Evidence-based guidelines for administering fresh frozen plasma in the NICU

Introduction

Fresh frozen plasma (FFP) is the most commonly used hemostatic agent in neonatal intensive care units (NICUs), especially among critically ill neonates and for those who need extracorporeal life support (ECLS). Current guidelines on FFP administration in neonates are mainly based on poor-quality evidence, and therefore a lack of consensus exists on its optimal use.

Making the right diagnosis of coagulopathy in neonates and determining when to use FFP can be difficult due to the age-related changes in coagulation proteins occurring during childhood. In addition, neonatal reference values for coagulation tests are based on limited data and are obtained with specific analyzers and reagents that may differ from one NICU to another. Consequently, in the absence of normal values tailored to the NICU equipment, coagulation results may be difficult to interpret.

In this chapter we update evidence based on available studies that evaluate the use of FFP, and we summarize relevant information by ranking the quality of evidence and strength of recommendations. We also discuss the role of standard laboratory tests and viscoelastic coagulation tests in the therapeutic decision-making process for administering FFP.

Data derived from clinical audits and surveys on FFP use in the NICU

Several clinical audits report that FFP administration continues to be a frequent intervention in NICUs with a related high level of prophylactic administration (without bleeding evidence). In retrospective reviews, the reported rate of FFP transfusion ranges from 2% to 12% of NICU admitted patients, with a significant percentage of use outside of published recommendations. Additionally, a UK-wide prospective study of FFP transfusion practices showed that 2.3% of all patients treated with FFP were children (aged 1–15 years), and 4.4% of these were less than 1 year old. Sixty-two percent of infants who received FFP did not have clinical bleeding, and 14% of infants treated with FFP did not have coagulation tests before the FFP administration. In a multicenter retrospective study involving 43 tertiary care pediatric hospitals in the United States , FFP was noted to have been administered to 2.85% of pediatric hospital admissions, and 29% of these transfusions were given to neonates. A prospective study involving 17 Italian NICUs recorded FFP administration to be a relatively frequent intervention, with 8% of admitted neonates receiving one or more transfusions. This study showed that a remarkably high proportion (60%) of transfusions was noncompliant with guidelines, and 63% of transfused neonates received FFP prophylactically without bleeding evidence. In a retrospective single-center analysis over a period of 16 years, changes on the use of FFP transfusions and the use of clotting tests in preterm neonates were evaluated over the study period; the percentage of preterm neonates receiving FFP transfusion decreased significantly from 5.7% to 2%, and similarly the rate of neonates undergoing coagulation testing decreased from 24.3% to 8%. In this study, 56% of FFP transfusions were administered prophylactically for concomitant coagulopathy, whereas 17% of transfusions were given for clinical bleeding. Over the same period, the percentage of neonates with major bleeding did not change significantly.

Due to the high risk of bleeding, neonates undergoing ECLS are high-use recipients of hemostatic blood products. A recent survey on the use of plasma and platelet transfusions during extracorporeal membrane oxygenation (ECMO) in pediatric population (48% of the subjects were neonates) showed 60% of the plasma transfusions were given for bleeding prophylaxis and the rest (40%) were prescribed for bleeding. Indications for plasma transfusions were mainly guided by evidence of coagulopathy with clotting tests. In addition, 76% of the participating centers recommended a more liberal plasma transfusion threshold for bleeding and for younger patients.

An international survey involving 17 hospitals from 15 different countries reported current neonatal and pediatric transfusion practice. This survey found that plasma transfusions seem to be more dependent on the diagnosis than on clotting tests or clotting factor thresholds, although four hospitals have several coagulation factor–based thresholds for plasma transfusions.

