quality. Twenty-seven RCTs were identified and grouped into four predefined categories: trials comparing RBC transfusion versus no transfusion/placebo (n = 3); different thresholds for transfusion (n = 6); differing doses or administration schedule (n = 4), or different types or products of RBC (n = 14). In the threshold group of trials, enrolling 679 neonates, no significant differences in mortality (relative risk 1·22, 95% confidence interval 0·84-1·75) or chronic lung disease were found. Only two trials assessed neurodevelopment outcomes, both within the threshold group, but with differing results. The largest subgroup of RCTs by number evaluated different media for storage of red cells (n = 7), enrolling 221 neonates. The methodological quality of many RCTs was poor. The design of future RCTs can be informed by the lessons from this review. Many trials failed to report on outcomes that would be considered of primary importance to clinicians. Consistent reporting of adverse events is required, and endpoints need to include neurodevelopmental outcomes.

Endotracheal intubation in a neonatal population remains associated with a high risk of adverse events.

INTRODUCTION: There has been a significant increase in premedication use for neonatal intubation in the UK over the past decade. We aimed to determine the adverse events during neonatal intubation using the most commonly used premedication regimen in the UK. DISCUSSION: We prospectively studied all intubations performed using morphine, suxamethonium and atropine during a 3-month period in three UK tertiary neonatal units. Premedication was administered for 87/93 (94%) of intubations. Median time taken to prepare premedication was 16 min (IQR 10-35). Median time to successful intubation was 5 min (IQR 2-9) following premedication. Median lowest recorded oxygen saturation after administration of premedication was 65% (IQR 39-85). A bradycardia in the range 61-99/min accompanied the procedure in 24/93 (26%) intubations, with a median duration of bradycardia of 8 s (IQR 1-10). CONCLUSION: Despite the widespread move to premedication for neonatal intubation, many deficiencies in everyday practice remain. The rate of haemodynamic complications is high in this commonly used premedication regimen. This study shows that there are important factors to control at the local level in terms of timely preparation and administration of premedication drugs, training and supervision of staff carrying out this high-risk procedure.

Retrospective study of neonatal ligation during 2002 in the United Kingdom of persistently patent arterial ducts.

Our aim was to ascertain the number of neonatal ligations of the patent arterial duct performed in the United Kingdom in 2002, and to determine the survival of the neonates after 30 days. A postal questionnaire was sent to the lead paediatician in every hospital in the United Kingdom possessing a special care or neonatal intensive care unit, requesting information on the number of babies referred for ligation of a persistently patent arterial duct. A separate questionnaire was sent to the paediatric cardiothoracic centres for information on babies who underwent the procedure. Cross-referencing the responses identified neonates who were not reported in the separate questionnaires. Additional information was requested from the central cardiac audit database. The overall response rate was 74%, with 172 forms returned of 234 distributed. From the combined responses, we ascertained that ligation has been performed in 244, with survival at 30 days of 94%. There were problems in identifying some babies because of the incomplete nature of the information received from both referring hospitals and specialist cardiothoracic centres. We would recommend a joint prospective study is conducted by paediatricians and paediatric cardiologists to determine the short and long term outcomes in this population known to be at high risk.

Platelets for neonatal transfusion - study 2: a randomised controlled trial to compare two different platelet count thresholds for prophylactic platelet transfusion to preterm neonates.

INTRODUCTION: Neonatal thrombocytopenia is a common and important clinical problem in preterm neonates. A trial assessing clinically relevant outcomes in relation to the different platelet count thresholds used to trigger transfusion has never been undertaken in preterm neonates with severe thrombocytopenia. OBJECTIVES: Platelets for Neonatal Transfusion - Study 2 (PlaNeT-2) aims to assess whether a higher prophylactic platelet transfusion threshold is superior to the lower thresholds in current standard practice in reducing the proportion of patients who have a major bleed or die up to study day 28. METHODS: PlaNeT-2 is a two-stage, randomised, parallel-group, superiority trial. PlaNet-2 compares clinical outcomes in preterm neonates (<34 weeks' gestation at birth) randomised to receive prophylactic platelet transfusions to maintain platelet counts at or above either 25 × 10(9)/l or 50 × 10(9)/l. The primary outcome measure is the proportion of patients who either die or experience a major bleed up to and including study day 28. A total of 660 infants will be randomised. RESULTS AND CONCLUSIONS: This trial will help define optimal platelet transfusion support for severely thrombocytopenic preterm neonates by evaluating the risks and benefits of two different prophylactic neonatal platelet transfusion thresholds.

A novel approach to standardised recording of bleeding in a high risk neonatal population.

BACKGROUND: Bleeding assessment tools have been developed in other specialties to standardise the recording of bleeding for clinical haemostatic outcomes in transfusion trials, but such tools have not been developed for routine use in neonatology. AIM: The objective of this study was to develop, refine and evaluate a neonatal bleeding assessment tool (NeoBAT) to standardise the clinical recording of bleeding in premature and term neonates in an intensive care setting. METHODS: This prospective neonatal international multicentre study included all episodes of bleeding in infants admitted to the intensive/high dependency care nursery over a 2-4-week period. The NeoBAT was developed to record neonatal bleeding episodes. We tested its reliability and reproducibility with duplicate assessments. RESULTS: Duplicate assessments revealed 98% concordance. Bleeding occurred in 25% (37/146) of infants overall and was most common in preterm infants. 11% (16/146) infants had major/severe bleeds, 1% (2/146) moderate and 13% (19/146) minor bleeds. CONCLUSIONS: Bleeding is common in premature and term neonates admitted to intensive/high dependency care nurseries. This novel bleeding assessment tool facilitates prospective recording of bleeding events in neonatal intensive care settings and may allow standardised bleeding assessments in this high risk population.

Segmental percutaneous central venous line cultures for diagnosis of catheter-related sepsis.

OBJECTIVE: Culture of percutaneous central venous line (PCVL) segments may assist the diagnosis of line colonisation and catheter-related sepsis (CRS). The authors aimed to determine if the diagnosis of CRS and colonisation of PCVLs in neonates is improved by the culture of the proximal and middle segments of the line in addition to the tip. PATIENTS AND METHODS: In a prospective study, proximal, middle and tip segments of PCVLs indwelling for more than 24 h in term and preterm infants were sent for culture at line removal. Definite CRS was considered as a positive peripheral blood culture plus any line segment growing the same organism in an infant with clinical signs of sepsis. RESULTS: 189 lines were removed from 143 neonates: 142 (75%) were from well infants and 47 (25%) were from neonates with suspected clinical sepsis. The overall CRS rate was 7.9% (15 of 189 line episodes). In well infants, bacterial colonisation rates were significantly higher for proximal segments than for tips (p=0.004). Comparative rates of segmental culture positivity and their positive predictive values for definite CRS were similar for all segments. The diagnosis of CRS was not improved beyond a sole line tip culture by additional middle or proximal segmental cultures or by combinations of the three segments. CONCLUSION: In well infants, the proximal segments of PCVLs were more often colonised than line tips, but in clinically septic infants preferential culture of proximal or middle segments or combinations of the three segments did not permit better prediction of definite CRS than the culture of the line tip alone. Further studies prior to antibiotic therapy are indicated in babies with suspected CRS.