Recommendations derived from clinical studies on the appropriate use of plasma in neonates

Various controlled studies evaluated the potential usefulness of plasma transfusions in neonates across different clinical settings. The main characteristics and results of randomized controlled trials are summarized in Tables 14.1 , 14.2 , and 14.3 . One study addressed the effectiveness of FFP in disseminated intravascular coagulation, and no differences in improvement of coagulation tests or in survival rate were observed. A possible beneficial effect of FFP administration in neonates with disseminated intravascular coagulation was described only in case reports. ^, Four studies evaluated the hypothesis that early volume expansion obtained with FFP administration would reduce morbidity and mortality in preterm neonates. In one of these studies a significant reduction in the occurrence of intracranial hemorrhage (ICH) was found among neonates receiving FFP, in comparison to controls. In contrast, the other three studies reported a similar rate of ICH and/or cerebral ultrasound abnormalities. ^{, ,} In addition, a meta-analysis that included these four studies showed no significant differences in the occurrence of any grade of intraventricular hemorrhage and mortality rate. In the Northern Neonatal Nursing Initiative trial, the largest of these four studies, where a 2-year follow-up was performed, no significant difference of severe disability between neonates receiving FFP and controls was observed. The potential benefit of FFP administration in neonates for the treatment of sepsis, respiratory distress syndrome, and hypotension was not established by controlled studies.

Some studies reported information of blood product usage for extracorporeal life support in the pediatric population. In a randomized clinical trial on infants undergoing cardiopulmonary bypass (CPB) for heart surgery, the circuit priming with a combination of packed red cells and FFP was demonstrated to have advantage over the use of fresh whole blood about reduction in hospital stay and improvement in cumulative fluid balance. In a systematic review that evaluated the use of FFP in patients undergoing cardiovascular surgery, a separate meta-analysis was obtained from four randomized clinical trials that included pediatric and neonatal patients. This analysis showed no significant differences in blood loss and in red cell transfusions at 24 hours between the prophylactic administration of FFP group and the comparison group that did not receive plasma transfusions. However, since there was a very serious risk of bias for these outcomes due to inadequate or unclear sequence generation and inadequate blinding of participants, clinicians, and/or analysts, the authors downgraded the quality of the evidence to low. In a randomized clinical trial of newborns and small infants undergoing cardiac surgery with CPB, the use of FFP in the priming solution appears slightly superior to late administration in terms of postoperative bleeding. Guidelines of the Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis suggest the addition of FFP to the CPB prime in neonates undergoing cardiac surgery.

In a clinical study on the effects of prophylactic FFP administration on ECMO circuit longevity, infants were randomized to receive FFP every 48 hours or usual care. Scheduled administration of FFP did not increase circuit life, and there was no difference in blood product transfusions between the two groups. Patients in the intervention group had similar hemorrhagic and thrombotic complications as the control group.

Partial exchange transfusion (PET) is traditionally used as the method to lower the hematocrit and treat hyperviscosity in neonatal polycythemia. Although there is no evidence that this procedure improves long-term outcome of neonates, the standard of care for polycythemic neonates with worsening symptoms continues to be PET in many NICUs. Three randomized clinical trials compared the efficacy between crystalloid solution and plasma used for PET to treat neonatal polycythemia (see Table 14.3 ). Two meta-analyses that included all these three studies showed no significant difference in the reduction of postexchange hematocrit. ^, In addition, both crystalloid solution and plasma were reported to be effective in the improvement of symptoms.

Congenital thrombotic thrombocytopenic purpura (ADAMTS-13 deficiency) may present in neonates as isolated thrombocytopenia or combined with a severe microangiopathic hemolytic anemia (Coombs negative) and jaundice. In children and infants, a dose of 15 to 20 mL/kg body weight of FFP on 1 to 3 consecutive days resolved most uncomplicated bouts of TTP, and a prophylactic administration of FFP with an interval of 3 to 4 days prevented severe sequelae in most children.

Recommendations of plasma administration in neonates, based on scientific evidence, are summarized in Box 14.1 . Level of evidence and strength of recommendation are consistent with the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) Working Group ( Box 14.2 ).